CA2325226A1 - Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances - Google Patents

Abstract

Use of polypeptides or nucleic acids encoding these for the diagnosis and/or prevention and/or treatment of disorders and/or wound healing, and their use for the identification of pharmacologically active substances.

Description

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NOTE_ .For additional volumes please contact~the Canadian Patent Office Switch Biotech AG 14. November 2000 529829CA BO/ZW/pvc Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances Description The invention relates to the use of polypeptides or nucleic acids encoding these for the diagnosis and/or prevention and/or treatment of disorders and/or wound healing, and their use for the identification of pharmacologically active substances. In particular, the present invention relates to the use in connection with disorders of skin cells and in wound healing.
Wounds in general heal without therapeutic intervention. However, there are numerous disorders in which wound healing plays a role, such as, for example, diabetes mellitus, arterial occlusive diseases, psoriasis, atopic dermatitis, contact dermatitis, Crohn's disease, epidermolysis bullosa, age-related skin changes or innervation disorders. Wound healing disorders lead to a delayed healing of wounds or to chronic wounds. These disorders can be caused by the nature of the wound (e.g. large-area wounds, deep and mechanically expanded operation wounds, burns, trauma, decubitus), medicinal treatment of the patients (e. g.
with corticoids) but also by the nature of the disorder itself. For example, 25% of the patients with Type II
diabetes thus frequently suffer from chronic ulcers ("diabetic foot"), of which approximately half necessitate expensive in-patient treatments and nevertheless finally heal poorly. Diabetic foot causes more stays in hospital than any other complication associated with diabetes. The number of these cases in diabetes Type I and II is on the increase and represents 2.5% of all hospital admissions. Moreover, wounds heal more poorly with increasing age of the patients. An acceleration of the natural wound healing process is often desirable as well in order to decrease, for example, the danger of bacterial infections or the rest periods of the patients.
Further disorders can also occur after successful wound closure. While foetal skin wounds heal without scar formation, after injuries in the postnatal period formation of scars always occurs, which often represent a great cosmetic problem. In the case of patients with large-area burn wounds, the quality of life can moreover be dramatically adversely affected, especially as in scarred skin the appendages, such as hair follicles, sweat and sebaceous glands are missing. In the case of appropriate genetic disposition, keloids can also occur, hypertrophic scars which proliferate into the surrounding skin.
The process of skin healing requires complex actions and interactions of various cell types which proceed in a coordinated manner. In the wound healing process, the following steps are differentiated:
clotting of blood in the area of the wound, the recruitment of inflammatory cells, reepithelialization, the formation of granular tissue and the restructuring of matrix. The exact reaction pattern of the cell types involved during the phases of proliferation, migration, matrix synthesis and contraction are, just like the regulation of genes such as, for example, growth factors, receptors and matrix proteins, little known up to now.
Thus until now only a few satisfactory therapies have been developed in order to be able to intervene in wound healing disorders. Established forms of therapy are restricted to physical assistance of wound healing (e.g. dressings, compresses, gels) or the transplantation of skin tissues, cultured skin cells and/or matrix proteins. In recent years, growth factors have been tested for improving wound healing without, however, improving the conventional therapy decisively.
The diagnosis of wound healing disorders is also based on not very meaningful optical analyses of the skin, since a deeper understanding of the gene regulation during wound healing was lacking until now. -Not very satisfactory therapies have been developed until now for other disorders of regenerative processes as well. Here too, the knowledge of gene regulation is advantageous for the development of diagnostics and therapies. It has been shown (Finch et al., 1997, Am. J. Pathol. 151: 1619-28; Werner, 1998, Cytokine Growth Factor Rev. 9: 153-165) that genes relevant to wound healing also play a crucial role in dermatological disorders which are based on disorders of the regeneration of the skin, and generally in regenerative processes. Thus the growth factor KGF not only plays a crucial role in the regulation of the proliferation and differentiation of keratinocytes during wound healing, but is also an important factor in the hyperproliferation of the keratinocytes in psoriasis and regeneration processes in the intestine (in Crohn's disease and ulcerative colitis).
It is therefore the object of the present invention to make available polypeptides and/or nucleic acids encoding these which are involved in processes in the case of disorders in mammalian cells, in particular in the case of disorders of skin cells and/or wound healing, and whose use decisively improves the diagnosis and/or prevention and/or treatment and also the identification and development of pharmaceuticals which are effective in connection with these disorders.

In the analysis of gene expression during the wound healing process, it was surprisingly possible to identify genes which until now were not connected with diagnosis and/or prevention and/or treatment of disorders or with wound healing or the identification of pharmacologically active substances, but whose regulation is essential for the healing process and which are thus in a causal relationship with diagnosis and/or prevention and/or treatment of disorders or the identification of pharmacologically active substances.
The polypeptides of these genes do not belong to the targets known until now for diagnosis - such as, for example, the indication - and/or prevention and/or the treatment - such as, for example, the modulation - of disorders or for the identification of pharmacologically active substances, such that completely novel therapeutic approaches result from this invention.
The object is therefore achieved according to the invention by the use of one or more polypeptides or variants thereof according to one of SEQ ID No. 1 to SEQ ID Nr. 4 and SEQ ID No . 7 to SEQ ID No . 9 and SEQ
ID No. 103 to SEQ ID No. 104 and SEQ ID No. 106 or nucleic acids encoding these or variants thereof for the diagnosis and/or prevention and/or treatment of disorders or for the identification of pharmacologically active substances.
The exact biological functions of the polypeptides according to the invention of SEQ ID No. 1 to SEQ ID
Nr. 4 or SEQ ID No. 7 to SEQ ID No. 9 or SEQ ID No. 103 to SEQ ID No. 104 and SEQ ID No. 106 are unknown. In the investigations in the context of this invention, it was possible for the first time to find a relationship between the polypeptides described above and disorders, for example skin disorders. The accession numbers of the polypeptide sequences used according to the invention and their cDNAs are listed in Table 2.
The following polypeptides and/or nucleic acids encoding these can be used according to the invention:
- MBNL from mouse (SEQ ID No. 103; GeneBank:
AAF72159) or human (SEQ ID No. 1; GeneBank:CAA74155).
Additionally, the polypeptide KIAA0428 (SEQ ID No.
104; trEMBL: 043311) from human, that is a variant of MBNL (SEQ ID No. 1) can be used.
- Wolf-Hirschhorn Syndrome Candidate 2 Protein from mouse (SEQ ID No. 2; trEMBL: Q9Z1V9) or human (SEQ ID No. 3; 095392)The gene encoding this protein in man is located in a 167 kb region, which is regarded critical for the genetic disposition for the Wolf-Hirschhorn Syndrome (Wright et al., 1997, Hum.
Mol. Gener. 6: 317-324).
- KIAA0494 from human (SEQ ID No. 4; Seki et al., 1997, DNA Res. 4:345-349).
- KIAA0614 from human (SEQ ID No. 7; GenBank:
BAA31589) or mouse (SEQ ID No. 106).
- KIAA0521 from human (SEQ ID No. 8; GenBank:
BAA25447) - KIAA0261 from human (SEQ ID No. 9; GeneBank:
BAA13391) In the analysis of gene expression during the wound healing process, it was possible to identify further genes whose already known and described functions were not connected until now with skin disorders, for example with disturbed wound healing, but whose regulation is essential for the wound healing process and which were thus brought for the first time into a causal relationship with skin disorders, for example with disturbed wound healing. The polypeptides of these genes do not belong to the targets of therapies of skin disorders and/or wound healing known until now, such that completely novel therapeutic approaches result from this invention.
The object of the invention is furthermore achieved by the use of at least one polypeptide or variants thereof according to one of SEQ ID No. 5 to SEQ ID No. 6, SEQ ID No. 10 to SEQ ID No. 48, SEQ ID
No. 55 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID 94, SEQ ID No . 105 or SEQ ID No . 10 9 to SEQ ID No . 114 or nucleic acids encoding these or variants thereof for the diagnosis and/or prevention and/or treatment, for example for the therapeutic and/or prophylactic treatment, of skin disorders or for the identification of pharmacologically active substances.
The following polypeptides and/or nucleic acids encoding these can be used according to the invention:
- KIAA0585 from man (SEQ ID No. 5; Nagase et al . , 1998, DNA Res. 5:31-39). A shorter variant of this protein is known from WO 98/57985 as a protein that binds to the "receptor interacting protein" (RIP; a protein involved in the Fas-mediated apoptosis signal transduction pathway). This variant is localized in the nucleus of human cells.
- HSPC028 from man (SEQ ID No. 6; GenBank:
AAD39844) or mouse (SEQ ID No. 106). The polypeptide from human is known from WO 99/15658 as protein which displays a weak homology to transcription factors.
- The protein calnexin from mouse (SEQ ID No. 10) or man (SEQ ID No. 11), which is negatively regulated in resting and differentiating cells (Honore et al., 1994, Electrophoresis 15: 482-90; Olsen et al., 1995, Electrophoresis 16: 2241-8).

_ 7 _ - The CREB-binding protein (CBP) from mouse (SEQ
ID No. 12) or man (SEQ ID No. 13), which - like the gene for p300 which is described in US 5,658,784 and closely related - is described as a coactivator for a large number of transcription factors involved in growth control and differentiation, such as, for example, GATA-1, p53 and E2F (Blobel et al., 1998, Proc. Natl. Acad. Sci. USA 95: 2061-6).
- The mas oncogene from mouse (SEQ ID No. 14) or the homologous MRG from man (SEQ ID No. 15) (Monnot et al., 1991, Mol. Endocrinol. 5:1477-1487; Metzger et al.
1995, FEBS Lett. 357: 27-32) which is described in US 5,320,941 in connection with a process for the treatment of tumours. In addition to the polypeptide of mouse known until now, the closely related polypeptide mentioned for the first time in this study having a differing sequence can also be used (SEQ ID No. 109).
The cDNA sequence, that codes for the polypeptide used according to the invention is depicted in the sequence listing according to SEQ ID No. 120.
- The acylamino acid-releasing enzyme from man disclosed in JP 3254680 (SEQ ID No. 16), which is activated in tumour cells (Schoenberger et al., 1986, J. Clin. Chem. Clin. Biochem. 24: 375-8).
- The protein JEM-1 from man identified in acute promyelocytic leukaemia cells and involved in cell maturation (SEQ ID No. 17) (Tong et al., 1998, Leukemia 12: 1733-40). In addition the closely related polypeptides of man (SEQ ID No. 110) or mouse (SEQ ID
No. 111 and SEQ ID No. 112) mentioned for the first time in this study can also be used, their coding nucleic acids are depicted in the sequence listing according to SEQ ID No. 121 (man) and SEQ ID No. 122 and SEQ ID No. 123 (mouse).

- The cardiac ankyrin repeat protein (CARP/MARP) from mouse (SEQ ID No. 18) or man (SEQ ID No. 19), which is crucial for the development of cardiac muscle (Zou et al., 1997, Development 124: 793-804). In addition to the sequence of mouse known until now, the polypeptide mentioned for the first time in this study having a differing sequence can also be used (SEQ ID
No. 113). The sequence of the nucleic acid encoding this polypeptide is depicted in the sequence listing according to SEQ ID No. 124.
- The transcription factor checkpoint suppressor 1 (CHES1) from man (SEQ ID No. 20), which suppresses various mutations in S. cerevisiae in connection with DNA repair and for which a function in cell cycle control is suspected (Pati et al., 1997, Mol. Cell.
Biol 17: 3037-46).
- The small GTP binding protein RAB2 from mouse ( SEQ ID No . 21 ) or man ( SEQ ID No . 22 ) , which plays an important role in neuronal development (Ayala et al., 1990, Neuron 4: 797-805).
- The nucleoporin-precursor Nup98-Nup96 from man (SEQ ID No. 23), which is proteolytically processed in vivo to form the nucleoporins Nup96 and Nup98 (Fontoura et al . , 1999, J. Cell Biol . 144: 1097-1112) . For Nup98 a function is described in acute myeloid leukaemia (AML) and it is in a functional relationship with CBP
and p300 (Kasper et al., 1999, Mol. Cell. Biol. 19:
764-76) .
- The ribonuclease L inhibitor (Mu-RLI) from mouse (SEQ ID No. 24) or man (SEQ ID No. 25), which in connection with ribonuclease L plays an important role in the antiviral and antiproliferative function of interferons and is regulated tissue-specifically (Benoit et al., 1998, Gene 209: 149-56). In addition to the polypeptides of man (Bisbal et al., 1995, J. Biol.

Chem. 270: 13308-17) and mouse (De Coignac et al., 1998, Gene 209: 149-56) known until now, the closely related polypeptides mentioned for the first time in this study and having a differing sequence can also be used ( SEQ ID No . 2 7 and SEQ ID No . 2 6 ) . The sequences of the nucleic acids encoding these polypeptide variants are depicted in the sequence listing according to SEQ ID No. 118 and SEQ ID No. 117.
- The p68 helicase from mouse (SEQ ID No. 28) or man (SEQ ID No. 29), which is described as a DNA or RNA
helicase located in the cell nucleus and could be involved in the replication, transcription or RNA
processing necessary for cell growth (Ford et al., 1988, Nature 332: 736-8). In addition to the known polypeptide variant from the mouse (SEQ ID No. 28) (Lemaire and Heinlein, 1993, Life Sci. 52: 917-26), the closely related polypeptide mentioned for the first time in this study and having a differing sequence can also be used (SEQ ID No. 30). The sequence of the nucleic acid encoding this polypeptide variant is depicted in the sequence listing according to SEQ ID
No. 119.
- The keratin-associated protein mKAPl3 (also PMG-1) (SEQ ID No. 31) and the homologue protein PMG-2 (SEQ
ID No. 32) from mouse. The PMG-1 transcript is expressed skin-specifically in the keratogenic zone of the cortical cells of the hair follicles and is specific for the keratinization of the cortical cell layer in mouse hair (Aoki et al., 1998, J. Invest.
Dermatol. 111: 804-9).
- The closely related PMG-2, likewise expressed in growing hair follicles was described as a protein, which together with PMG-1 is involved in the differentiation of all epithelial cells which form epidermal appendages (Kuhn et al., 1999, Mech. Dev 86:
193-196). In addition to the known polypeptide of mouse the polypeptides of man mentioned for the first time in this study can also be used (SEQ ID No. 55 (Example 7) and SEQ ID No. 89 to SEQ ID No. 94). The nucleic acids, that encode the above described polypeptides according to SEQ ID No. 89 to SEQ ID No. 94 are indicated in the sequence listing according to SEQ ID No. 95 to SEQ ID
No. 100.
- The protein MA-3 from mouse (SEQ ID No. 33) or man (SEQ ID No. 34) involved in apoptosis (Matsuhashi et al., 1997, Res. Commun. Biochem. Cell Mol. Biol.
1:109-120; Shibahara et al., 1995, Gene 166: 297-301).
In addition to the known polypeptide from man, the polypeptide from man obtained in this study can also be used (SEQ ID No. 58). The sequence of the nucleic acid coding for this polypeptide variant is indicated in the sequence listing according to SEQ ID No. 116.
- The antiproliferative protein BTG1 from mouse (SEQ ID No. 35) or man (SEQ ID No. 36), for which a high expression in dying cells and a function in the regulation of the cell status of advanced atherosclerotic lesions is described (Corjay et al., 1998, Lab. Invest. 78: 847-58).
- The CD9 f rom mouse ( SEQ ID No . 3 7 ) or man ( SEQ
ID No. 38) which is expressed in the epidermis in a widespread manner, which forms complexes with beta 1 integrins and for which a role in the regulation of the motility and differentiation of keratinocytes is suspected (Jones et al., 1998, Cell Adhes. Commun 4:
297-305).
- The stearoyl-CoA desaturase (SCD1) from mouse (SEQ ID No. 39) or man (SEQ ID No. 40), which is regulated by the nuclear factor 1 (NF1) and is involved in the differentiation of preadipocytes to adipocytes (Singh and Ntambi, 1998, Biochim. Biophys. Acta 1398:
148-56).

- The protein syndecan 4 (ryudocan) from mouse ( SEQ ID No . 41 ) or man ( SEQ ID No . 4 2 ) involved in the focal adhesion of fibroblasts, which is described as a transmembrane adhesion component (V~Ioods and Couchman, 1994, Mol. Biol. Cell., 5: 183-92).
- The protein ALF1 from mouse (SEQ ID No. 43) or man (SEQ ID No. 44) and belonging to the class consisting of the E2A basic helix-loop-helix transcription factors, which regulates the growth of mouse fibroblasts (Loveys et al., 1996, Nucleic. Acids Res. 24: 2813-20).
- The potentially prenylated protein tyrosine phosphatase (PRL) from mouse (SEQ ID No. 45) or man (SEQ ID No. 46) , which is described in connection with signal transduction in the regenerating liver and in muscle growth, in particular of the heart (Zeng et al., 1998, Biochem. Biophys. Res. Commun. 244: 421-7).
- Nuclear factor (NF1-B) from mouse (SEQ ID No.
47) or man (SEQ ID No. 48), which is described in connection with alternative splicing and whose function was investigated in oncogenesis in chicken fibroblasts (Schuur et al., 1995, Cell Growth Differ. 6: 219-27).
In addition to the indicated polypeptide sequence of NF1-B of man (SEQ ID No. 48) the slightly differing polypeptide sequence of man (SEQ ID No. 114), that is indicated in the sequence listing as well, can be used.
- The cysteine proteinase cathepsin Z from mouse (SEQ ID No. 56) or man (SEQ ID No. 57) , for which participation in tumour growth is suspected (Santamaria et al., 1998, J. Biol. Chem. 273: 16818-23).
A connection with skin disorders, for example with disturbed wound healing, was not described or suggested until now for any of these polypeptides or their coding nucleic acids. It was therefore unexpected, that these compounds can be used according to the invention. The accession numbers of the polypeptides used according to the invention are indicated in Table 3.
The object of the invention is furthermore achieved by the use of at least one nucleic acid according to one of SEQ ID No. 49 or SEQ ID No. 50 or variants thereof for the diagnosis and/or prevention and/or treatment, for example for the therapeutic and/or prophylactic treatment, of skin disorders or for the identification of pharmacologically active substances.
- The nucleic acids used according to the invention are:
- The nucleic acid for the so-called steroid receptor coactivator from mouse (SEQ ID No. 49) or man (SEQ ID No. 50), whose mRNA is not translated and is functional as an RNA. The steroid receptor coactivator is described as active only in connection with steroid hormone receptors (steroid receptor coactivator: Lanz et al., 1999, Cell 97: 17-27). A connection with skin disorders was unknown until now.
A connection with skin disorders, for example with disturbed wound healing, was not described or suggested until now for any of these nucleic acids. It was therefore unexpected that these compounds can be used according to the invention. The accession numbers of the nucleic acids according to the invention and their cDNAs are shown in Table 3.
In the analysis of gene expression during the wound healing process, it was additionally possible to identify genes whose already known and described functions were not connected until now with wound healing, but whose regulation is essential for the wound healing process and which were thus brought into a causal relationship with wound healing for the first time. The polypeptides of these genes do not belong to the targets of therapies known until now in connection with the pathological alteration of wound healing, such that completely novel therapeutic approaches result from this invention.
The object of the invention is therefore additionally achieved by the use of at least one polypeptide or variants thereof according to one of SEQ
ID No. 51 to SEQ ID No. 54 and SEQ ID No. 101 to SEQ ID
No. 102 or nucleic acid encoding this or variants thereof for the identification of pharmacologically active substances or for diagnosis and/or prevention and/or treatment in wound healing.
The following polypeptides and/or nucleic acids encoding these can be used according to the invention:
- The SR calcium ATPase (SERCA) of mouse (SEQ ID
No. 51) or of man (SEQ ID No. 52), which is described in connection with the muscle growth of the heart (Baker et al., 1998, Nucleic Acids Res., 26: 1092-8). A
connection of SERCA with Darier's disease, a skin disease, has furthermore been described (Sakuntabhai et al., 1999, Nat. Genet. 21: 271-7).
The protein calgranulin (MRP8) of mouse (SEQ ID
No. 53) or of man (SEQ ID No. 54) expressed in inflammatory dermatosis after lesions of the skin, (Kelly et al., 1989, J. Pathol. 159: 17-21), whose involvement in wound healing was also unknown until now.
- The calcium binding protein MRP-14 from mouse (SEQ ID No. 101) or human (SEQ ID No.102) known from DE
198 13 839, US 5,776,348 and US 5,614,397 (Odink et al., 1987, Nature 330: 80-82; Lagasse and Weissmann 1992, Blood 79: 1907-1915). The protein forms heterodimers with MRP8 and is upregulated in macrophages in acutely inflamed tissues (Sorg, 1992, Behring Inst. Mitt. 91: 126-137). In addition increased amounts of MRP-14 have been observed in the epidermis of patients with Lichen planus, Lupus erythematosus and Psoriasis vulgaris (Kunz et al., Arch. Dermatol. Res.
284: 386-390). The MRPB/MRP14 heterodimer binds fatty acids, in particular arachidonic acid with high specificity while the monomers show no binding activity (Kerkhoff et al., 1999, J. Biol. Chem., 274: 32672-32679). In addition to the role in inflammatory processes a function of MRP8 and/or MRP14 in the differentiation processes of keratinocytes during wound healing could be shown for the first time in this study.
A connection with wound healing was not described or suggested until now for any of these polypeptides or these coding nucleic acids. It was therefore unexpected that these polypeptides could be used according to the invention. The accession numbers of the polypeptides according to the invention and their cDNAs are shown in Figure 6.
The polypeptides used according to the invention can furthermore be characterized in that they are synthetically prepared. Thus, the entire polypeptide or parts thereof can be synthesized, for example, with the aid of the conventional synthesis (Merrifield technique). Parts of the polypeptides described above are particularly suitable to obtain antisera (see Example 10), with whose aid suitable gene expression banks can be searched in order thus to arrive at further functional variants of the polypeptide used according to the invention.
The term "variants" within the meaning of the present invention also comprises functionally active variants. Functionally active variants has to be understood to mean polypeptides that are regulated as, for example, the polypeptides used according to the present invention during disorders in particular skin disorders, or regenerative processes of the skin, in particular wound healing disorders. The term "regulation" has to be understood to mean, for example, the increase or decrease of the amount of polypeptides or nucleic acids coding for them, wherein this change is affected on, for example, the transcriptional level.
Functional variants include, for example, polypeptides which are encoded by nucleic acids, which are isolated from non-wound-healing-specific tissue, e.g. embryonic tissue, but after expression have the indicated functions in a cell involved in wound healing.
Variants within the meaning of the present invention are also polypeptides which have a sequence homology, in particular a sequence identity of about 70%, preferably about 80%, in particular about 90%, especially about 95% to the polypeptide having the amino acid sequence according to one of SEQ ID No. 1 to SEQ ID No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID
No. 89 to SEQ ID No. 94, SEQ ID No. 101 to SEQ ID
No. 106 and SEQ ID No. 109 to SEQ ID No. 114. Examples of those variants, that can also be functionally active, are accordingly the corresponding polypeptides which originate from other organisms than man or mouse, preferably from non-human mammals such as, for example, monkeys, pigs and rats. Other examples are polypeptides which are encoded in various individuals or in various organs of organism by different alleles of the gene (see Example 6).
Variants of the polypeptide can also be parts of the polypeptide used according to invention with at least 6 amino acids length, preferably with at least 8 amino acids length, in particular with at least 12 amino acids length. Also included are deletions of the polypeptide used according to the invention, in the range from about 1-60, preferably from about 1-30, in particular from about 1-15, especially from about 1-5 amino acids. For example, the first amino acid methionine can be absent without the function of the polypeptide being significantly altered.
The term "coding nucleic acid" relates to a DNA
sequence which codes for an isolatable bioactive polypeptide used according to the invention or a precursor. The polypeptide can be encoded by a sequence of full length or any part of the coding sequence as long as the specific, for example enzymatic, activity is retained.
It is known that small alterations in the sequence of the nucleic acids used according to the invention can be present, for example, due to the degeneration of the genetic code, or that untranslated sequences can be attached to the 5' and/or 3' end of the nucleic acid without its activity being significantly altered. This invention therefore also comprises so-called "variants"
of the nucleic acids described above.
The term "variants" indicates all DNA sequences which are complementary to a DNA sequence, which hybridize with the reference sequence under stringent conditions and that encode a peptide with a similar activity to the polypeptide encoded by the reference sequence.
"Stringent hybridization conditions" are understood as meaning those conditions in which hybridization takes place at 60°C in 2.5 x SSC buffer, followed by a number of washing steps at 37°C in a lower buffer concentration, and remains stable.
Variants of the nucleic acids can also be parts of the nucleic acids used according to the present invention with at least 8 nucleotides length, preferably with at least 18 nucleotides length, in particular with at least 24 nucleotides length.

Preferentially, the nucleic acids used according to the invention are DNA or RNA, preferably a DNA, in particular a double-stranded DNA. The sequence of the nucleic acids can furthermore be characterized in that it has at least one intron and/or one polyA sequence.
The nucleic acids used according to the invention can also be used in the form of their antisense sequence.
For the expression of the gene concerned, in general a double-stranded DNA is preferred, the DNA
region coding for the polypeptide being particularly preferred. This region begins with the first start codon (ATG) lying in a Kozak sequence (Kozak, 1987, Nucleic. Acids Res. 15: 8125-48) up to the next stop codon (TAG, TGA or TAA), which lies in the same reading frame to the ATG.
A further use of the nucleic acid sequences used according to the invention is the construction of anti-sense oligonucleotides (Zheng and Kemeny, 1995, Clin.
Exp. Immunol. 100: 380-2; Nellen and Lichtenstein, 1993, Trends Biochem. Sci. 18: 419-23; Stein, 1992, Leukemia 6: 967-74) and/or ribozymes (Amarzguioui, et al. 1998, Cell. Mol. Life Sci. 54: 1175-202; Vaish, et al., 1998, Nucleic Acids Res. 26: 5237-42; Persidis, 1997, Nat. Biotechnol. 15: 921-2; Couture and Stinchcomb, 1996, Trends Genet. 12: 510-5). Using anti-sense oligonucleotides, the stability of the nucleic acid described above can be decreased and/or the translation of the nucleic acid described above inhibited. Thus, for example, the expression of the corresponding genes in cells can be decreased both in vivo and in vitro. Oligonulecotides can therefore be suitable as therapeutics. This strategy is suitable, for example, even for skin, epidermal and dermal cells, in particular if the antisense oligonucleotides are complexed with liposomes (Smyth et al., 1997, J.
Invest. Dermatol. 108: 523-6; White et al., 1999, J.

Invest. Dermatol. 112: 699-705; White et al., 1999, J.
Invest. Dermatol. 112: 887-92). For use as a probe or as an "antisense" oligonucleotide, a single-stranded DNA or RNA is preferred.
Furthermore, a nucleic acid which has been prepared synthetically can be used for carrying out the invention. Thus, the nucleic acid used according to the invention can be synthesized, for example, chemically with the aid of the DNA sequences described in Figures 4 to 6 and/or with the aid of the protein sequences likewise described in these figures with reference to the genetic code, e.g. according to the phosphotriester method (see, for example, Uhlmann, E. & Peyman, A.
(1990) Chemical Reviews, 90, 543-584, No. 4).
As a rule, oligonucleotides are rapidly degraded by endo- or exonucleases, in particular by DNases and RNases occurring in the cell. It is therefore advantageous to modify the nucleic acid in order to stabilize it against degradation, so that a high concentration of the nucleic acid is maintained in the cell over a long period (Beigelman et al., 1995, Nucleic Acids Res. 23: 3989-94; Dudycz, 1995, W09511910; Macadam et al., 1998, W09837240; Reese et al., 1997, W09729116). Typically, such a stabilization can be obtained by the introduction of one or more internucleotide phosphorus groups or by the introduction of one or more non-phosphorus internucleotides.
Suitable modified internucleotides are summarized in Uhlmann and Peymann (1990 Chem. Rev. 90, 544) (see also Beigelman et al., 1995 Nucleic Acids Res. 23:
3989-94; Dudycz, 1995, WO 95/11910; Madadam et al., 1998, WO 98/37240; Reese et al., 1997, WO 97/29116).
Modified internucleotide phosphate radicals and/or non-phosphorus bridges in a nucleic acid which can be employed in one of the uses according to the invention contain, for example, methylphosphonate, phosphorothioate, phosphoramidate, phosphorodithioate, phosphate ester, while non-phosphorus internucleotide analogues, for example, contain siloxane bridges, carbonate bridges, carboxymethyl esters, acetamidate bridges and/or thioether bridges. It is also intended that this modification should improve the shelf life of a pharmaceutical composition which can be employed in one of the uses according to the invention.
In a further embodiment of the invention, the nucleic acids used according to the invention are used for the preparation of a vector, preferably in the form of a shuttle vector, phagemid, cosmid, expression vector or vector having gene therapy activity.
Furthermore, knock-out gene constructs or expression cassettes can be prepared using the nucleic acids described above.
Thus, the nucleic acid used according to the invention can be contained in a vector, preferably in an expression vector or vector having gene therapy activity. Preferably, the vector having gene therapy activity contains wound- or skin-specific regulatory sequences which are functionally associated with the nucleic acid described above.
The expression vectors can be prokaryotic or eukaryotic expression vectors. Examples of prokaryotic expression vectors are, for expression in E.coli, e.g.
the vectors pGEM or pUC derivatives, examples of eukaryotic expression vectors are for expression in Saccharomyces cerevisiae, e.g. the vectors p426Met25 or p426GALl (Mumberg et al. (1994) Nucl. Acids Res., 22, 5767-5768), for expression in insect cells, e.g.
Baculovirus vectors such as disclosed in EP-Bl-0 127 839 or EP-B1-0 549 721, and for expression in mammalian cells, e.g. the vectors Rc/CMV and Rc/RSV or SV40 vectors, which are all generally obtainable.

In general, the expression vectors also contain promoters suitable for the respective host cell, such as, for example, the trp promoter for expression in E.coli (see, for example, EP-B1-0 154 133), the Met 25, GAL 1 or ADH2 promoter for expression in yeasts (Russel et al. (1983), J. Biol. Chem. 258, 2674-2682; Mumberg, supra), the Baculovirus polyhedrin promoter, for expression in insect cells (see, for example, EP-B1-0 127 839). For expression in mammalian cells, for example, suitable promoters are those which allow a constitutive, regulatable, tissue-specific, soil-cycle-specific or metabolically specific expression in eukaryotic cells. Regulatable elements according to the present invention are promoters, activator sequences, enhancers, silencers and/or repressor sequences.
Examples of suitable regulatable elements which make possible constitutive expression in eukaryotes are promoters which are recognized by the RNA polymerase III or viral promoters, CMV enhancer, CMV promoter (also see Example 13), SV40 promoter or LTR promoters, a . g . f rom MMTV (mouse mammary tumour virus ; Lee et al .
(1981) Nature 214, 228-232) and further viral promoter and activator sequences, derived from, for example, HBV, HCV, HSV, HPV, EBV, HTLV or HIV.
Examples of regulatable elements which make possible inducible expression in eukaryotes are the tetracycline operator in combination with a corresponding repressor (Gossen M. et al. (1994) Curr.
Opin. Biotechnol. 5, 516-20).
Preferably, the expression of wound-healing-relevant genes takes place under the control of tissue-specific promoters, where skin-specific promoters such as, for example, the human K10 promoter (Bailleul et al., 1990. Cell 62: 697-708), the human K14 promoter (Vassar et al., 1989, Proc. Natl. Acad. Sci. USA 86:
1563-67) or the bovine cytokeratin IV promoter (Fuchs et al., 1988; The biology of wool and hair (ed.
G.E. Rogers, et al.), pp. 287-309. Chapman and Hall, London/New York) are particularly to be preferred.
Further examples of regulatable elements which make possible tissue-specific expression in eukaryotes are promoters or activator sequences from promoters or enhancers of those genes which code for proteins which are only expressed in certain cell types.
Examples of regulatable elements which make possible cell cycle-specific expression in eukaryotes are promoters of the following genes: cdc25, cyclin A, cyclin E, cdc2, E2F, B-myb or DHFR (Zwicker J. and Miiller R. (1997) Trends Genet. 13, 3-6) .
Examples of regulatable elements which make possible metabolically specific expression in eukaryotes are promoters which are regulated by hypoxia, by glucose deficiency, by phosphate concentration or by heat shock.
In order to make possible the introduction of nucleic acids used according to the invention and thus the expression of the polypeptide in a eu- or prokaryotic cell by transfection, transformation or infection, the nucleic acid can be present as a plasmid, as part of a viral or non-viral vector.
Suitable viral vectors here are particularly:
baculoviruses, vaccinia viruses, adenoviruses, adeno associated viruses and herpesviruses. Suitable non viral vectors here are particularly: virosomes, liposomes, cationic lipids, or poly-lysine-conjugated 3 0 DNA .
Examples of vectors having gene therapy activity are virus vectors, for example adenovirus vectors or retroviral vectors (Lindemann et al., 1997, Mol. Med.
3: 466-76; Springer et al., 1998, Mol. Cell. 2: 549-58). Eukaryotic expression vectors are suitable in isolated form for gene therapy use, as naked DNA can penetrate into skin cells on topical application (Hengge et al., 1996, J. Clin. Invest. 97: 2911-6; Yu et al., 1999, J. Invest. Dermatol. 112: 370-5).
Vectors having gene therapy activity can also be obtained by complexing the nucleic acid used according to the invention with liposomes, since a very high transfection efficiency, in particular of skin cells, can thus be achieved (Alexander and Akhurst, 1995, Hum.
Mol. Genet. 4: 2279-85). In the case of lipofection, small unilamellar vesicles are prepared from cationic lipids by ultrasonic treatment of the liposome suspension. The DNA is bound sonically to the surface of the liposomes, namely in such a ratio that a positive net charge remains and the plasmid DNA is complexed to 100% of the liposomes. In addition to the lipid mixtures DOTMA (1,2-dioleyloxypropyl-3-trimethyl-ammonium bromide) and DPOE (dioleoylphosphatidyl-ethanolamine) employed by Felgner et al. (1987, supra), meanwhile numerous novel lipid formulations were synthesized and tested for their efficiency in the transfection of various cell lines (Behr, J.P. et al.
(1989), Proc. Natl. Acad. Sci. USA 86, 6982-6986;
Felgner, J.H. et al. (1994) J. Biol. Chem. 269, 2550-2561; Gao, X. & Huang, L. (1991), Biochim. Biophys.
Acta 1189, 195-203). Examples of the novel lipid formulations are DOTAP N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium ethyl-sulphate or DOGS
(TRANSFECTAM; diocta-decylamidoglycylspermine).
Auxiliaries which increase the transfer of nucleic acids into the cell can be, for example, proteins or peptides which are bound to DNA or synthetic peptide-DNA molecules which make possible the transport of the nucleic acid into the nucleus of the cell (Schwartz et al. (1999) Gene Therapy 6, 282; Branden et al. (1999) Nature Biotech. 17, 784). Auxiliaries also include molecules which make possible the release of nucleic acids into the cytoplasm of the cell (Planck et al.
(1994) J. Biol. Chem. 269, 12918; Kichler et al. (1997) Bioconj. Chem. 8, 213) or, for example, liposomes (Uhlmann and Peymann (1990) supra). Another particularly suitable form of gene therapy vectors can be obtained by applying the nucleic acid used according to the invention to gold particles and shooting these into tissue, preferably into the skin, or cells with the aid of the so-called gene gun (Example 13; Wang et al., 1999, J. Invest. Dermatol., 112: 775-81, Tuting et al., 1998, J. Invest. Dermatol. 111: 183-8).
A further form of a vector having gene therapy activity can be prepared by the introduction of "naked"
expression vectors into a biocompatible matrix, for example a collagen matrix. This matrix can be introduced into wounds in order to transfect the immigrating cells with the expression vector and to express the polypeptides according to the invention in the cells (Goldstein and Banadio, US 5,962,427).
For gene therapy use of the nucleic acid described above, it is also advantageous if the part of the nucleic acid which codes for the polypeptide contains one or more non-coding sequences including intron sequences, preferably between promoter and the start codon of the polypeptide, and/or a polyA sequence, in particular the naturally occurring polyA sequence or an SV40 virus polyA sequence, especially at the 3' end of the gene, as a stabilization of the mRNA can be achieved thereby (Jackson, R.J. (1993) Cell 74, 9-14 and Palmiter, R.D. et al. (1991) Proc. Natl. Acad. Sci.
USA 88, 478-482).
Knock-out gene constructs are known to the person skilled in the art, for example, from the US patents 5,625,122; US 5,698,765; US 5,583,278 and US 5,750,825.

The present invention further relates to a host cell, in particular a skin cell, which is transformed using a vector according to the invention or a knock-out gene construct. Host cells can be either prokaryotic or eukaryotic cells, examples of prokaryotic host cells are E.coli and examples of eukaryotic cells are Saccharomyces cerevisiae or insect cells.
A particularly preferred transformed host cell is a transgenic embryonic non-human stem cell, which is characterized in that it comprises a knock-out gene construct according to the invention or an expression cassette according to the invention. Processes for the transformation of host cells and/or stem cells are well known to the person skilled in the art and include, for example, electroporation or microinjection.
The invention further relates to a transgenic non-human mammal whose genome comprises a knock-out gene construct as described above or an expression cassette as described above. Transgenic animals in general show a tissue-specifically increased expression of the nucleic acids and/or polypeptides and can be used for the analysis of wound healing disorders. Thus, for example, an activin A transgenic mouse exhibits improved wound healing (Munz et al., 1999, EMBO J. 18:
5205-15) while a transgenic mouse having a dominantly negative KGF receptor exhibits delayed wound healing (Werner et al., 1994, Science 266: 819-22).
Processes for the preparation of transgenic animals, in particular of the mouse, are likewise known to the person skilled in the art from DE 196 25 049 and US 4,736,866; US 5,625,122; US 5,698,765; US 5,583,278 and US 5,750,825 and include transgenic animals which can be produced, for example, by means of direct injection of expression vectors (see above) into embryos or spermatocytes or by means of the transfection of expression vectors into embryonic stem cells (Polites and Pinkert: DNA Microinjection and Transgenic Animal Production, page 15 to 68 in Pinkert, 1994: Transgenic animal technology: a laboratory handbook, Academic Press, London, UK; Houdebine, 1997, Harwood Academic Publishers, Amsterdam, The Netherlands; Doetschman: Gene Transfer in Embryonic Stem Cells, page 115 to 146 in Pinkert, 1994, supra;
Wood: Retrovirus-Mediated Gene Transfer, page 147 to 176 in Pinkert, 1994, supra; Monastersky: Gene Transfer Technology; Alternative Techniques and Applications, page 177 to 220 in Pinkert, 1994, supra).
If nucleic acids used according to the invention are integrated into so-called targeting vectors (Pinkert, 1994, supra), it is possible after transfection of embryonic stem cells and homologous recombination, for example, to generate knock-out mice which, in general, as heterozygous mice, show decreased expression of the nucleic acid, while homozygous mice no longer exhibit expression of the nucleic acid. The animals thus produced can also be used for the analysis of wound healing disorders. Thus, for example, the eNOS
(Lee et al., 1999, Am. J. Physiol. 277: H1600-1608), Nf-1 (Atit et al., 1999, J. Invest. Dermatol. 112: 835-42) and osteopontin (Liaw et al., 1998, J. Clin.
Invest. 101: 967-71) knock-out mice exhibit impaired wound healing. Here too, a tissue-specific reduction of the expression of wound healing-relevant genes, for example in skin-specific cells using the Cre-loxP
system (stat3 knock-out, Sano et al., EMBO J 1999 18:
4657-68), is particularly to be preferred. Transgenic and knock-out cells or animals produced in this way can also be used for the screening and for the identification of pharmacologically active substances vectors having gene therapy activity.

The invention further relates to a process for preparing a polypeptide for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, which is characterized in that a nucleic acid as described above is used.
The polypeptide is prepared, for example, by expression of the nucleic acid described above in a suitable expression system, as already explained above, according to the methods generally known to the person skilled in the art. Suitable host cells are, for example, the E.coli strains DHS, HB101 or BL21, the yeast strain Saccharomyces cerevisiae, the insect cell line Lepidoptera, e.g. from Spodoptera frugiperda, or the animal cells COS, Vero, 293, HaCaT, and HeLa, which are all generally obtainable.
The invention further relates to a process for preparing a fusion protein for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, in which a nucleic acid as described above is used.
Fusion proteins are prepared here as explained above which contain the polypeptides described above as, the fusion proteins themselves already having the function of a polypeptide as described above or the specific function being functionally active only after cleavage of the fusion portion. Especially included here are fusion proteins having a proportion of about 1-300, preferably about 1-200, in particular about 1-100, especially about 1-50, foreign amino acids.
Examples of such peptide sequences are prokaryotic peptide sequences, which can be derived, for example, from the galactosidase of E.coli. Furthermore, viral peptide sequences, such as, for example, of the bacteriophage M13 can also be used in order thus to produce fusion proteins for the phage display process known to the person skilled in the art.
Further preferred examples of peptide sequences for fusion proteins are peptides, that facilitate easier detection of the fusion proteins, these are, for example, "Green-Fluorescent-protein" or variants thereof.
For the purification of the proteins described above (a) further polypeptide(s) (tag) can be attached.
Suitable protein tags allow, for example, high-affinity absorption to a matrix, stringent washing with suitable buffers without eluting the complex to a noticeable extent and subsequently targeted elution of the absorbed complex. Examples of the protein tags known to the person skilled in the art are a (His)6 tag, a Myc tag, a FLAG tag, a haemaglutinin tag, glutathione transferase (GST) tag, intein having an affinity chitin-binding tag or maltose-binding protein (MBP) tag. These protein tags can be situated N- or C-terminally and/or internally.
The invention further relates to a process for producing an antibody, preferably a polyclonal or monoclonal antibody, for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, in which a polypeptide or functional equivalents thereof or parts thereof having at least 6 amino acids, preferably having at least 8 amino acids, in particular having at least 12 amino acids is used according to the present invention.

The process is carried out according to methods generally known to the person skilled in the art by immunizing a mammal, for example a rabbit, with the polypeptide described above or the mentioned parts thereof, if appropriate in the presence of, for example, Freund's adjuvant and/or aluminium hydroxide gels (see, for example, Diamond, B.A. et al. (1981) The New England Journal of Medicine, 1344-1349). The polyclonal antibodies formed in the animal as a result of an immunological reaction can then be easily isolated from the blood according to generally known methods and purified, for example, by means of column chromatography. Monoclonal antibodies can be produced, for example, according to the known method of Winter &
Milstein (Winter, G. & Milstein, C. (1991) Nature, 349, 293-299).
The present invention further relates to an antibody for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, which is directed against a polypeptide described above and reacts specifically with the polypeptides described above, where the abovementioned parts of the polypeptide are either immunogenic themselves or can be rendered immunogenic by coupling to suitable carriers, such as, for example, bovine serum albumin, or can be increased in their immunogenicity. This antibody is either polyclonal or monoclonal, preferably it is a monoclonal antibody. The term antibody is understood according to the present invention as also meaning antibodies or antigen-binding parts thereof prepared by genetic engineering and optionally modified, such as, for example, chimeric antibodies, humanized antibodies, multifunctional antibodies, bi- or oligospecific antibodies, single-stranded antibodies, Flab) or F(ab)2 fragments (see, for example, EP-Bl-0 368 684, US 4,816,567, US 4,816,397, WO 88/01649, WO 93/06213, WO 98/24884).
The antibodies according to the invention can be used for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances.
Thus, for example, the local injection of monoclonal antibodies against TGF beta 1 can improve wound healing in the animal model (Ernst et al., 1996, Gut 39: 172-5).
The present invention also relates to a process for producing a medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, in which at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention is combined with suitable additives and auxiliaries.
The present invention furthermore relates to a medicament produced by this process for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, which contains at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention, if appropriate together with suitable additives and auxiliaries. The invention furthermore relates to the use of this medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing.
The therapy of the disorders, in particular skin disorders and/or disorders in wound healing, can be carried out in a conventional manner, e.g. by means of dressings, plasters, compresses or gels which contain the medicaments according to the invention. It is thus possible to administer the pharmaceuticals containing the suitable additives or auxiliaries, such as, for example, physiological saline solution, demineralized water, stabilizers, proteinase inhibitors, gel formulations, such as, for example, white petroleum jelly, highly liquid paraffin and/or yellow wax, etc., topically and locally in order to influence wound healing immediately and directly. The administration of the medicaments according to the invention can furthermore also be carried out topically and locally in the area of the wound, if appropriate in the form of liposome complexes or gold particle complexes.
Furthermore, the treatment can be carried out by means of a transdermal therapeutic system (TTS), which makes possible a temporally controlled release of the medicaments according to the invention. The treatment by means of the medicaments according to the invention, however, can also be carried out by means of oral dosage forms, such as, for example, tablets or capsules, by means of the mucous membranes, for example the nose or the oral cavity, or in the form of dispositories implanted under the skin. TTS are known for example, from EP 0 944 398 A1, EP 0 916 336 A1, EP 0 889 723 Al or EP 0 852 493 A1.
The present invention furthermore relates to a process for preparing a diagnostic for the diagnosis of disorders, in particular skin disorders or disorders in wound healing, which is characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention is used, if appropriate together with suitable additives and auxiliaries.
For example, it is possible according to the present invention to prepare a diagnostic based on the polymerase chain reaction (Examples 5, 8 and 9 PCR
diagnostic, e.g. according to EP 0 200 362) or an RNase protection assay, such as shown in detail in Example 4, with the aid of a nucleic acid described above. These tests are based on the specific hybridization of the nucleic acids described above with the complementary counter strand, usually of the corresponding mRNA. The nucleic acid useable according to the invention can in this case also be modified, such as described, for example, in EP 0 063 879. Preferably a DNA fragment as described above is labeled according to generally known methods by means of suitable reagents, e.g.
radioactively with a-P32-dCTP or non-radioactively with biotin or digoxigenin, and incubated with isolated RNA, which has preferably been bound beforehand to suitable membranes of, for example, cellulose or nylon. With the same amount of investigated RNA from each tissue sample, the amount of mRNA which was specifically labeled by the probe can thus be determined and compared to the amount of mRNA from healthy tissue.
Alternatively, the determination of mRNA can also be carried out in tissue sections with the aid of in situ hybridization (see, for example, Werner et al., 1992, Proc. Natl. Acad. Sci. USA 89: 6896-6900).
With the aid of the diagnostic according to the invention, a tissue sample can thus also be specifically measured in vitro for the strength of expression of the corresponding gene in order to be able to safely diagnose a possible wound healing disorder or dermatological disorders (Examples 4, 5, 8, 9 and 10) . Such a process is particularly suitable for the early prognosis of disorders. This makes possible commencement of preventive therapy and the analysis of predispositions. Thus the expression of the gene spit is already decreased in the unwounded state in intact skin which exhibited wound healing disorders after wounding. The expression of the gene spit therefore makes possible a prediction of the wound healing disorder even in the intact tissue.
The present invention furthermore relates to a diagnostic for the diagnosis of disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid, at least one polypeptide or at least one antibody according to the invention, if appropriate together with suitable additives and auxiliaries.
A further diagnostic according to the invention contains the polypeptide used according to the invention or the immunogenic parts thereof described in greater detail above. The polypeptide or the parts thereof, which are preferably bound to a solid phase, e.g. of nitrocellulose or nylon, can be brought into contact in vitro, for example, with the body fluid to be investigated, e.g. wound secretion, in order thus to be able to react, for example, with autoimmune antibodies. The antibody-peptide complex can then be detected, for example, with the aid of labeled antihuman IgG or antihuman IgM antibodies. The labeling involves, for example, an enzyme, such as peroxidase, which catalyses a color reaction. The presence and the amount of autoimmune antibody present can thus be detected easily and rapidly by means of the color reaction.
Another diagnostic contains the antibodies according to the invention themselves. With the aid of these antibodies, it is possible, for example, to easily and rapidly investigate a tissue sample as to whether the concerned polypeptide is present in an increased amount in order to thereby obtain an indication of a possible wound healing disorder. In this case, the antibodies according to the invention are labeled, for example, with an enzyme, as already described above. The specific antibody-peptide complex can thereby be detected easily and also rapidly by means of an enzymatic colour reaction (see examples 11 and 12 ) .
A further diagnostic according to the invention comprises a probe, preferably a DNA probe, and/or primer. This opens up a further possibility of obtaining the nucleic acids useable according to the invention, for example by isolation from a suitable gene bank, for example from a wound-specific gene bank, with the aid of a suitable probe (see, for example, J.
Sambrook et al., 1989, Molecular Cloning. A Laboratory Manual 2nd edn., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY Chapter 8 page 8.1 to 8.81, Chapter 9 page 9.47 to 9.58 and Chapter 10 page 10.1 to 10.67).
Suitable probes are, for example, DNA or RNA
fragments having a length of about 100-1000 nucleotides, preferably having a length of about 200-500 nucleotides, in particular having a length of about 300-400 nucleotides, whose sequence can be derived from the polypeptide sequences according to SEQ ID No. 1 to SEQ ID No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID
No . 8 9 to SEQ ID No . 94 , SEQ ID No . 1 O l to SEQ ID No .
106 and SEQ ID No. 109 to SEQ ID No. 114 of the sequence protocol, the nucleic acid sequences according to SEQ ID No. 49 to SEQ ID No. 50 of the sequence protocol and/or with the aid of the cDNA sequences of the database entries indicated in Figures 4 to 6 (see also Example 4 and 10).
Alternatively, it is possible with the aid of the derived nucleic acid sequences to synthesize oligonucleotides which are suitable as primers for a polymerase chain reaction. Using this, the nucleic acid according to the invention or parts of this can be amplified and isolated from cDNA, for example wound-specific cDNA (Examples 5 and 6). Suitable primers are, for example, DNA fragments having a length of about 10-100 nucleotides, preferably having a length of about 15 to 50 nucleotides, in particular having a length of 20-30 nucleotides, whose sequence can be derived from the polypeptides according to SEQ ID No. 1 to SEQ ID
No. 48, SEQ ID No. 51 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID No. 94, SEQ ID No. 101 to SEQ ID No. 106 and SEQ ID No. 109 to SEQ ID No. 114 of the sequence protocol, the nucleic acid sequences according to SEQ
ID No. 49 to SEQ ID No. 50 of the sequence protocol and/or with the aid of the cDNA sequences of the database entries indicated in Figures 4 to 6 (Example 4) .
The invention furthermore relates to a process for preparing a test for the discovery of functional interactors in connection with disorders, in particular skin disorders or treatment in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention, if appropriate together with suitable additives and auxiliaries, is used for preparing the test.
The term "functional interactors" in the sense of the present invention is understood as meaning all those molecules, compounds and/or compositions and substance mixtures which can interact under suitable conditions with the nucleic acids, polypeptides or antibodies as described above, if appropriate together with suitable additives and auxiliaries. Possible interactors are simple chemical organic or inorganic molecules or compounds, but can also include peptides, proteins or complexes thereof. On account of their interaction, the functional interactors can influence the functions) of the nucleic acids, polypeptides or antibodies in vivo or in vitro or alternatively only bind to the nucleic acids, polypeptides or antibodies as described above or enter into other interactions of covalent or non-covalent manner with them.
The invention furthermore comprises a test produced according to the invention for the identification of functional interactors in connection with disorders, in particular skin disorders or treatment in wound healing, which comprises at least one nucleic acid, at least one polypeptide or at least one antibody according to the present invention, if appropriate together with suitable additives and auxiliaries.
A suitable system can be produced, for example, by the stable transformation of epidermal or dermal cells with expression vectors which contain selectable marker genes and the nucleic acids described above. In this process, the expression of the nucleic acids described above is altered in the cells such that it corresponds to the pathologically disturbed expression in vivo.
Anti-sense oligonucleotides which contain the nucleic acid sequence useable according to the invention can also be employed for this purpose. It is therefore of particular advantage for these systems to know the expression behavior of the genes in disturbed regenerative processes, such as disclosed in this application. Often, the pathological behavior of the cells in vitro can thus be imitated and substances can be sought which reproduce the normal behavior of the cells and which have a therapeutic potential.
Suitable cells for these test systems are, for example, HaCaT cells, which are generally obtainable, and the expression vector pCMV4 (Anderson et al., 1989, J. Biol. Chem. 264: 8222-9). The nucleic acid useable according to the invention can in this case be integrated into the expression vectors both in the sense and in the anti-sense orientation, such that the functional concentration of mRNA of the corresponding genes in the cells is either increased, or is decreased by hybridization with the antisense RNA. After the transformation and selection of stable transformers, the cells in culture in general show an altered proliferation, migration and/or differentiation behavior in comparison with control cells. This behavior in vitro is often correlated with the function of the corresponding genes in regenerative processes in the body (Yu et al., 1997, Arch. Dermatol. Res. 289:
352-9; Mils et al., 1997, Oncogene 14: 15555-61;
Charvat et al., 1998, Exp Dermatol 7: 184-90; Mythily et al., 1999, J. Gen. Virol. 80: 1707-13; Werner, 1998, Cytokine Growth Factor Rev. 9: 153-65) and can be detected using tests which are simple and rapid to carry out, such that test systems for pharmacologically active substances based thereon can be constructed.
Thus, the proliferation behavior of cells can be detected very rapidly by, for example, the incorporation of labeled nucleotides into the DNA of the cells (see, for example, Fries and Mitsuhashi, 1995, J. Clin. Lab. Anal. 9: 89-95; Perros and Weightman, 1991, Cell Prolif. 24: 517-23; Savino and Dardenne, 1985, J. Immunol. Methods 85: 221-6), by staining the cells with specific stains (Schulz et al., 1994, J. Immunol. Methods 167: 1-13) or by means of immunological processes (Frahm et al., 1998, J.
Immunol. Methods 211: 43-50). The migration can be detected simply by the migration index test (Charvat et al., supra) and comparable test systems (Benestad et al., 1987, Cell Tissue Kinet. 20: 109-19, Junger et al., 1993, J. Immunol. Methods 160: 73-9). Suitable differentiation markers are, for example, keratin 6, 10 and 14 and also loricrin and involucrin (Rosenthal et al., 1992, J. Invest. Dermatol. 98: 343-50), whose expression can be easily detected, for example, by means of generally obtainable antibodies.

Another suitable test system is based on the identification of functional interactions using the so-called two-hybrid system (Fields and Sternglanz, 1994, Trends in Genetics, 10, 286-292; Colas and Brent, 1998 TIBTECH, 16, 355-363). In this test, cells are transformed using expression vectors which express fusion proteins from the polypeptide useable according to the invention and a DNA binding domain of a transcription factor such as, for example, Gal4 or LexA. The transformed cells additionally contain a reporter gene, whose promoter contains binding sites for the corresponding DNA binding domains. By transformation of a further expression vector which expresses a second fusion protein from a known or unknown polypeptide having an activation domain, for example of Gal4 or herpesvirus VP16, the expression of the reporter gene can be greatly increased if the second fusion protein interacts functionally with the polypeptide useable according to the invention. This increase in expression can be utilized in order to identify novel interactors, for example by preparing a cDNA library from regenerating tissue for the construction of the second fusion protein. Moreover, this test system can be utilized for the screening of substances which inhibit an interaction between the polypeptide useable according to the invention and a functional interactor. Such substances decrease the expression of the reporter gene in cells which express fusion proteins of the polypeptide useable according to the invention and of the interactor (Vidal and Endoh, 1999, Trends in Biotechnology; 17: 374-81). Novel active compounds which can be employed for the therapy of disorders of regenerative processes can thus be rapidly identified.
Functional interactors of the polypeptides used according to the invention can also be nucleic acids which are isolated by means of selection processes, such as, for example, SELEX (see Jayasena, 1999, Clin.
Chem. 45: 1628-50; Klug and Famulok, 1994, M. Mol.
Biol. Rep. 20: 97-107; Toole et al., 1996, US 5582981).
In the SELEX process, typically those molecules which bind to a polypeptide with high affinity (aptamers) are isolated by repeated amplification and selection from a large pool of different, single-stranded RNA molecules.
Aptamers can also be synthesized and selected in their enantiomorphic form, for example as the L-ribonucleotide (Nolte et al., 1996, Nat. Biotechnol.
14: 1116-9; Klussmann et al., 1996, Nat. Biotechnol.
14: 1112-5). Thus isolated forms have the advantage that they are not degraded by naturally occurring ribonucleases and therefore have greater stability.
The invention further relates to a process for preparing an array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, in which at least one nucleic acid, at least one polypeptide and/or at least one antibody as described above is used for preparation.
Processes for preparing such arrays are known, for example, from WO 89/10977, WO 90/15070, WO 95/35505 and US 5,744,305 by means of spotting, printing or solid phase chemistry in connection with photolabile protective groups.
The invention further relates to an array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid, at least one polypeptide and/or at least one antibody as described above.
A preferred embodiment of the process for preparing an array immobilized on a support material according to the invention is a process for preparing DNA-chips and/or protein-chips for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, in which at least one nucleic acid, at least one polypeptide and/or at least one antibody as described above is used for preparation.
Processes for preparing such DNA-chips and/or protein-chips are known, for example, from WO 89/10977, WO 90/15070, WO 95/35505 and US 5,744,305 by means of spotting, printing or solid phase chemistry in connection with photolabile protective groups.
Accordingly a preferred subject matter of the invention comprises a DNA chip and/or protein chip for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, which comprises at least one nucleic acid and/or at least one polypeptide and/or at least one antibody according to the present invention. DNA chips are known, for example, from US 5,837,832.
The present invention also relates to a medicament for the indication and therapy, which contains a nucleic acid useable according to the invention or a polypeptide useable according to the invention and, if appropriate, suitable additives and auxiliaries and a process for preparing such a medicament for the treatment of dermatological disorders, in particular of wound healing disorders, in which a nucleic acid useable according to the invention or a polypeptide useable according to the invention is formulated with a pharmaceutically acceptable carrier.
For gene therapy use in man, a medicament is especially suitable which contains the nucleic acid useable according to the invention in naked form or in the form of one of the vectors having gene therapy activity described above or in a form complexed with liposomes or gold particles. The pharmaceutical vehicle is, for example, a physiological buffer solution, preferably having a pH of about 6.0-8.0, preferably of about 6.8-7.8, in particular of about 7.4, and/or an osmolarity of about 200-400 milliosmol/litre, preferably of about 290-310 milliosmol/litre. In addition, the pharmaceutical vehicle can contain suitable stabilizers, such as, for example, nuclease inhibitors, preferably complexing agents such as EDTA
and/or other auxiliaries known to the person skilled in the art.
The administration of the nucleic acid described above, if appropriate in the form of the virus vectors described above in greater detail or as liposome complexes or gold particle complex usually takes place topically and locally in the area of the wound. It is also possible to administer the polypeptide itself with suitable additives or auxiliaries, such as, for example, physiological saline solution, demineralized water, stabilizers, proteinase inhibitors, gel formulations, such as, for example, white petroleum jelly, highly liquid paraffin and/or yellow wax, etc., in order to influence the wound healing immediately and directly.
The nucleic acids of the polypeptides useable according to the invention were isolated from cDNA
libraries which were prepared from intact and wounded skin. In the course of this, the cDNAs were selected which had different abundancies in well-healing wounds in comparison with poorly healing wounds (Example 1).
This took place, for example, with the aid of subtractive hybridization (Diatchenko et al., 1996, Proc. Natl. Acad. Sci. USA 93: 6025-30) and/or with the comparative counting out of clones in cDNA libraries by means of sequencing ("ESTs", Adams et al., 1992, Nature 355, 632-4; Adams et al., 1991, Science 252, 1651-6).
The cDNAs counted out in this way are derived from genes which are expressed either more strongly or more weakly in wound healing disorders than in normally proceeding wound healing.
Generally, the analysis of differentially expressed genes in tissues is afflicted with distinctly more errors in the form of false-positive clones than in the analysis of cell culture systems. This problem can not be circumvented by the use of defined cell culture systems, as suitable cell systems are not available due to the high complexity of the wound healing process and existing simple cell culture systems do not adequately mimick the tissue. This problem is especially prominent in the skin, which consists of a variety of different cell types.
Furthermore, the process of wound healing is a highly complicated process, which comprises temporal and spatial changes of cellular processes like proliferation and differentiation of these various cell types. Due to these problems, the success of the screening depended critically on the selection of the experimental parameters. By targeted choice of parameters a novel screening- and verification strategy was used. The point in time for taking biopsies is critical for the success of the screening: impaired wound healing and skin disorders are often caused by disturbed cell proliferation and cell differentiation.
These processes are initiated at day 1 after wounding, which is why the analysis of the molecular processes prior to this point in time would allow little insight into those processes, that are essential to normally progressing wound healing. However, during the progress of wound healing the composition of cell types in the wound strongly changes after day 1 after wounding. This can result in the measurement of differential expression of a specific gene in a wound, which is not caused by the changed expression in the cells, but is only caused by the altered cell composition. This corroborates, that the selection of the point in time when biopsies are taken is decisive for the success of the screening.
Moreover, there are enormous variabilities in the wound condition at the time of a possible biopsy of the patient on initial contact with the physician. An animal model was therefore used for the identification of the above described nucleic acids. BALB/c mice were wounded and wound biopsies were taken at various points in time. This process has the advantage that the boundary conditions such as genetic background, nature of the wound, time of the biopsy etc. can be exactly controlled and thus only allow a reproducible analysis of gene expression. Even under the defined mouse conditions, further methodological problems result such as redundancy of the analysed clones and underrepresentation of weakly expressed genes, which complicate the identification of relevant genes. In addition, we observed an overrepresentation of genes, which are differentially expressed during the process of wound healing, but which are not suited for the use in wound healing or for skin disorders. These genes comprise, for example, genes encoding proteins of the basic metabolism, e.g. glycolysis, citrate cycle, gluconeogenesis and the respiratory chain, but also genes encoding ribosomal proteins, e.g. L41 and S20.
In the present analysis of gene expression, during the wound healing process, in addition to genes whose function was completely unknown until now, genes were also identified which until now were unconnected with wound healing disorders. Novel variants of some of the known genes were furthermore identified with sequences which significantly differ from the sequences published and/or patented until now.
Of the part of the identified genes not connected with wound healing disorders until now, it was known until now that they have a function in proliferation (NF1-B: Schuur et al., 1995, Cell Growth Differ. 6:
219-27; potentially prenylated protein tyrosine phosphatase: Zeng et al., 1998, 244: 421-7; mas oncogene: van 't Veer et al., 1988, Oncogene Res. 3:
247-54; CBP: Blobel et al., 1998, Proc. Natl. Acad.
Sci. USA 95: 2061-6; BTG1: Rouault et al., 1992, EMBO
J. 11: 1663-70; Acylamino acid-releasing enzyme:
Schoenberger et al., 1986, J. Clin. Chem. Clin.
Biochem. 24: 375-8; ALFl: Loveys et al., 1996, Nucleic.
Acids Res. 24: 2813-20, p68 RNA helicase: Ford et al. , 1988, Nature 332: 736-8, Nup98: Kasper et al., 1999, Mol. Cell. Biol. 19: 764-76; ribonuclease L inhibitor:
Benoit et al., 1998, Gene 209: 149-56; cathepsin Z:
Santamaria et al., 1998, J. Biol. Chem. 273: 16818-23) cell cycle control (Checkpoint suppressor 1: Pat et al., 1997, Mol. Cell. Biol 17: 3037-46), cell migration (Ryoducan: Woods and Couchman, 1994, Mol. Biol. Cell 5:
1183-92), differentiation (mKAPl3: Aoki et al., 1998, J. Invest. Dermatol. 111: 804-9; pmg-2: Kuhn et al., 1999, Mech. Dev 86: 193-196, calnexin: Olsen et al., 1995, Electrophoresis 16: 2241-8, JEM-1: Tong et al., 1998, Leukemia 12: 1733-40; CD9: Jones et al., 1996, Cell Adhes. Commun. 4: 297-305; rab2: Ayala et al., 1990, Neuron 4: 797-805; stearoyl-COA desaturase: Singh and Ntambi, 1998, Biochim. Biophys. Acta 1398: 148-56;
cardiac ankyrin repeat protein: Zou et al., 1997, Development 124: 793-804) and/or apoptosis (MA-3:
Shibahara et al., 1995, Gene 166: 297-301). However, these genes were not connected with wound healing until now (Table 4) .

In addition to the known polypeptides of man (Bisbal et al., 1995, J. Biol. Chem. 270: 13308-17) and mouse (De Coignac et al., 1998, Gene 209: 149-56) ribonuclease L inhibitor and mouse p68 RNA helicase (Lemaire and Heinlein, 1993, Life Sci. 52: 917-26), closely related polypeptides having a significantly differing sequence were identified. From the known mouse mKAPl3/Pmgl polypeptide (Aoki et al., 1998, J.
Invest. Dermatol. 111, 804-9), the sequence of the corresponding polypeptide of man was identified for the first time (Example 7) (SEQ ID No. 55). In addition to this polypeptide from man 6 further homologues of mKAPl3 were identified that were not known until now (SEQ ID No. 89 to SEQ ID No. 94). Furthermore SEQ ID
No. 109 depicts an additional variant of the mas oncogene of mouse, that was not known until now (Metzger et al., 1995, FEBS Lett.357: 27-32).
Furthermore, in addition to the known Jem-1 of man (Tong et al., 1998, Leukemia 12: 1733-1740) a further variant from man (SEQ ID No. 110) not known until now, as well as two variants from mouse (SEQ ID No. 112 and SEQ ID No. 111) that were not known until now could be identified. In addition to the already known sequences of MCARP from mouse (Zhou et al., 1997, Development, 124: 793-804) and NF-1B(GP:BAA92677) from man closely related polypeptides with differing sequence were identified (SEQ ID No. 113 and SEQ ID No. 114).
Furthermore, in addition to the polypeptides HSPC028 and KIAA0614 described from man (Table 2) the corresponding sequences from mouse were identified for the first time (SEQ ID No. 107 SEQ ID No. 108).
The polypeptides of these genes do not belong to the targets known until now of therapies of wound healing disorders, such that completely novel therapeutic approaches result from this invention. Of the remaining identified genes, still no relevant functional description exists (Table 2). Moreover, it was possible to find a gene whose mRNA is not translated and is functional as an RNA (SEQ ID No. 49 to SEQ ID No. 50; steroid receptor coactivator: Lanz et al., 1999, Cell 97: 17-27).
After the primary identification of the genes, it is necessary to confirm the wound healing-specific expression by a further method. This was carried out with the aid of so-called reverse Northern blots, RNase protection assays or TaqMan assays. Using these methods, the amount of mRNA in tissue extracts from various wound healing states of 10 weeks old control mice and/or 1 year old mice and/or of 4 weeks old (=young) mice and/or mice with diabetes (db/db mouse) was determined. For example, the wound-specific expression of the clones in a subtractive cDNA library was thus determined with the aid of a reverse Northern blot (Example 2). It was seen that about 20% of all clones in the libraries showed different signals with hybridization probes from wound cDNA in comparison with probes from intact skin (Figure 1). After the identification of the clones, these were partially sequenced, redundant clones sorted out, and the sequence matched with sequence databases with the aim of identifying full-length sequences of the mouse genes and the human genes (Example 3). The sequencing and redundancy analysis of the positive clones showed that more than 75% of the clones were present a number of times and thus only about 5% of all starting clones were able to be further used. A minority of these wound-specific genes in turn exhibited decreased expression in poorly healing wounds. Of these, it was possible in about 50% to confirm the differential expression in the RNase protection assay, "Real-time RT-PCR" or "TaqMan assay" (Examples 4 and 5). It was thus seen that the gene spit used as a marker gene was expressed about 10 times more strongly in wound tissue in comparison with intact skin. It was also shown that the expression of the gene in poorly healing wounds of dexamethasone-treated and of old animals was about 2 times weaker than in normal well-healing wounds of control animals (Table 1).
For the testing or generation of full-length cDNA
sequences of the nucleic acids useable according to the invention, full-length clones were generated with the aid of colony hybridization (Sambrook et al., 1989, Molecular cloning: A Laboratory Manual, Cold Spring Harbor, Cold Spring Harbor Laboratory Press, New York, Chapter 8-10) and/or PCR-based methods ("RACE", Frohman et al., 1988, Proc. Natl. Acad. Sci. USA 85: 898-9002, Chenchik et al., 1996, in A Laboratory Guide to RNA:
Isolation, Analysis, and Synthesis, Ed. Kreig, Wiley-Liss, pages 272-321; "LDPCR", Barnes, 1994, Proc. Natl.
Acad. Sci. USA 91: 2216-20) both for the mouse genes and for the human genes and the sequence of these clones was determined (Example 6).
Mice are exceptionally well suited to serve as a model system for wound healing processes. To confirm that the homologous human genes, that were identified in the mouse as genes relevant to wound healing, are differentially expressed in human wound tissue, intact skin and wound tissue from man and from mouse were investigated in parallel by means of "TaqMan analysis".
In addition it was possible to obtain detailed information, in which region of the skin a wound healing specific regulated expression takes place, through in situ hybridization or immunolocalization of the nucleic acids or polypeptides used according to the invention in intact skin and wound tissue. This provides information about the function of the wound relevant gene in the wound healing process as well as about the importance of differential expression in disturbed wound healing processes or skin disorders. In addition, the relevance and the therapeutic potential of the genes relevant for wound healing could be confirmed by the in vivo application of the gene in an animal model.
The invention will now be further illustrated below with the aid of the figures and examples, without the invention being restricted hereto.
Priority application DE 199 55 349.1 filed November 17, 1999, US 60/172,511 filed December 17 and DE 100 30 149.5 filed June 20, 2000 including the specification, drawings, claims, sequence listing and abstract, is hereby incorporated by reference. All publications cited herein, are incorporated in their entireties by reference.
Description of the tables, figures and sequences:
Table 1: Tabular arrangement of the altered expression of various genes relevant to wound healing in different wound healing stages.
Table 2: Tabular survey of the polypeptide sequences having unknown biological function identified in the analysis of gene expression during the wound-healing process and their cDNAs and accession numbers.
Table 3: Tabular survey of the polypeptide sequences having already known and described functions identified in the analysis of gene expression during the wound-healing process and their cDNAs and accession numbers.
Table 4: Tabular survey of the polypeptide sequences having already known and described functions additionally identified in the analysis of gene expression during the wound-healing process and their cDNAs and accession numbers.
Table 5: Quantitative RTPCR of spit. The number of cycles until reaching the fluorescence threshold (Ct) for three independent measurements in each case and the mean value (Ct mean), the difference in the Ct values of GAPDH and spit (OCt), the abundance of spit calculated therefrom relative to GAPDH and the relative induction of spit relative to the intact skin of control animals is presented.
Table 6: Tabular survey of the amounts of mRNA of wound relevant genes in different wound healing stages of the mice as determined by means of "TaqMan assay".
Table 7: Tabular survey of the amount of mRNA of wound relevant genes in human day 1- and day 5-wounds determined by means of "TaqMan assay".
Table 8: Tabular survey of the amount of wound relevant mRNA in intact skin of ulcer patients, at the edge of a wound of ulcer patients and at the ground of a wound of ulcer patients as determined by means of "TaqMan Assay".
Figure 1: Autoradiogram of hybridizations of membranes with an identical pattern of applied cDNA
fragments using four different probes. The cDNA fragments were all derived from a wound-specific, subtractive cDNA library which was enriched for those cDNAs which were expressed in the wound tissue more strongly in comparison with intact skin. All probes were prepared from cDNAs which originated from subtractive hybridizations. A: wound-specific probe (subtraction wound versus intact skin), B: skin-specific probe (subtraction intact skin versus wound), C: probe specific for well-healing wound (subtraction wound control animals versus wound dexamethasone-treated animals), D: probe specific for poorly healing wounds (subtraction wound dexamethasone-treated animals versus wound control animals).
Figure 2: Part of the cDNA sequence of the marker gene spit (SEQ ID No. 61). The sequence is the consensus sequence of two sequencings of clones which were contained in the wound-specific, subtractive cDNA library. Vector and primer sequences of the cDNA synthesis were removed, such that only the sequences of the insert for the consensus sequence were taken into account. The quality of the sequence analysis (<10% error) allows only the identification of the full-length cDNA, but does not allow an exact determination of the sequence of the inserts. The position of the recognition site of the restriction endonuclease HindIII, which served for the linearization of the plasmid in the preparation of the probe for the RNase protection assay, is underlined.
Figure 3: Full-length sequence of the spit-cDNA (SEQ ID
No. 62, EMBL database entry MMSPI201, accession No. M64086). The sequence of the nucleic acids contained in the wound-specific cDNA library is underlined (compare Figure 3, complementary sequence). The coding region (bold) of the cDNA extends from the start codon (ATG) in position 61 as far as the stop codon (TGA) in position 1317. The position of the primers for the quantitative RTPCR
(Example 5) in the coding region is underlined.
Figure 4: Partial sequence of the mouse cDNA of GAPDH
(SEQ ID No. 63), as a reference sequence, used in the RNase protection assay.
Figure 5: RNase protection assay of spit with RNA of various wound healing states. Radio-labelled probes of GAPDH (1: intact probe) and spit (2: intact probe) were hybridized with total RNA, obtained from intact skin (3, 5 and 7) or from wounds (4, 6 and 8) of control mice (3 and 4), of dexamethasone-treated mice (5 and 6) or of old mice (7 and 8) and separated by gel electrophoresis after RNase treatment.
In each lane, the signal intensities of the Spi2 signals were standardized with the signals of the GAPDH probe. The relative intensities with respect to intact skin of control animals are lane 3: 1.0; lane 4:
13.28; lane 5: 0.84; lane 6: 7.72; lane 7:
0.54; lane 8: 5.2.
Figure 6: Correction of the sequence of spit (SEQ ID
No. 64). The primers of the PCR are shown in bold; differences from the published database sequence are underlined.
Figure 7: Comparison of the determined amino acid sequence of spit (spit-Consensus. pro) with the published amino acid sequence of the database entry (JH0494.pro).

Figure 8: Sequence of the human homologue of mKAPl/Pmg-1. The Primer of the PCR are underlined.
SEQ ID No. 1 to SEQ ID No. 58 and SEQ ID No. 89 to SEQ ID No. 89 to SEQ ID No. 124 show the polypeptide or cDNA sequences useable according to the invention from man or mouse.
SEQ ID No. 59 to SEQ ID No. 64 show polypeptide and cDNA sequences of the marker genes spit and GADPH.
SEQ ID No . 65 to SEQ ID No . 84 and SEQ ID No . 12 5 and SEQ ID No. 128 show DNA sequences of oligonucleotides which were used for the experiments of the present invention.
SEQ ID No. 85 to SEQ ID No. 88 show amino acid sequences of oligopeptides, which were used for the experiments of the present invention.
Examples Example 1: Preparation of cDNA libraries by means of subtractive hybridization Total RNA was isolated from intact skin and from wound tissue (wounding on the back 1 day before tissue sampling by scissor cut) of Balb/c mice by standard methods (Chomczynski and Sacchi, 1987, Anal. Biochem.
162: 156-159, Chomczynski and Mackey, 1995, Anal.
Biochem. 225: 163-164). The RNAs were then transcribed into cDNA with the aid of a reverse transcriptase. The cDNA synthesis was carried out using the "SMART PCR
cDNA synthesis kit" from Clontech Laboratories GmbH, Heidelberg, according to the directions of the corresponding manual. In order to identify those cDNAs which occurred with differing frequency in the two cDNA
pools, a subtractive hybridization (Diatchenko et al., 1996, Proc. Natl. Acad. Sci. USA 93: 6025-30) was carried out. This was effected using the "PCR select cDNA subtraction kit" from Clontech Laboratories GmbH, Heidelberg, according to the directions of the corresponding manual, the removal of excess oligonucleotides after the cDNA synthesis being carried out by means of agarose gel electrophoresis. The resulting cDNA fragments were integrated into the vector pT-Adv (Clontech Laboratories GmbH) by means of T/A cloning and transformed in E.coli (SURE
electroporation-competent cells, Stratagene) by means of electroporation. Two cDNA libraries were set up, where one was enriched for cDNA fragments which are expressed more strongly in the wound tissue in comparison with intact skin ("wound-specific cDNA
library"), while the other was enriched in cDNA
fragments which are more strongly expressed in intact skin in comparison with wound tissue ("skin-specific cDNA library").
Example 2: Identification of wound healing-regulated 2 5 cDNA fragment s In order to identify those clones of the two cDNA
libraries in Example 1 which contained cDNA fragments relevant to wound healing, the expression of the corresponding cDNAs was analysed in the "reverse Northern blot" in intact and wounded skin and also in well-healing and poorly healing wounds. Here, the cDNA
fragments are immobilized on membranes in the form of arrays of many different cDNAs, and hybridized with a complex mixture of radio-labelled cDNA (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, Cold Spring Harbor Laboratory Press, New York, Chapter 9 page 9.47 to 9.58 and Chapter 10 page 10.38 to 10.50; Anderson and Young: Quantitative filter hybridisation; in: Nucleic Acids Hybridisation, A
Practical Approach, 1985, Eds. Hames and Higgins, IRL
Press Ltd.; Oxford, Chapter 4, page 73 to 112).
In order to prepare suitable membranes for the analysis, 1536 clones were isolated from each library and the cDNA insertions were amplified by means of polymerase chain reaction. 2 ~,1 each of suspension culture of the clones were lysed at 96°C for 1 minute in 40 ~.l of TE buffer (10 mM Tris-HC1, 1 mM EDTA, pH -8.0) and a 20 ~1 PCR reaction ("Advantage cDNA
polymerase mix kit" from Clontech) was inoculated with 1 ~,l of lysate. The amplification was carried out in 35 PCR cycles (1 min 96°C followed by 35 cycles of 2-stage PCR: 96°C/30" and 68°C/3') with universal primers (TCGAGCGGCCGCCCGGGCAGGT (SEQ ID No. 65) and AGCGTGGTCGCGGCCGAGGT (SEQ ID No. 66)), which are used in the "PCR-select cDNA subtraction kit" for the obtainment of the cDNA fragments and thus include all cDNA insertions. 5 ~1 of PCR reaction were treated with 35 ~1 of buffer (1.16 M NaCl, 20 mM Tris, pH - 7.5, 0.001% Bromophenol Blue) in 384-well microtitre plates and punched out onto Qiabrane membranes (Qiagen, Hilden) in 20 repetitions with the Nunc 384 pin replicator using the Nunc replicator system (Nunc GmbH
& Co. KG, Wiesbaden). The membranes were incubated with 0.4 M NaOH for 30 minutes for denaturation of the DNA
and neutralized for 3 minutes with 1 M Tris-HC1, pH -7.5. The DNA was then immobilized by W irradiation (120 mJ/cm2) followed by baking for 30 min at 80°C.
For the preparation of suitable hybridization probes, RNA was isolated from intact and wounded skin (see above) and also from well-healing and poorly healing wound tissue. In order to obtain tissue from mice having poorly healing wounds, BALB/c mice were treated before wounding with dexamethasone (injection of 0.5 mg of dexamethasone in isotonic saline solution per kg of body weight twice per day for 5 days) or old mice (12 months) were wounded. The RNA from wound tissue of these animals and also from controls was isolated as described above and cDNA was in each case synthesized. Two subtractive hybridizations (cDNA from dexamethasone-treated animals versus cDNA from control animals and conversely) were then carried out as described above. This took place as described above using the "PCR select cDNA subtraction kit". These subtracted cDNAs and also the subtractive cDNAs described above (intact skin versus wound and conversely) were treated with the restriction endonuclease RsaI and purified by means of agarose gel electrophoresis (Sambrook et al., supra, Chapter 6, page 6.1 to 6.35), in order to separate the cDNA
synthesis and amplification primers (see "PCR-select cDNA subtraction kit" manual, Clontech). The cDNAs were then radio-labelled using the "random hexamer priming"
method (Feinberg and Vogelstein, 1983, Anal. Biochem.
132: 6-13) in order to prepare hybridization probes.
The membrane was preincubated in 25 ml of hybridization solution for 30 min at 65°C (25 mM sodium phosphate, pH - 7.5, 125 mM NaCl, 7% SDS). The hybridization probe was denatured at 100°C for 10 min, then cooled on ice, about 100 CPM per ml were added to the hybridization solution and the hybridization was carried out in a hybridization oven for 16 hours at 65°C. The membrane was then washed twice with the hybridization solution without probe at 65°C for 10 min. The membrane was then washed at 65°C a number of times for 10 min in each case in wash solution (2.5 mM
sodium phosphate, pH - 7.5, 12.5 mM NaCl, 0.7% SDS) until it was no longer possible to detect any activity in the solution poured off. The radioactive signals were analysed using a phosphoimager (BioRad, Quantity One~) (Figure 1). Those cDNAs were then selected which produced different signal intensities with the various probes. Plasmid DNA preparations were prepared from the corresponding clones according to standard methods (Sambrook et al., supra) and the DNA sequence of the inserts was analysed. Figure 1 shows a survey of the expression patterns of various genes which it was possible to determine by this method.
Example 3: Analysis of cDNA sequences relevant to wound healing The cDNA sequence of the inserts from Example 2 was analysed for redundancy using the program SeqMan 4.01 from DNAStar Inc. (GATC GmbH, Constance, Germany) and non-redundant sequences were compared with the program BLAST 2.0 (Altschul et al., Nucleic Acids Res.
25: 3389-402) with the present EMBL (Stoesser et al., 1999, Nucleic Acids Res., 27: 18-24), TREMBL (Bairoch and Apweiler, 1997, Nucleic Acids Res. 25: 31-26) and PIR (George et al., 1996, Nucleic Acids Res. 24: 17-20) and/or GenBank (Benson et al., 1999, Nucleic. Acids Res. 27: 12-7) database. It emerged here that some cDNA
sequences relevant to wound healing originate from known genes which until now, however, were still not connected with regenerative processes.
It was thus possible to identify the spit gene as a gene relevant to wound healing. Figure 2 shows the starting sequence which was present twice in the wound-specific cDNA library (see above), Figure 3 the full-length sequence of spit from the EMBL database (entry MMSPI201, accession No. M64086 (SEQ ID No. 60), which agrees with the starting sequence with high significance (BLAST score - 883). A comparison of the two sequences shows that the starting sequence contains the 3' end of the spit cDNA (underlined sequence in Figure 3). The Spi2 spit-cDNA codes for the protein "alpha-1-antichymotrypsin-like protein EB22/4" (PIR:
JH0494), whose functional variant in man is "alphal-antichymotrypsin" (database entries: protein: PIR:
E55627, cDNA: EMBL: K01500 (SEQ ID No. 71)). The functional variants of the protein in mouse and man have about 60% sequence homology. Corresponding analyses were carried out with all other determined cDNA fragments and a list of those database entries found, that have a significant diagnostic and therapeutic potential was generated (Tables 2 to 4).
Example 4: Verification of the expression pattern of cDNAs relevant to wound healing by means of "RNase protection assays"
The differential expression of the genes was verified with the aid of the "RNase protection assay".
The test was carried out as described in the literature (Sambrook et al., supra Chapter 7, page 7.71 to 7.78;
Werner et al., 1992; Growth Factors and Receptors: A
Practical Approach 175-197, Werner, 1998, Proc. Natl.
Acad. Sci. USA 89: 6896-6900). Counter-strand RNA of the isolated clones which was transcribed in vitro and radio-labelled was employed as a hybridization probe. A
counter-strand RNA probe of the murine GAPDH-cDNA
(length of the transcript without vector sequence: 120 base pairs, Figure 9), cloned into pBluescript II KS
(+) (Stratagene) with the aid of the restriction endonucleases XbaI and HindII, served as an internal control. This plasmid was linearized with XhoI before transcription. The plasmids of the cloned cDNA
fragments of the identified cDNAs were likewise linearized with restriction endonucleases before transcription. Thus the spit clone, for example, was linearized with HindIII (length of the transcript without vector sequence: 322 base pairs, Figure 3). The transcriptions were carried out with T7 polymerase (Roche Diagnostics, Mannheim) in the presence of 32P-UTP
(35~.Ci/batch) (Amersham, Brunswick) according to the details of the manufacturer. After a DNase digestion (Boehringer, 40U/batch), the unincorporated nucleotides were removed with the aid of column chromatography (Pharmacia, Microspin Combi-Pack 5200) according to the details of the manufacturer and the probes were purified by gel electrophoresis and elution (Sambrook et al., supra, Chapter 6, page 6.36 to 6.48). For the hybridization reaction, about 105 CPM each of the labelled transcripts were employed. For this, 20 ~g of total RNA were precipitated with appropriate amounts of transcript (specific sample spit and internal control GAPDH), taken up in 30 ~1 of hybridization buffer (80%
deionized formamide, 400 mM NaCl, 40 mM Pipes pH 4.6, 1 mM EDTA) and hybridized overnight at 42°C. An RNase T1 digestion (Boehringer, 200 U/batch) was then carried out. After inactivation of the RNase by proteinase K
digestion (Boehringer, 44 ~g/batch) and phenol extraction, the samples were precipitated with isopropanol according to standard methods (Sambrook et al., supra). The samples were then separated by gel electrophoresis on a denaturing 5% acrylamide gel (6M
urea). The gel was dried and the radioactive signals were analysed (Figure 5) using a phosphoimager (BioRad, Quantity One°) .
Example 5: Verification of the ex ression pattern of cDNAs relevant to wound healing by means of real-time quantitative RTPCR
A further verification of the differential expression of the nucleic acids according to the invention was carried out by means of a real-time RTPCR
in the ABI Prism 7700 sequence detection system (PE

Applied Biosystems). The apparatus was equipped with the ABI Prism 7200/7700 SDS software version 1.6.3 (1998). The detection of PCR products was carried out during the amplification of the cDNA with the aid of the stain SYBR Green l, whose fluorescence is greatly increased by binding to double-stranded DNA (Karlsen et al. 1995, J. Virol. Methods. 55: 153-6; Wittwer et al., 1997, BioTechniques 22: 130-8, Morrison et al., 1998, BioTechniques 24: 954-62). The basis for the quantification is the PCR cycle (threshold cycle, CT
value) which is achieved when the fluorescence signal exceeds a defined threshold. The analysis is carried out by means of the D0-CTCT method (User Bulletin #2, Relative Quantitation of Gene Expression, PE Applied Biosystems, 1997). The abundances of the cDNAs were determined relative to an endogenous reference (GAPDH).
The results are shown in Table 5.
Normally healing day 1-wounds and intact skin was obtained from 10 weeks old BALB/c mice treated with isotonic saline solution by scissors cut as described above. To obtain tissue from mice with poorly healing wounds BALB/c mice were treated prior to wounding with dexamethasone (injection of 0.5 mg of dexamethosone in isotonic saline solution per kg of body weight twice per day for 5 days).
Total RNA was obtained from skin and wound tissue as described above and 1 ~,g of total RNA was subj ected to reverse transcription in a thermocycler (GeneAmp PCR
system 9700, PE) using the TaqMan reverse transcription reagent kit (PE) according to the recommendations of the manufacturer (SYBR Green PCR and RT-PCR Reagents Protocol, PE Applied Biosystems, 1998). The primers for the amplification of the Spi2 cDNA
(spit primer 1: CTGTCCTCTGCTTCCCAGATG (SEQ ID
No. 67), spit primer 2: TCCAGTTGTGTCCCATTGTCA (SEQ ID

No. 68) and the reference (GAPDH primer 1:
ATCAACGGGAAGCCCATCA (SEQ ID No. 69), GAPDH primer 2:
GACATACTCAGCACCGGCCT (SEQ ID No. 70)) were selected with the aid of the nucleic acid useable according to the invention and the known sequence of GAPDH using the Primer Express software for Macintosh PC Version 1.0 (PE Applied Biosystems, P/N 402089, 1998). For the PCR, the SYBR Green PCR Core Reagents Kit (4304886, PE
Applied Biosystems) was used. The concentration of the primers in the PCR was initially optimized in the range from 50 nM to 600 nM and the specificity of the PCR was tested by analysis of the length of the amplified products in an agarose gel electrophoresis. The efficiency of the PCR system was then determined by means of a dilution series (User Bulletin ##2, Relative Quantitation of Gene Expression, PE Applied Biosystems, 1997). It emerged here that for both cDNAs the efficiency of the amplification was 100%, i.e. at each 1:2 dilution of the cDNA one more cycle was needed in order to exceed the fluorescence threshold value.
For the quantification, each batch of cDNA was amplified from 10 ng of reverse-transcribed total RNA
in a total volume of 25 ~1. The running conditions for the PCR corresponded to the details of the manufacturer (PE Applied Biosystems, SYBR Green PCR and RT-PCR
Reagents Protocol, 1998). The CT values were analysed and the abundance of spit was calculated. It was also possible with the second assay to confirm the induction of spit in well-healing wounds, the reduction of the induction in poorly healing wounds of dexamethasone-treated animals and the reduction of the expression in intact skin of dexamethasone-treated animals. The slight differences in the absolute values are to be attributed to the different test systems.

Example 6: Verification of the sequence of the cDNA of spit In order to verify the cDNA sequence of spit, oligonucleotides were synthesized with the aid of the database sequence (primer 1: ACTGCAGAACACAGAAGATGG-CTTTCATTG (SEQ ID No. 71), primer 2: CCGGGAAGAAG-CGTCAACACTTGGGGAGTT (SEQ ID No. 72)). Using these primers, starting from mouse wound cDNA (see above) the coding region of the cDNA of spit (Figure 3) was amplified with the aid of the advantage cDNA PCR kit.
The PCR reaction was set up according to the details of the manufacturer and the amplification was carried out for 40 cycles (30" 94°C, 30" 64°C, 1.5' 72°C), the denaturation time in the first cycle being extended to 1.5 minutes and the synthesis time in the last cycle to 6.5 minutes. The PCR product (1309 bp) was purified by agarose gel electrophoresis (Sambrook et al., supra) and cloned into the vector pCR2 with the aid of the pCR2.1TOP0 cloning kit (Invitrogen) according to the details of the manufacturer. The sequence of 3 independent clones was analyzed using standard methods and the consensus sequence was determined (Figure 6) with the aid of the program SeqMan2 (see above) . It is seen here that the cDNA sequence determined here in the wound tissue differs slightly from the published sequence (Inglis et al., 1991, Gene 106: 213-20), as well as the coded proteins of both sequences (Figure 7). Both polypeptides have comparative degrees of homology of 60% to the human sequence, such that it can be assumed therefrom that the polypeptides are functional variants of the gene. Reasons for the difference could be based on the different starting material for the cDNA synthesis (wound tissue versus chondrocyte cell line) or on different alleles of the gene in the donor.

Example 7: Cloning of the human homologue to mKAPl3 Using the published protein sequence of mKAPl3 (Aoki et al., 1998, J. Invest. Dermatol. 111, 804-9), the human EST database GenBank dbest (Benson et al., supra) was searched for homologous sequences with the aid of the BLAST program (Altschil et al., supra). Four sequence entries were found (W76571, W72002, AA055832 and AA055833) which had similarities to the mouse mKAPl3 and/or to the ESTs found. From the four sequences, the consensus sequence was determined with the aid of the program SeqMan and PCR primers constructed (AACTCAGCTGAACTCACATCTCCCGTCAAC (SEQ ID
No. 73) and GTCTGAAAGAACTAGCCTGTCCAGCCAGTA (SEQ ID
No. 74)). Using these primers, as described above (see Example 6) the human homologue of mKAPl3 was amplified, cloned and sequenced (Figure 8) with the aid of the PCR
from cDNA which was obtained from intact human skin (see Example 1). It emerged here that owing to the generally known poor quality of the EST sequences, the actual sequence differed considerably from the sequence predicted by the EST assemblage such that the selection of the primers was very critical for the success of the cloning.
Example 8: Analysis of the expression pattern of cDNAs relevant to wound healing at different wound healing stages of the mouse by means of "TaqMan analysis"
The regulation of the expression of cDNAs relevant to wound healing in different wound healing stages of mouse was carried out by means of "TaqMan analysis" in the Gene-Amp 5700 of Applied Biosystems. Normally healing day 1-wounds and intact skin of 10 weeks old BALB/c mice treated with isotonic saline solution was obtained by scissors cut as described above. To obtain tissue of mice with poorly healing wounds, BALB/c mice were treated prior to use with dexamethasone (injection of 0.5 mg of dexamethosone in isotonic saline solution per kg of body weight twice per day for 5 days). Intact skin of mice that were treated with dexamethasone as described above was used as control. To obtain tissue of young and old mice untreated day 1-wounds and intact skin of 4 weeks old and 12 months old BALB/c mice was used. Wound tissue and intact skin of mice with diabetes (db/db mouse) was obtained by isolating untreated day 1-wounds and intact skin of 10 weeks old C57B/Ks-db/db/Ola mice by scissors cut. C57B/Ks wild-type mice were used as control animals. From the latter animals similarly intact skin as well as untreated day 1-wounds were obtained.
The isolation of RNA was carried out by homogenizing of the biopsies in RNAclean buffer (AGS, Heidelberg) that was supplemented with 2-mercapto ethanol at 1/100 of the total volume using a disperser.
Subsequently the RNA was extracted by twofold phenolization by means of water saturated acidic phenol in the presence of 1-bromo-3-chloro-propane.
Subsequently an isopropanol and ethanol precipitation was carried out and the RNA was washed with 75%
ethanol. Thereafter a DNase I digestion of the RNA was carried out. For this 20 ~g RNA (add to 50 ~,1 with DEPC-treated water) with 5.7 ~1 transcription buffer (Roche) , 1 ~,1 RNase inhibitor (Roche; 40 U/~,1) and 1 ~,1 DNase I (Roche; 10 U/~.1) was incubated for 20 minutes at 37°C. Then 1 ~1 DNase I was added again and was further incubated for 20 minutes at 37°C. Subsequently the RNA was treated with phenol, precipitated with ethanol and washed. All steps indicated above were carried out with solutions or liquids treated with DEPC
(Diethylpyrocarbonat) as long these did not contain reactive amino groups. Thereafter cDNA was produced from the extracted RNA. This was carried out in the presence of 1 x TaqMan RT-buffer (Perkin Elmer), 5.5 mM
MgCl2 (Perkin Elmer) , 500 ~,M dNTPs each (Perkin Elmer) , 2.5 ~,M random hexamere (Perkin Elmer) , 1.25 U/~,1 multiScribe Reverse Transcriptase (50 U/~,l Perkin Elmer) , 0.4 U/~,1 RNase inhibitor (20 U/~,1, Perkin Elmer), 20 ~,1 RNA (50 ng/~l) and DEPC-treated water (added to 100 ~1 volume). After addition of RNA and thorough mixing the solution was distributed to two 0.2 ml reaction vessels (50 ~,1 each) and the reverse transcription was carried out in a temperature cycler (10 min at 25°C; 30 min at 48°C and 5 min at 95°C). The subsequent quantification of cDNA was carried out by means of quantitative PCR using the SYBR Green PCR
master mixes (Perkin Elmer), wherein for each of the cDNA species to be determined a triple determination was carried out (with target primers and GAPDH primers each time) . A base solution for each triplet contained within 57 ~1 total volume 37.5 ~l 2 x SYBR Master Mix, 0.75 ~l AmpErase UNG (1 U/~l) and 18.75 ~,l DEPC treated water. For each triplicate determination 1,5 ~,l forward and reverse primer were added in a previously optimized concentration ratio to 57 ~,l base solution. 60 ~1 of each of the base solution/primer mix was mixed with 15 ~1 cDNA solution (2 ng/~,1) and distributed into 3 wells. A base solution with primers for the determination of GAPDH (SEQ ID No. 69 and SEQ ID No.
70) was produced in parallel, mixed with further 15 ~,1 of the same cDNA solution and distributed into 3 wells.
In addition in order to produce a standard curve for the GAPDH-PCR, different cDNA solutions were generated by serial dilutions (4 ng/~,1; 2 ng/~.1; 1 ng/~,1; 0.5 ng/~.l and 0.25 ng/~,1) . 15 ~,1 of each cDNA solution was mixed with 60 ~1 base solution/primer mix for determination of GAPDH and distributed into 3 wells.
Similarly a standard curve for the PCR of the target gene was generated; in this process the same dilutions, that were also used for the GAPDH standard curve, were employed. A PCR reaction without cDNA served as a control. In each case 15 ~l DEPC water were added to 60 ~,1 base solution/primer mix of target and GAPDH, respectively, mixed and distributed into 3 wells in each case. The amplification of the reaction set-ups were carried out in a GeneAmp 5700 (2 min at 50°C; 10 min at 95°C, followed by 3 cycles with 15 sec at 96°C
and 2 min at 60°C, afterwards 37 cycles with 15 s at 95°C and 1 min at 60°C). The evaluation was carried out by determining a relative abundance of each target gene in relation to the GAPDH reference. For this a standard curve was generated initially by plotting the CT-values of the dilution series against the logarithm of the cDNA amount in the PCR set up (in ng of translated RNA) and the slopes) of the rectilinear was determined. The efficiency (E) of the PCR then results as follows: E -10-l~s -1. The relative abundance (X) of the cDNA species investigated (Y) in relation to GAPDH equals: X -(1+EGAPDH)CT(GAPDH)/(1i-Ey)CT(y). AfterWardS the values were standardized by equating the amount of cDNA from intact skin of 10 weeks old BALB/c control animals or the intact skin of C57B/Ks control animals with one. The relative change of expression in different wound healing stages is put together in Table 6.
Thus it could be shown by using, for example, suitable primers (p68-primer l: CCTTATCTCTGTGCTTTCG-GGAA) (SEQ ID No. 83; p68-primer 2: CGACCTGAACCTCTG-TCTTCG (SEQ ID No. 84)), that significantly less p68 helicase mRNA were present in wounds of control animals in comparison to intact skin. Furthermore a significant decrease of expression was also observed in wounds of old and young mice. On the other hand the amount of p68 helicase mRNA in poorly healing wounds of animals treated with dexamethasone was strongly increased. In addition an increase in expression in comparison to intact skin was also detected in wounds of diabetic mice while, in wounds of control animals a decrease of expression was detected. This exemplifies that p68 helicase is differentially expressed during wound healing. In addition this experiment shows that an increase in p68 helicase expression is accompanied by impaired wound healing, and that preferentially a decrease in p68 helicase expression and/or in protein activity is essential for the normal progression of wound healing.
Example 9: Detection of differential expression of genes relevant to wound healing by means of "TaqMan assay"
Mice have proven to be a suitable model system for investigating wound healing in man. However, it should be reconfirmed whether the expression pattern specific to wound healing of the nucleic acids useable according to the invention, that was observed in the mouse, could also be shown in man. For that purpose skin samples were taken from healthy trial participants of untreated intact skin, of day 1-wounds or of day 5-wounds by means of 4 mm and 6 mm punch, respectively. Of each group (intact skin, day 1-wound, day 5-wound) biopsies of 14 trial participants were pooled each time. In addition punch biopsies were taken at the same time from patients with chronic venous ulcers (Ulcera cruris venosum) from intact skin as well as from ground of wound and edge of wound. For each group (intact skin, edge of wound, ground of wound) biopsies of six trial participants were pooled each time. RNA was isolated from all biopsies as described in Example 8, then DNase I digested and thereafter transcribed into cDNA. The quantification of cDNAs relevant to wound healing was similarly carried out as described in Example 8. The results of the experiments are compiled in Table 7. For the analysis of the p68 helicase the primers for amplification (hGAPDH-primerl:
CATGGGTGTGAACCATGAGAAG(SEQ ID No. 75); hGAPDH-primer2:
CTAAGCAGTTGGTGGTGCAGG (SEQ ID No. 76); hp 68-primerl:
GAGGCCATTTCCAGCGACT (SEQ ID No. 77); hp 68-primer2:
GAATAACCCGACATGGCGTC (SEQ ID No. 78)) were based on the known sequences of human GAPDH (GenBank: M17851) and human p68 helicase (Embl: X15729). cDNA from lOmg reverse transcribed total-RNA in a total volume of 25 ~,l was amplified for each reaction set-up for quantification. The PCR was carried out according to the instruction of the manufacturer (PE applied Biosystems, SYBR Green PCR and RT-PCR Reagents Protocol, 1998). The CT-values were analyzed and therefrom the abundance of hp68 helicase mRNA relative to GAPDH mRNA was calculated. It could be shown that the amount of hp68 helicase mRNA in human day 1-wounds was reduced in comparison to intact skin by approximately 60% (Table 7). This correlates with the regulation of the expression of the murine p68 helicase homologue in normally healing wounds of 10 weeks old control mice as well as in wounds of young and old BALB/c mice in comparison to intact skin, respectively (Table 6). In this experiment a 30%-70% reduced expression was observed in day 1-wounds.
In human day 5-wounds an increase of the amount of hp 68 helicase mRNA to 60% of the value for intact skin was observed indicating that the regulation of expression is essential in a very early phase of wound healing. The analysis of normally healing day 5-wounds of 10 weeks old BALB/c mice showed that the amount of murine p68 helicase mRNA increased in the murine cell system to 67% of the value in intact skin.
Consequently, the kinetic of expression of p68 helicase is also comparable in normal healing wounds both in mouse and man. Therefore, it could be shown in this experiments that the genes identified in the mouse system to be relevant to wound healing were also differentially expressed in men. This corroborates the results of the experiments of Example 8, that showed that p68 helicase is essential for wound healing.
Furthermore it was shown, that in an ulcer, which represents a disturbed wound healing process, no decrease of p68 helicase expression as in normally progressing wound healing is detectable, but rather a slight increase of expression is observable. This is particularly evident at the ground of a wound. This shows that the regulation of expression not only plays an essential role for wound healing in man but furthermore is essential for the normal progression of wound healing. A disturbed expression, preferentially an increased expression of p68 helicase, can lead to severe wound healing disorders.
Example 10: Localization of genes relevant to wound healing in intact human skin and in wounds by means of in situ hybridization To obtain further information on the importance of genes that were identified to be relevant to wound healing mRNA was detected in sections of human wounds and intact skin by means of radioactive or non-radioactive in situ hybridization. The success of in situ hybridization critically depends on a variety of parameters like, for example, the abundance of the mRNA
in the tissue, an optimal hybridization temperature or the stringency of the washing steps subsequent to hybridization. The selection of a suitable probe sequence is also essential. For the success of such an experiment elaborate optimization steps are necessary.
In spite of the experimental hurdles it was possible to further substantiate the relevance of MRP-8, MRP-14 and p68 helicase for wounds, that was already shown in Example 8, by means of in situ hybridization.
For the experiment biopsies were taken from intact skin as well as from normally healing day 5-wounds of~
healthy patients as described in Example 9. Tissue sections were fixed in 4% paraformaldehyd, treated with proteinase K (1 ~g/ml isotonic saline solution) for 10 minutes at 37°C, and again with paraformaldehyd and finally with acetanhydrid (0.5 ml in 0.1 M
triethanolamine, pH 8.0).
The localization of the mRNA of human MRP-8 and MRP-14 was carried out by means of non-radioactive in situ hybridization. For this a partial human MRP-8 cDNA
fragment was amplified by means of PCR. The primers used therein contained in addition to a section homologous to MRP-8 an RNA-polymerase promoter for the production of riboprobes (the antisense primer used (T7-MRP-8): TAATACGACTCACTATAGGGCCCACGCCCATCTTTATCACCAG
(SEQ ID No. 79); the sense primer used (T3-MRP-8):
AATTAACCCTCACTAAAGGGGGAATTTCCATGCCGTCTACAGG (SEQ ID No.
80). The amplified cDNA fragment was cloned into the PCR 2.1 TOPO vector (Invitrogen) and thereafter verified by sequencing. The production of the antisense riboprobe and the sense control was done using the DIG
RNA labeling mixes (Roche) and the respective RNA
polymerase according to the instruction of the manufacturer. The subsequent in situ hybridization was carried out as described by Komminoth et al. (1992, Histochemistry 98: 217-228).
In comparison to intact skin a strong induction of mRNA expression in the suprabasal cell layers of the hyperproliferative epithelium was detected in human day 5-wounds by means of the antisense probe, while no staining was detected with the sense probe . This is in agreement with the result of the quantitative analysis of the amount of murine MrpB mRNA by means of "TaqMan's analysis", in which a marked upregulation was detected in day 1-wounds (Table 6) and also in day 5-wounds. In addition to the verification of the upregulation of gene expression the localization in hyperproliferative epithelium emphasizes that the gene plays an important role in a central process of wound healing. Therefore, it was possible to corroborate the relevance for wounds in man for MRP-8, that was identified in the mouse system.
The localization of MRP-14 was carried out analogous to the localization of MRP-8, wherein Sp6-MRP-14 primer (ATTTAGGTGACACTATAGAATAC CCC GAG GCC TGG
CTT ATG GT; SEQ No. 125) was used as antisense primer and T3-MRP-14 primer (AATTAACCCTCACTAAAGGGG GTG GCT CCT
CGG CTT TGA CA; SEQ No. 126) as control sense primer.
The localisation in intact skin and in day 5-wounds was done as described for MRP-8.
It was shown that MRP-14 mRNA is also strongly expressed in the suprabasal cell layer of the hyperproliferating epithelium while no staining was detected with the sense probe. This is in agreement with the result of the quantitative analysis of the amount of murine Mrp-14 mRNA by means of "TaqMan analysis" in which a marked upregulation was detected in day 1-wounds (Table 6) and also in day 5-wounds.
Thus, it was possible to corroborate in this experiment the relevance of mrp-14 for wounds in man, that was identified in the mouse system. Moreover, this experiment proves that both monomers of the MRP-14/MRP-8 heterodimer are wound regulated in a similar way. The expression of MRP-14/MRP-8 in suprabasal keratinocytes of the hyperproliferative epithelium shows in addition that the dimer is not only involved in inflammatory processes, as suspected until now, but also has an essential function in proliferation and/or differentiation of keratinocytes during the progress of wound healing.
The localization of p68 helicase in human skin and wound biopsies was carried out by radioactive in situ hybridization. To that end, paraformaldehyd fixed sections of probes of interact skin and day 5-wounds were embedded into paraffin. The production of the hybridization probe was based on the in vitro transcription of a partial cDNA fragment of human p68 helicase in the presence of a-35 S-UTP. The production of the PCR-product was carried out with primers having attached thereto the promoter sequences for transcription in sense and antisense direction (T3-p68-primer: AATTAACCCTCACTAAAGGGGGCAACATTACTTCCATATTGC
(antisense primer with T3-promoter; SEQ No. 81), T7-p68-primer: TAATACGACTCACTATAGGGCGAGACAGGGAAAACTATGAC
(sense control primer with T7-promoter; SEQ No. 82).
60~Ci 35S-UTP and 5 mM ATP, GTP and CTP each, as well as either 25 U T3 or T7 RNA polymerase (Roche), 1 ~g PCR-product, 10 mM dithiothreitol, 40 U RNAse inhibitor (Roche) and 1X TB-buffer (Roche) were used for in vitro transcription.
The human tissue sections (see above) were treated with proteinase K on glass slides and acetylated subsequently. Thereafter, the sections were covered with 30 ~,1 hybridization solution and incubated for 2.5 h at 60 °C in a chamber in which humid Whatman papers soaked with 50°s formamid/4 x SSC were layered. Then the sections were incubated with 0.7 x 106 cpm radioactively labeled riboprobe in 30 ~1 hybridization solution for 16 h at 60°C. Subsequently, the sections were washed under stringent conditions, incubated with RNAseA and dehydrated with ethanol. The sections were then overlaid with photo emulsion (Kodak IBO 1433) and stored under exclusion of light and oxygen for 2-6 weeks and thereafter developed according to the manufacturers instruction by means of developer and fixative (Kodak IBO 1433).
It was shown that p68 helicase is expressed in the basal cell layer of the epithelium in intact skin, while no hybridization was detectable with the sense control riboprobe. A marked decrease in expression in the basal cell layer of the epithelium was observed in human day 5-wounds. This is an agreement with a result of the "TaqMan analysis" of human intact skin and human day 5-wounds (Example 9, Table 7) and the "TaqMan analysis" of murine tissue samples (Example 8; Table 6). Furthermore, the localization in the strongly proliferating basal cell layer of the epithelium corroborates, that the differential expression of p68 helicase plays an important role during wound healing.
The experiment further reaffirms the result of Example 8, that showed that the regulation of p68 helicase expression, preferentially the inhibition of expression was essential for wound healing.
Example 11: Verification of differential expression of polypeptides relevant to wound healing To confirm the essential function of the polypeptides, that were identified in the mouse system to be relevant to wound healing, by a further method tissue section of human intact skin and human normally healing wounds were investigated by means of immunostaining. The success of immunostaining critically depends, as already for in situ hybridization (Example 10), on the experimental conditions. In case of immunostaining, for example, the pretreatment of the tissue sections, the affinity of the antibody and the detection method are critical for the success. In spite of the variety of experimental problems expression specific to wounds could be verified for MBNL and Rab2 and CBP (Example 8) by means of immunostaining.
Localization of human MBNL was carried out with a polyclonal rabbit antibody of (Eurogenetec)directed against the peptides ArgGluPheGlnArgGlyThrCysSer-ArgProAspThrGluCys (SEQ ID No. 85; Eurogentec) and ArgGluTyrGlnArgGlyAsnCysAsnArgGlyGluAsnAspCysArg (SEQ
ID No. 86; Eurogentec). Native cryo section of intact skin and day 5-wounds of healthy patients were generated by cutting of biopsies in a refrigerated microtom at -20°C. The sections were fixed in aceton for 10 min. The incubation with the specific antiserum was carried out at room temperature in a humid chamber.
To that end the sections were incubated with 100 ~,1 diluted serum (1:200 in PBS, 1 % BSA). A peroxidase coupled anti-rabbit antibody from goat (Dianova) was used as secondary antibody, that was employed in a 1:1000 dilution (in PBS, 1% BSA). The sections were covered with 100 ~1 of the secondary antibody solution and incubated for 1 h in the humid chamber.
Subsequently, the glass slides were rinsed three times with PBS and the detection reaction was carried out. To that end the sections were incubated in staining solution for 10 minutes (freshly prepared from 10 ml AEC-solution (5 mg/ml 3-amino-9-ethylcarbazol in dimethylformamid) ; 200 ml 50 mM sodium acetat, pH 5.2;
~.l Hz02) and briefly rinsed with PBS. Counterstaining was carried out with Mayer's Hematoxylin solution (Sigma) for 5 minutes at room temperature. After 30 rinsing with tap water the sections were incubated for 1 minute in "Scott's Tab Water Substitute" (Sigma), again rinsed with tab water and mounted with Immu-Mount (Shandon).
The MBNL protein is strongly expressed in the basal cell layer of intact skin. In comparison the supra basal cell layers show significantly weaker expression. An even distribution of the protein is found throughout all cell layers of the epidermis in the hyperproliferative epithelium of a wound (at day 5 after wounding) and in the epidermis in the vicinity of the wound. A stronger concentration of the protein in the basal cell layer is not detectable in this case.
The experiment clearly shows that the expression of the MBNL gene, that is relevant for wounds is not only temporally but also spatially differentially regulated, which implies an interplay between different cell types. This example clearly shows that due to the complexity of the wound healing process that, for example, comprises a temporal and spatial change of the cell types involved, great difficulties can occur during the identification of cDNAs relevant for wounds.
This further corroborates, that the ability to identify MBNL to be relevant for wounds was surprising and that the correct design of the screen critically contributed to the identification of wound relevant genes useable according to the invention.
Immunolocalisation of both Rab2 as well as CBP in intact human skin and human day 5-wounds were carried out on native cryo sections as described above. The immunostaining reaction was based on the Vectastain Universal Elite ABC Kit (Vector Laboratories, Inc., #PK-6200). To this end the sections were covered with blocking solution (horse serum in PBS) and incubated at room temperature for 20 min in a humid chamber. After this, the solution was sucked off. Then the sections were covered with 100 ~cl of the polyclonal rabbit anti-Rab2 antibody (Santa Cruz, #sc-307; dilution: 1:200 in PBS/1% BSA) or the polyclonal rabbit anti-CBP antibody (Upstate Biotechnology, ## 06-294; dilution: 1:1500 in PBS/1% BSA). The incubation time was 30 minutes in a humid chamber. Thereafter, the glass slides were washed three times with PBS and subsequently incubated for 30 minutes with 100 ~1 secondary antibody (peroxidase coupled horse anti-abbit and anti-mouse antibody;
Vector Laboratories, Inc.; #BA-1400). The object lights were again rinsed 3 times with PBS and subsequently covered with 100 ~l Vectastain Elite ABC Reagent (Vector Laboratories, Inc.) each for 30 minutes. Then the glass slides were rinsed with PBS and the staining steps (peroxidase-substrate-staining and hematoxylin counterstaining) was carried out as described in the previous section.
Immunostaining with the anti-Rab2 antibody showed a strong induction of protein expression in human day 5-wounds in the supra basal cell layer of the hyperproliferative epithelium. This is seemingly in contradiction with the results of the "TaqMan analysis"
in the murine system, that showed a slight decrease of the amount of mRNA in day 1-wounds (Table 6). A more accurate analysis of the kinetics of the expression in murine wounds, however, showed that a steady increase of the amount of mRNA could be detected by means of "TaqMan analysis" starting at day 3 after wounding, which resulted at day 5 in a doubling and at day 7 in quadrupling of the ra~b2 mRNA relative to the amount at day 3. This again correlates with the observed increase of protein expression in human day 5-wounds. This data clearly shows, as already has been the case for the MBNL expression (see the preceding section), that the complexity of the wound healing process, in this case the complexity of the kinetics of expression, significantly impedes the identification of genes relevant to wounds. Therefore, the essential function of Rab2 could be confirmed by immunostaining.
Immunostaining with the anti-CBP-antibody showed that the "CREB binding protein" (CBP) was expressed in intact skin primarily in basal cells of the epithelium.
At day 5 after wounding significantly fewer cells that expressed this protein could be found in the hyperproliferative epithelium. This is in agreement with the observation by means of "TaqMan analysis" that the amount of CBP mRNA in wounds of 10 weeks old control animals as well as in day 1-wounds of young or old mice is significantly lesser than in intact skin (Table 6). This wound specific regulation could also be confirmed in human day 5-wounds by means of "TaqMan analysis". Therefore, it was possible again to corroborate the central function of the gene useable according to the invention in wound healing.
Example 12: Analysis of differential protein expression of p68 helicase in intact skin, in normally healing wounds and in ulcer of man by means of immunostaininq.
It was possible to show that the mRNA of the p68 helicase is differentially regulated in wound healing both in man as well as in mouse (Example 8 and 9).
Thereby it could be proven that p68 helicase is essential for wound healing (Example 8). A further experiment that serves to substantiate the importance of p68 helicase is the immunolocalization of p68 helicase in punch biopsies of intact human skin, of human day 5-wounds of healthy patients and punch biopsies of human venous skin ulcers (Ulcera cruris venosum) .
This was carried out with a polyclonal rabbit antibody (Eurogenetec), that was directed against the peptide CysAspGluLeuThrArgLysMetArgArgAspGlyTrpProAla (SEQ ID No. 87; Eurogentec) and AsnThrPheArg-AspArgGluAsnTyrAspArgGlyTyrSerSerCys (SEQ ID No. 88;
Eurogentec). The native cryo sections of the tissue samples were generated by cutting the biopsies in a refrigerated microtom at -20°C. Subsequently, the sections were fixed with aceton. The incubation with the specific antiserum was carried out at room temperature in a humid chamber for 1 hour. To that end the sections were incubated with 100 ~,l diluted serum (1:200 in PBS, 1% BSA). A peroxidase coupled anti-rabbit antibody from goat (Dianova) that was employed in a 1:1000 dilution (in PBS, 1% BSA) was used as secondary antibody. The section were covered with 100 ~l of the secondary antibody solution and incubated in the humid chamber for 1 hour. Afterwards the glass slides were washed three times with PBS and the detection reaction was carried out. To this end the sections were incubated for 10 minutes in staining solution (freshly prepared from 10 ml AEC-solution (5 mg/ml 3-amino-9-ethylcarbazol in dimethylformaned); 200 ml 50 mM sodium acetat, pH 5.2; 30 ml H202) and briefly washed with PBS. Counterstaining was carried out with Mat'er's hematoxylin solution (Sigma) for 5 minutes at room temperature. After rinsing with tap water the sections were incubated for one minute in "Scott's tap water substitute" (Sigma), again rinsed with tap water and mounted with Immu-mount (Shandon).
The evaluation of the immunostaining showed that p68 helicase is stronger expressed in the basal keratinocytes than in the suprabasal cell layers in intact skin. On the other hand the protein is markedly less strong expressed in normally healing day 5-wounds in the area of the edge of the wound, whereby a spatial protein gradient is generated. However, in ulcer with delayed wound healing this gradient formation and decrease of expression towards the edge of the wound does not take place. This confirms that p68 helicase is differentially expressed during the progress of wound healing and that the exact regulation is essential for normally progressing wound healing. Therefore, it could _ 77 _ be exemplary confirmed that the misregulation of p68 helicase, that is relevant to wounds, leads to wound healing disorders in man and that p68 helicase is suitable as a therapeutic target: wound healing disorders can be treated by the modulation, preferentially by the inhibition of p68 helicase activity.
Example 13: Detection of the relevance for wound healing of MRP-8 by means of in vivo ap lication of the gene to rabbit wounds To verify that MRP-8 plays an essential role for the process of normally progressing wound healing the influence of MRP-8 on wound healing was studied in male white New Zealand rabbits in vivo. Wound healing was determined based on the amount of collagen in granulation tissue, wherein a decreased amount of collagen in relation to a normal healing wound indicates an impaired wound healing. Towards this end an expression plasmid pMHintMRP8 was generated that contained the coding sequence of MRP-8. Initially a suitable expression vector pMHint was generated starting from pMH (Roche) by introducing Intron II of the insulin gene from rat between the CMV promoter and the multiple cloning site using the HindIII restriction site. Then using the multiple cloning site the MRP-8 cDNA was cloned into pMHint. For this the coding region of MRP-8 cDNA was amplified by means of PCR (MRP8-primer 1. GAG AGA GGT ACC ATG CCG TCT GAA CTG GAG (SEQ
3 0 ID No . 12 7 ) and MRP8 primer 2 : GAG AGA GAC ACG TGC TAC
TCC TTG TGG CTG TCT TTG (SEQ ID No. 128)), afterwards cut with KpnI and PnlI ligated with the expression vector pMHint that had been cut with KpnI and PnlI and thereby obtaining the expression plasmid pMHintMRP8.

_ 78 _ For the analysis of the influence of MRP-8 on wound healing two rabbits were used, that were anesthetized with xylazin and ketamin (13 or 87 mg/kg i.m.) and treated with a depilatory. Afterwards an adrenalin solution (2 % xylocain and adrenalin, 1:
100000, ASTRA) was injected intradermally to achieve vasoconstriction and to separate the skin from the ear cartilage underneath. Four 8 mm large wounds were placed at the inner side of the ear by means of punching. Each wound was bombarded by means of the Helios Gene Gun (BIORAD) either with pMHintMRP8 or as a control with pMHint, in which the luciferase gene had been cloned, at a pressure of 500 psi, wherein 0.5 ~g expression plasmid, that had been immobilized on gold particles (BIORAD) were employed per shot. Subsequently the wounds were covered with semi-occlusive bandage. At day 10 after wounding the animals were sacrificed, wound biopsies were removed and granulation tissue was analyzed. The tissue was homogenized in 1 N NH40H and examined for the amount of collagen by means of HPLC. A
total collagen content of 195 mg/g tissue was measured in the control, while in tissue, that had been bombarded with pMHintMRP8, a 74% lower amount of collagen was determined. This clearly shows that an increased amount of MRP-8 in wound tissue leads to an impaired wound healing, if the amount of the binding partner MRP-14 is not effected. This shows, that the MRPS homodimer has a negative effect on wound healing.
Since conditions, which inhibit the formation of a homodimer, positively influence the wound healing process, the expression and/or acitivity of MRP-8 has to be modulated, preferentially to be inhibited: e.g.
the formation of MRP8 homodimers can be inhibited by the use of MRP-8-antisense-oligonucleotides. Also, the use of an anti-MRP-8 antibody or of a functional interactor for the sequestration of the MRP-8 monomers _ 79 _ would have this effect. In addition, the MRP-8/MRP-14 heterodimer can be used as a therapeutically active substance, which would result in an increase in amount of heterodimer relative to the amount of the homodimer which has a negative effect on the wound healing process. The administration can be carried out e.g.
through recombinantly produced proteins or through gene therapeutic expression plasmids.

SEQUENCE LISTING
<110> Switch Biotech AG
<120> Use of polypeptides or nucleic acids encoding these for the diagnosis or treatment of skin disorders, and their use for the identification of pharmacologically active substances <130> 529829CA
<140>
<141>
<150> DE 199 55 349.1 <151> 1999-11-17 <150> US 60/172,511 <151> 1999-12-17 <150> DE 100 30 149.5 <151> 2000-06-20 <160> 128 <170> PatentIn Ver. 2.1 <210> 1 <211> 388 <212> PRT
<213> Homo sapiens <400> 1 Met Ala Val Ser Val Thr Pro Ile Arg Asp Thr Lys Trp Leu Thr Leu Glu Val Cys Arg Glu Phe Gln Arg Gly Thr Cys Ser Arg Pro Asp Thr Glu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gln Val Glu Asn Gly Arg Val Ile Ala Cys Phe Asp Ser Leu Lys Gly Arg Cys Ser Arg Glu Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gln Leu Glu Ile Asn Gly Arg Asn Asn Leu Ile Gln Gln Lys Asn Met Ala Met Leu Ala Gln Gln Met Gln Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu Gln Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Asn Ala Ser Ala Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu Val Pro Ala Glu Ile Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn Pro Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gln Lys Leu Met Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gln Arg Gly Asn Cys Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser Thr Met Ile Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr Ile Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro Ala His Leu Gln Ala Lys Ile Lys Ala Ala Gln Tyr Gln Val Asn Gln Ala Ala Ala Ala Gln Ala Ala Ala Thr Ala Ala Ala Met Thr Gln Ser Ala Val Lys Ser Leu Lys Arg Pro Leu Glu Ala Thr Phe Asp Leu Gly Ile Pro Gln Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu Lys Thr Asn Gly Ala Thr Ala Val Phe Asn Thr Gly Ile Phe Gln Tyr Gln Gln Ala Leu Ala Asn Met Gln Leu Gln Gln His Thr Ala Phe Leu Pro Pro Val Pro Met Val His Gly Ala Thr Pro Ala Thr Val Ser Ala Ala Thr Thr Ser Ala Thr Ser Val Pro Phe Ala Ala Thr Ala Thr Ala Asn Gln Ile Pro Ile Ile Ser Ala Glu His Leu Thr Ser His Lys Tyr Val Thr Gln Met <210>2 <211>521 <212>PRT

<213>Mus musculus <400> 2 Asp Thr Gly Leu Trp Leu His Asn Lys Leu Gly Ala Thr Asp Glu Leu Trp Ala Pro Pro Ser Ile Ala Ser Leu Leu Thr Ala Ala Val Ile Asp Asn Ile Arg Leu Cys Phe His Arg Leu Ser Ser Ala Val Lys Leu Lys Leu Leu Leu Gly Thr Leu His Leu Pro Arg Arg Thr Val Asp Glu Met Asn Ala Ala Leu Met Asp Ile Ile Gln Leu Ala Thr Leu Asp Ser Asp Pro Trp Val Leu Met Val Ala Asp Ile Leu Lys Ser Phe Pro Asp Thr Gly Ser Leu Asn Leu Asp Leu Glu Glu Gln Asn Pro Asn Val Gln Glu Ile Leu Gly Glu Leu Arg Glu Lys Val Ser Glu Cys Glu Ala Ser Ala Met Leu Pro Leu Glu Cys Gln Tyr Leu Asn Lys Asn Ala Leu Thr Thr Leu Ala Gly Pro Leu Thr Pro Pro Val Lys His Phe Gln Leu Lys Arg Gln Gln Ala Leu Ala Asn Met Gln Lys Pro Lys Ser Ala Thr Leu Arg Ala Glu Leu Leu Gln Ile Ser Thr Glu Thr Ala Gln Gln Leu Lys Arg Ser Ala Gly Val Pro Phe His Ala Lys Gly Arg Gly Leu Leu Arg Lys Met Asp Thr Thr Thr Pro Leu Lys Gly Ile Pro Lys Gln Ala Pro Phe Arg Ser Pro Thr Thr Pro Ser Val Phe Ser Pro Ser Gly Asn Arg Thr Pro Ile Pro Pro Ser Arg Thr Pro Leu Gln Lys Glu Arg Gly Val Lys Leu Leu Asp Ile Ser Glu Leu Asn Thr Val Gly Ala Gly Arg Glu Ala Lys Arg Arg Arg Lys Thr Leu Asp Thr Glu Val Val Glu Lys Pro Thr Lys Glu Glu Thr Val Val Glu Asn Ala Thr Pro Asp Tyr Ala Ala Gly Leu Val Ser Thr Gln Lys Leu Gly Ser Leu Asn Ser Glu Pro Thr Leu Pro Ser Thr Ser Tyr Leu Pro Ser Thr Pro Ser Val Val Pro Ala Ser Ser Tyr Ile Pro Ser Ser Glu Thr Pro Pro Ala Thr Pro Ser Arg Glu Ala Ser Arg Pro Pro Glu Glu Pro Ser Ala Pro Ser Pro Thr Leu Pro Thr Gln Phe Lys Gln Arg Ala Pro Met Tyr Asn Ser Gly Val Ser Pro Ala Thr Pro Ala Ala Pro Thr Ser Pro Arg Thr His Thr Thr Pro Pro Ala Val Thr Pro Thr Ala Gln Thr Pro Pro Val Ala Met Val Ala Pro Gln Thr Gln Ala Pro Ala Pro Val Gln Gln Gln Pro Lys Lys Asn Leu Ser Phe Thr Arg Glu Gln Met Phe Ala Ala Gln Glu Met Phe Lys Thr Ala Asn Lys Val Thr Arg Pro Glu Lys Ala Leu Ile Leu Gly Phe Met Ala Gly Ser Arg Glu Asn Pro Cys ProGlu GlnGlyAsp ValIleGln IleLysLeu Ser Glu Thr Glu 465 470 475 His AspLeu ProLysAla AspGlyGln GlySerThr Thr Met Val Asp Leu ThrVal PheGluMet AsnTyrAla ThrGlyGln Trp Thr Phe Lys Arg LysTyr LysProMet ThrAsnVal Ser <210> 3 <211> 525 <212> PRT
<213> Homo Sapiens <300>
<301> Wright, T. J.
<302> Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region <303> Genomics <304> 1999 <305> 59 <306> 203-212 <308> PIR 63860187 <309> 1998-10-26 <313> 1 TO 525 <400> 3 Met Arg Glu Ser Asp Thr Gly Leu Trp Leu His Asn Lys Leu Gly Ala Thr Asp Glu Leu Trp Ala Pro Pro Ser Ile Ala Ser Leu Leu Thr Ala Ala Val Ile Asp Asn Ile Arg Leu Cys Phe His Gly Leu Ser Ser Ala ValLysLeu LysLeuLeu LeuGly ThrLeuHisLeu ProArgArgThr ValAspGlu MetLysGly AlaLeu MetGluIleIle GlnLeuAlaSer LeuAspSer AspProTrp ValLeu MetValAlaAsp IleLeuLysSer PheProAsp ThrGlySer LeuAsn LeuGluLeuGlu Gl l u G AsnPro n AsnValGln IleLeu GlyGlu LeuArgGluLys ValGlyGluCys Asp Glu Ala Ser Ala Met Leu Pro Leu Glu Cys Gln Tyr Leu Asn Lys Asn Ala Leu Thr Thr Leu Ala Gly Pro Leu Thr Pro Pro Val Lys His Phe Gln Leu Lys Arg Lys Pro Lys Ser Ala Thr Leu Arg Ala Glu Leu Leu Gln Lys Ser Thr Glu Thr Ala Gln Gln Leu Lys Arg Ser Ala Gly Val Pro Phe His Ala Lys Gly Arg Gly Leu Leu Arg Lys Met Asp Thr Thr Thr Pro Leu Lys Gly Ile Pro Lys Gln Ala Pro Phe Arg Ser Pro Thr Ala Pro Ser Val Phe Ser Pro Thr Gly Asn Arg Thr Pro Ile Pro Pro Ser Arg Thr Leu Leu Arg Lys Glu Arg Gly Val Lys Leu Leu Asp Ile Ser Glu Leu Asp Met Val Gly Ala Gly Arg Glu Ala Lys Arg Arg Arg Lys Thr Leu Asp Ala Glu Val Val Glu Lys Pro Ala Lys Glu Glu Thr Val Val Glu Asn Ala Thr Pro Asp Tyr Ala Ala Gly Leu Val Ser Thr Gln Lys Leu Gly Ser Leu Asn Asn Glu Pro Ala Leu Pro Ser Thr Ser Tyr Leu Pro Ser Thr Pro Ser Val Val Pro Ala Ser Ser Tyr Ile Pro Ser Ser Glu Thr Pro Pro Ala Pro Ser Ser Arg Glu Ala Ser Arg Pro Pro Glu Glu Pro Ser Ala Pro Ser Pro Thr Leu Pro Ala Gln Phe Lys Gln Arg Ala Pro Met Tyr Asn Ser Gly Leu Ser Pro Ala Thr Pro Thr Pro Ala Ala Pro Thr Ser Pro Leu Thr Pro Thr Thr Pro Pro Ala Val Ala Pro Thr Thr Gln Thr Pro Pro Val Ala Met Val Ala Pro Gln Thr Gln Ala Pro Ala Gln Gln Gln Pro Lys Lys Asn Leu Ser Leu Thr Arg Glu Gln Met Phe Ala Ala Gln Glu Met Phe Lys Thr Ala Asn Lys Val Thr Arg Pro Glu Lys Ala Leu Ile Leu Gly Phe Met Ala Gly Ser Arg Glu Asn Pro Cys Gln Glu Gln Gly Asp Val Ile Gln Ile Lys Leu Ser Glu His Thr Glu Asp Leu Pro Lys Ala Asp Gly Gln Gly Ser Thr Thr Met Leu Val Asp Thr Val Phe Glu Met Asn Tyr Ala Thr Gly Gln Trp Thr Arg Phe Lys Lys Tyr Lys Pro Met Thr Asn Val Ser <210> 4 <211> 495 <212> PRT
<213> Homo sapiens <400> 4 Met Lys Lys Arg Lys Glu Leu Asn Ala Leu Ile Gly Leu Ala Gly Asp Ser Arg Arg Lys Lys Pro Lys Lys Gly Pro Ser Ser His Arg Leu Leu Arg Thr Glu Pro Pro Asp Ser Asp Ser Glu Ser Ser Ser Glu Glu Glu Glu Glu Phe Gly Val Val Gly Asn Arg Ser Arg Phe Ala Lys Gly Asp Tyr Leu Arg Cys Cys Lys Ile Cys Tyr Pro Leu Cys Gly Phe Val Ile Leu Ala Ala Cys Val Val Ala Cys Val Gly Leu Val Trp Met Gln Val Ala Leu Lys Glu Asp Leu Asp Ala Leu Lys Glu Lys Phe Arg Thr Met Glu Ser Asn Gln Lys Ser Ser Phe Gln Glu Ile Pro Lys Leu Asn Glu Glu Leu Leu Ser Lys Gln Lys Gln Leu Glu Lys Ile Glu Ser Gly Glu Met Gly Leu Asn Lys Val Trp Ile Asn Ile Thr Glu Met Asn Lys Gln Ile Ser Leu Leu Thr Ser Ala Val Asn His Leu Lys Ala Asn Val Lys Ser Ala Ala Asp Leu Ile Ser Leu Pro Thr Thr Val Glu Gly Leu Gln Lys Ser Val Ala Ser Ile Gly Asn Thr Leu Asn Ser Val His Leu Ala Val Glu Ala Leu Gln Lys Thr Val Asp Glu His Lys Lys Thr Met Glu Leu Leu Gln Ser Asp Met Asn Gln His Phe Leu Lys Glu Thr Pro Gly Ser Asn Gln Ile Ile Pro Ser Pro Ser Ala Thr Ser Glu Leu Asp Asn Lys Thr His Ser Glu Asn Leu Lys Gln Asp Ile Leu Tyr Leu His Asn Ser Leu Glu Glu Val Asn Ser Ala Leu Val Gly Tyr Gln Arg Gln Asn Asp Leu Lys Leu Glu Gly Met Asn Glu Thr Val Ser Asn Leu Thr Gln Arg Val Asn Leu Ile Glu Ser Asp Val Val Ala Met Ser Lys Val Glu Lys Lys Ala Asn Leu Ser Phe Ser Met Met Gly Asp Arg Ser Ala Thr Leu Lys Arg Gln Ser Leu Asp Gln Val Thr Asn Arg Thr Asp Thr Val Lys Ile Gln Ser Ile Lys Lys Glu Asp Ser Ser Asn Ser Gln Val Ser Lys Leu Arg Glu Lys Leu Gln Leu Ile Ser Ala Leu Thr Asn Lys Pro Glu Ser Asn Arg Pro Pro Glu Thr Ala Asp Glu Glu Gln Val Glu Ser Phe Thr Ser Lys Pro Ser Ala Leu Pro Lys Phe Ser Gln Phe Leu Gly Asp Pro Val Glu Lys Ala Ala Gln Leu Arg Pro Ile Ser Leu Pro Gly Val Ser Ser Thr Glu Asp Leu Gln Asp Leu Phe Arg Lys Thr Gly Gln Asp Val Asp Gly Lys Leu Thr Tyr Gln Glu Ile Trp Thr Ser Leu Gly Ser Ala Met Pro Glu Pro Glu Ser Leu Arg Ala Phe Asp Ser Asp Gly Asp Gly Arg Tyr Ser Phe Leu Glu Leu Arg Val Ala Leu Gly Ile <210> 5 <211> 416 <212> PRT
<213> Homo sapiens <400> 5 Arg Arg Met Asn His Lys Ser Lys Lys Arg Ile Arg Glu Ala Lys Arg Ser Ala Arg Pro Glu Leu Lys Asp Ser Leu Asp Trp Thr Arg His Asn Tyr Tyr Glu Ser Phe Ser Leu Ser Pro Ala Ala Val Ala Asp Asn Val Glu Arg Ala Asp Ala Leu Gln Leu Ser Val Glu Glu Phe Val Glu Arg Tyr Glu Arg Pro Tyr Lys Pro Val Val Leu Leu Asn Ala Gln Glu Gly Trp Ser Ala Gln Glu Lys Trp Thr Leu Glu Arg Leu Lys Arg Lys Tyr Arg Asn Gln Lys Phe Lys Cys Gly Glu Asp Asn Asp Gly Tyr Ser Val Lys Met Lys Met Lys Tyr Tyr Ile Glu Tyr Met Glu Ser Thr Arg Asp Asp Ser Pro Leu Tyr Ile Phe Asp Ser Ser Tyr Gly Glu His Pro Lys Arg Arg Lys Leu Leu Glu Asp Tyr Lys Val Pro Lys Phe Phe Thr Asp Asp Leu Phe Gln Tyr Ala Gly Glu Lys Arg Arg Pro Pro Tyr Arg Trp Phe Val Met Gly Pro Pro Arg Ser Gly Thr Gly Ile His Ile Asp Pro Leu Gly Thr Ser Ala Trp Asn Ala Leu Val Gln Gly His Lys Arg Trp Cys Leu Phe Pro Thr Ser Thr Pro Arg Glu Leu Ile Lys Val Thr Arg Asp Glu Gly Gly Asn Gln Gln Asp Glu Ala Ile Thr Trp Phe Asn Val Ile Tyr Pro Arg Thr Gln Leu Pro Thr Trp Pro Pro Glu Phe Lys Pro Leu Glu Ile Leu Gln Lys Pro Gly Glu Thr Val Phe Val Pro Gly Gly Trp Trp His Val Val Leu Asn Leu Asp Thr Thr Ile Ala Ile Thr Gln Asn Phe Ala Ser Ser Thr Asn Phe Pro Val Val Trp His Lys Thr Val Arg Gly Arg Pro Lys Leu Ser Arg Lys Trp Tyr Arg Ile Leu Lys Gln Glu His Pro Glu Leu Ala Val Leu Ala Asp Ser Val Asp Leu Gln Glu Ser Thr Gly Ile Ala Ser Asp Ser Ser Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Asp Ser Asp Ser Glu Cys Glu Ser Gly Ser Glu Gly Asp Gly Thr Val His Arg Arg Lys Lys Arg Arg Thr Cys Ser Met Val Gly Asn Gly Asp Thr Thr Ser Gln Asp Asp Cys Val Ser Lys Glu Arg Ser Ser Ser Arg Ile Arg Asp Thr Cys Gly Gly Arg Ala His Pro <210> 6 <211> 419 <212> PRT
<213> Homo sapiens <300>

<301> Zhang, Q.
<302> Human HSPC028 gene, complete cds <400> 6 Met Asn Lys His Gln Lys Pro Val Leu Thr Gly Gln Arg Phe Lys Thr Arg Lys Arg Asp Glu Lys Glu Lys Phe Glu Pro Thr Val Phe Arg Asp Thr Leu Val Gln Gly Leu Asn Glu Ala Gly Asp Asp Leu Glu Ala Val Ala Lys Phe Leu Asp Ser Thr Gly Ser Arg Leu Asp Tyr Arg Arg Tyr Ala Asp Thr Leu Phe Asp Ile Leu Val Ala Gly Ser Met Leu Ala Pro Gly Gly Thr Arg Ile Asp Asp Gly Asp Lys Thr Lys Met Thr Asn His Cys Val Phe Ser Ala Asn Glu Asp His Glu Thr Ile Arg Asn Tyr Ala Gln Val Phe Asn Lys Leu Ile Arg Arg Tyr Lys Tyr Leu Glu Lys Ala Phe Glu Asp Glu Met Lys Lys Leu Leu Leu Phe Leu Lys Ala Phe Ser Glu Thr Glu Gln Thr Lys Leu Ala Met Leu Ser Gly Ile Leu Leu Gly Asn Gly Thr Leu Pro Ala Thr Ile Leu Thr Ser Leu Phe Thr Asp Ser Leu Val Lys Glu Gly Ile Ala Ala Ser Phe Ala Val Lys Leu Phe Lys Ala Trp Met Ala Glu Lys Asp Ala Asn Ser Val Thr Ser Ser Leu Arg Lys Ala Asn Leu Asp Lys Arg Leu Leu Glu Leu Phe Pro Val Asn Arg Gln Ser Val Asp His Phe Ala Lys Tyr Phe Thr Asp Ala Gly Leu Lys Glu Leu Ser Asp Phe Leu Arg Val Gln Gln Ser Leu Gly Thr Arg Lys Glu Leu Gln Lys Glu Leu Gln Glu Arg Leu Ser Gln Glu Cys Pro Ile Lys Glu Val Val Leu Tyr Val Lys Glu Glu Met Lys Arg Asn Asp Leu Pro Glu Thr Ala Val Ile Gly Leu Leu Trp Thr Cys Ile Met Asn Ala Val Glu Trp Asn Lys Lys Glu Glu Leu Val Ala Glu Gln Ala Leu Lys His Leu Lys Gln Tyr Ala Pro Leu Leu Ala Val Phe Ser Ser Gln Gly Gln Ser Glu Leu Ile Leu Leu Gln Lys Val Gln Glu Tyr Cys Tyr Asp Asn Ile His Phe Met Lys Ala Phe Gln Lys Ile Val Val Leu Phe Tyr Lys Ala Asp Val Leu Ser Glu Glu Ala Ile Leu Lys Trp Tyr Lys Glu Ala His Val Ala Lys Gly Lys Ser Val Phe Leu Asp Gln Met Lys Lys Phe Val Glu Trp Leu Gln Asn Ala Glu Glu Glu Ser Glu Ser Glu Gly Glu Glu Asn <210> 7 <211> 1630 <212> PRT
<213> Homo Sapiens <400> 7 Lys Thr Phe Gly Leu His Gly Val Val Leu Asp Val Asp Ser Val Asn Glu Leu Val Gln Val Glu Thr Tyr Leu Arg Ser Glu Gly Val Leu Val Arg Tyr Trp Tyr Pro Ile Asp Met Leu Glu Arg Pro Pro Ala Gly Tyr Arg Arg Thr Ala Thr Asn Gly Leu Val Thr Leu Asp Asn Thr Asn Leu Gln Ile His Arg Glu Leu Leu Arg Cys Glu Ala Ala Leu Ala Arg Leu Tyr Cys Arg Met Ala Leu Leu Asn Ile Phe Ala Pro Lys Leu Pro His Leu Phe Thr Arg Leu Phe His Ile Pro Ala Ile Arg Asp Ile Thr Leu Glu His Leu Gln Leu Leu Ser Asn Gln Leu Leu Ala Pro Pro Leu Pro Asp Gly Thr Ile Ser Ser Ser Ser Ile Leu Leu Ala Gln Ser Leu Gln His Cys Ile His Ser Gln Asn Cys Ser Ala Thr Asp Leu Phe Tyr Gln Gly Asn Ser Gln Thr Val Arg Glu Trp Leu Asn Val Ala Ile Thr Arg Thr Leu His Gln Gly Glu Glu Ser Leu Leu Glu Leu Thr Lys Gln Ile Cys Ser Phe Leu Gln Thr Ala Pro Glu Gln Phe Pro Ser Glu Glu Phe Pro Ile Ser Glu Ser Lys Val Asn Met Asp Val Asn Phe Pro Gly Ala Ala Phe Val Val Val Ser Cys Lys Glu Ser Gln Ser Gly Phe Arg Lys Asp Ser Ser Leu Tyr Lys Ala Pro Trp Ala Arg Val Leu Val Tyr Gly Leu Gly His Lys Val Lys Arg Asn Gly Gln Leu Asn Leu Ile Glu Ala Ala Cys Tyr Pro Arg Asp Ala Ser Pro Ala Asn Thr Gly Leu Ala Pro Pro Pro Thr Ala Asp Gln Tyr Pro Ser Val Val Leu Ser Thr Asp Arg Val His Ile Lys Leu Gly Val Ser Pro Pro Pro Gly Ala Val Leu Val Leu His Ser Leu Pro Leu Glu Phe Pro Leu Ala Met Ala Phe Ala Glu Gln Leu Leu Ser Trp Lys Ser Glu Asp Ser Glu Gly Lys Ser Glu Asp Glu Pro Asp Thr Ile Pro Thr Ser Val Leu Leu Gln Val Val Glu Leu Leu Gly Asn Phe Leu Trp Thr Thr Asp Met Ala Ala Cys Val Lys Glu Leu Val Phe His Leu Leu Ala Glu Leu Leu Arg Thr Val His Thr Leu Glu Gln Arg Arg His Pro Ala Gly Leu Ser Ser Ser Ile Ala Leu Gln Leu Asn Pro Cys Leu Ala Met Leu Met Ala Leu Gln Ser Glu Leu His Lys Leu Tyr Asp Glu Glu Thr Gln Asn Trp Val Ser Gly Gly Ala Cys Gly Gly Ser Gly Gly Ala Ala Ala Gly Asp Gln Gly Arg Phe Ser Thr Tyr Phe His Ala Leu Met Glu Gly Cys Leu Ala Val Ala Glu Val Thr Leu Pro Thr Asn Met Ser Val Thr Ala Ser Gly Val Thr Ser Ala Thr Ala Pro Asn Leu Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Pro Gly Gln Thr Pro Gln Ser Pro Ser Leu Leu Ser Lys Arg Lys Lys Val Lys Met Lys Arg Glu Lys Ala Ser Ser Ser Gly Lys Arg Gln Ser Ser Arg Thr Val Asp Ser Asp Pro Thr Val Leu Ser Ile Gly Gly Ser Lys Pro Glu Asp Met Leu Trp Phe His Arg Ala Leu Thr Leu Leu Ile Ile Leu Arg His Leu Thr Arg Lys Asp Pro Gln Gly Leu Gly Val Thr Ser Asp Ala Ile Ala Asp Ala Cys Gln Ala Leu Val Gly Pro Thr Ala His Ser Arg Leu Leu Val Ile Ser Gly Ile Pro Thr His Leu Asp Glu Gly Val Val Arg Gly Ala Ile Arg Lys Ala Cys Asn Ala His Gly Gly Val Phe Lys Asp Glu Ile Tyr Ile Pro Leu Gln Glu Glu Asp Thr Lys Lys Pro Lys Asp Lys Ala Glu Gly Gly Asp Gly Lys Val Glu Pro Glu Lys Thr Leu Ala Phe Pro Gly Thr Asp Ser Met Glu Val Ser Thr Ser Ser Ser Leu Thr Pro Ala Met Ser Ile Ser Ala Ser Ala Ser Thr Ser Gln Ala Ser Ile Cys Ser Ser Gln Gly Ile Ser Gln Thr Val Ser Asp Leu Ser Val Asp Pro Leu Pro Ala Gly Leu Glu Leu Pro Ile Pro Pro Gly Leu Leu Glu Pro His Ala Val Ser Ser Gln Glu Ser Leu Asp Ile Ser Leu Cys Ser Thr Gly Ser Leu Gly Ser Leu Gly Ser Leu Gly Glu Pro Leu Asp Asn Ala Glu Thr Ala Ser Val Ser Asp Met Gly Ser Met Tyr Thr Val Thr Ser Leu Asp Asn Gln Pro Leu Ala Ala Arg Pro Ile Lys Gly Phe Ala Val Val Glu Ile Arg Ser Arg Ala Lys Ile Glu Lys Ile Arg Ala Ser Leu Phe Asn Asn Asn Asp Leu Ile Gly Leu Ser Ser Leu Asp Gly Glu Asp Glu Leu Met Glu Met Ser Thr Glu Glu Ile Leu Thr Val Ser Val Val Asn Gln Ser Leu Phe Asp Thr Gln Gly Ser Pro Gly Leu Glu Asp Tyr Phe Asn Asp Lys Ser Ile Lys Gly Glu Lys Leu Val Pro Gly Ala Arg Glu Val Leu Thr Glu Ile Phe Lys Ser Cys Ala His Ser Glu Gln Thr Leu Ser Leu Thr Pro Ala Lys Pro Ile Arg Val Ser Asp Ile Tyr Leu Ser Lys Glu Gln Ile Asn Ser Gln Thr Pro Gly Asn Leu Leu His Leu Phe Phe Thr Asn Val Arg Pro Pro Lys Lys Val Leu Glu Asp Gln Leu Thr Gln Ile Leu Arg Lys Tyr Gly Val Pro Lys Pro Lys Phe Asp Lys Ser Lys Tyr Ser Lys Ala Gly Lys Glu Gln His Pro Val Lys Val Val Ser Thr Lys Arg Pro Ile Thr Lys Pro Pro Ala Lys Asp Lys Ala Val Leu Asn Ser Val Ser Arg Thr Ala Leu Ser Glu Lys Lys Pro Thr Val Lys Pro Lys Ser Pro Glu Lys Ser Lys Pro Asp Glu Lys Asp Pro Glu Lys Ser Pro Thr Lys Lys Gln Glu Val Pro Glu Glu Lys Tyr Leu Thr Leu Glu Gly Phe His Lys Phe Val Ile Asp Arg Ala Arg Gln Asp Ile Arg Ser Val Trp Arg Ala Ile Leu Ser Cys Gly Tyr Asp Leu His Phe Glu Arg Cys Ala Cys Ile Asp Val Arg His Ala Gln Lys Ala Ser Arg Lys Trp Thr Leu Glu Met Asp Val Ala Leu Val Gln Tyr Ile Asn Gln Leu Cys Arg His Leu Ala Ile Thr Pro Ala Arg Leu His Pro His Glu Val Tyr Leu Asp Pro Ala Asp Ala Ala Asp Pro Arg Val Ala Cys Leu Leu Asn Val Pro Ile Glu Ser Leu Arg Leu Arg Phe Ala Leu Leu Gln Ser Leu Asn Thr Thr Leu Glu Thr Phe Phe Leu Pro Leu Val Glu Leu Arg Gln Thr Pro Met Tyr Thr His Ser Ile Ala Ala Leu Leu Lys Glu Ala Lys Gly Leu Ile Phe Tyr Asp Thr Lys Val Thr Val Met Asn Arg Val Leu Asn Ala Thr Val Gln Arg Thr Ala Asp His Ala Ala Pro Glu Ile Thr Leu Asp Pro Leu Glu Ile Val Gly Gly Glu Ile Arg Ala Ser Glu Asn Ser Tyr Phe Cys Gln Ala Ala Arg Gln Leu Ala Ser Val Pro Ser Ser Gln Leu Cys Val Lys Leu Ala Ser Gly Gly Asp Pro Thr Tyr Ala Phe Asn Ile Arg Phe Thr Gly Glu Glu Val His Gly Thr Ser Gly Ser Phe Arg His Phe Leu Trp Gln Val Cys Lys Glu Leu Gln Ser Ser Ser Leu Ser Leu Leu Leu Leu Cys Pro Ser Ser Ala Val Asn Lys Asn Lys Gly Lys Tyr Ile Leu Thr Pro Ser Pro Ile Thr Tyr Gly Glu Glu Gln Leu Leu His Phe Leu Gly Gln Leu Leu Gly Ile Ala Ile Arg Ala Asp Val Pro Leu Pro Leu Asp Leu Leu Pro Ser Phe Trp Lys Thr Leu Val Gly Glu Pro Leu Asp Pro Glu Gln Asp Leu Gln Glu Ala Asp Ile Leu Thr Tyr Asn Tyr Val Lys Lys Phe Glu Ser Ile Asn Asp Glu Thr Glu Leu Glu Ala Leu Cys Ala Glu Ile Ala Ser Gln His Leu Ala Thr Glu Ser Pro Asp Ser Pro Asn Lys Pro Cys Cys Arg Phe Thr Tyr Leu Thr Met Thr Gly Glu Glu Val Glu Leu Cys Ser Arg Gly Arg His Ile Leu Val Ala Trp Glu Asn Lys Asp Ile Tyr Ala Ala Ala Ile Arg Ser Leu Arg Leu Arg Glu Leu Gln Asn Val Glu Cys Val Thr Ala Val Arg Ala Gly Leu Gly Ser Ile Ile Pro Leu Gln Leu Leu Thr Met Leu Ser Pro Leu Glu Met Glu Leu Arg Thr Cys Gly Leu Pro Tyr Ile Asn Leu Glu Phe Leu Lys Ala His Thr Met Tyr Gln Val Gly Leu Met Glu Thr Asp Gln His Ile Glu Phe Phe Trp Gly Ala Leu Glu Met Phe Thr Gln Glu Glu Leu Cys Lys Phe Ile Lys Phe Ala Cys Asn Gln Glu Arg Ile Pro Phe Thr Cys Pro Cys Lys Asp Gly Gly Pro Asp Thr Ala His Val Pro Pro Tyr Pro Met Lys Ile Ala Pro Pro Asp Gly Thr Ala Gly Ser Pro Asp Ser Arg Tyr Ile Arg Val Glu Thr Cys Met Phe Met Ile Lys Leu Pro Gln Tyr Ser Ser Leu Glu Ile Met Leu Glu Lys Leu Arg Cys Ala Ile His Tyr Arg Glu Asp Pro Leu Ser Gly <210> 8 <211> 1050 <212> PRT
<213> Homo sapiens <400> 8 Trp Arg Arg Ala Ala Cys Gly Arg Ser Gly Arg Ala Ser Leu Lys Glu His Pro Arg Gly Thr Leu Leu Ser Asp Gly Ser Pro Ala Leu Ser Arg Asn Val Gly Met Thr Val Ser Gln Lys Gly Gly Pro Gln Pro Thr Pro Ser Pro Ala Gly Pro Gly Thr Gln Leu Gly Pro Ile Thr Gly Glu Met Asp Glu Ala Asp Ser Ala Phe Leu Lys Phe Lys Gln Thr Ala Asp Asp Ser Leu Ser Leu Thr Ser Pro Asn Thr Glu Ser Ile Phe Val Glu Asp Pro Tyr Thr Ala Ser Leu Arg Ser Glu Ile Glu Ser Asp Gly His Glu Phe Glu Ala Glu Ser Trp Ser Leu Ala Val Asp Ala Ala Tyr Ala Lys Lys Gln Lys Arg Glu Val Val Lys Arg Gln Asp Val Leu Tyr Glu Leu Met Gln Thr Glu Val His His Val Arg Thr Leu Lys Ile Met Leu Lys Val Tyr Ser Arg Ala Leu Gln Glu Glu Leu Gln Phe Ser Ser Lys Ala Ile Gly Arg Leu Phe Pro Cys Ala Asp Asp Leu Leu Glu Thr His Ser His Phe Leu Ala Arg Leu Lys Glu Arg Arg Gln Glu Ser Leu Glu Glu Gly Ser Asp Arg Asn Tyr Val Ile Gln Lys Ile Gly Asp Leu Leu Val Gln Gln Phe Ser Gly Glu Asn Gly Glu Arg Met Lys Glu Lys Tyr Gly Val Phe Cys Ser Gly His Asn Glu Ala Val Ser His Tyr Lys Leu Leu Leu Gln Gln Asn Lys Lys Phe Gln Asn Leu Ile Lys Lys Ile Gly Asn Phe Ser Ile Val Arg Arg Leu Gly Val Gln Glu Cys Ile Leu Leu Val Thr Gln Arg Ile Thr Lys Tyr Pro Val Leu Val Glu Arg Ile Ile Gln Asn Thr Glu Ala Gly Thr Glu Asp Tyr Glu Asp Leu Thr Gln Ala Leu Asn Leu Ile Lys Asp Ile Ile Ser Gln Val Asp Ala Lys Val Ser Glu Cys Glu Lys Gly Gln Arg Leu Arg Glu Ile Ala Gly Lys Met Asp Leu Lys Ser Ser Ser Lys Leu Lys Asn Gly Leu Thr Phe Arg Lys Glu Asp Met Leu Gln Arg Gln Leu His Leu Glu Gly Met Leu Cys Trp Lys Thr Thr Ser Gly Arg Leu Lys Asp Ile Leu Ala Ile Leu Leu Thr Asp Val Leu Leu Leu Leu Gln Glu Lys Asp Gln Lys Tyr Val Phe Ala Ser Val Asp Ser Lys Pro Pro Val Ile Ser Leu Gln Lys Leu Ile Val Arg Glu Val Ala Asn Glu Glu Lys Ala Met Phe Leu Ile Ser Ala Ser Leu Gln Gly Pro Glu Met Tyr Glu Ile Tyr Thr Ser Ser Lys Glu Asp Arg Asn Ala Trp Met Ala His Ile Gln Arg Ala Val Glu Ser Cys Pro Asp Glu Glu Glu Gly Pro Phe Ser Leu Pro Glu Glu Glu Arg Lys Val Val Glu Ala Arg Ala Thr Arg Leu Arg Asp Phe Gln Glu Arg Leu Ser Met Lys Asp Gln Leu Ile Ala Gln Ser Leu Leu Glu Lys Gln Gln Ile Tyr Leu Glu Met Ala Glu Met Gly Gly Leu Glu Asp Leu Pro Gln Pro Arg Gly Leu Phe Arg Gly Gly Asp Pro Ser Glu Thr Leu Gln Gly Glu Leu Ile Leu Lys Ser Ala Met Ser Glu Ile Glu Gly Ile Gln Ser Leu Ile Cys Arg Arg Leu Gly Ser Ala Asn Gly Gln Ala Glu Asp Gly Gly Ser Ser Thr Gly Pro Pro Arg Arg Ala Glu Thr Phe Ala Gly Tyr Asp Cys Thr Asn Ser Pro Thr Lys Asn Gly Ser Phe Lys Lys Lys Val Ser Ser Thr Asp Pro Arg Pro Arg Asp Trp Arg Gly Pro Pro Asn Ser Pro Asp Leu Lys Leu Ser Asp Ser Asp Ile Pro Gly Ser Ser Glu Glu Ser Pro Gln Val Val Glu Ala Pro Gly Thr Glu Ser Asp Pro Arg Leu Pro Thr Val Leu Glu Ser Glu Leu Val Gln Arg Ile Gln Thr Leu Ser Gln Leu Leu Leu Asn Leu Gln Ala Val Ile Ala His Gln Asp Ser Tyr Val Glu Thr Gln Arg Ala Ala Ile Gln Glu Arg Glu Lys Gln Phe Arg Leu Gln Ser Thr Arg Gly Asn Leu Leu Leu Glu Gln Glu Arg Gln Arg Asn Phe Glu Lys Gln Arg Glu Glu Arg Ala Ala Leu Glu Lys Leu Gln Ser Gln Leu Arg His Glu Gln Gln Arg Trp Glu Arg Glu Arg Gln Trp Gln His Gln Glu Leu Glu Arg Ala Gly Ala Arg Leu Gln Glu Arg Glu Gly Glu Ala Arg Gln Leu Arg Glu Arg Leu Glu Gln Glu Arg Ala Glu Leu Glu Arg Gln Arg Gln Ala Tyr Gln His Asp Leu Glu Arg Leu Arg Glu Ala Gln Arg Ala Val Glu Arg Glu Arg Glu Arg Leu Glu Leu Leu Arg Arg Leu Lys Lys Gln Asn Thr Ala Pro Gly Ala Leu Pro Pro Asp Thr Leu Ala Glu Ala Gln Pro Pro Ser His Pro Pro Ser Phe Asn Gly Glu Gly Leu Glu Gly Pro Arg Val Ser Met Leu Pro Ser Gly Val Gly Pro Glu Tyr Ala Glu Arg Pro Glu Val Ala Arg Arg Asp Ser.Ala Pro Thr Glu Ser Arg Leu Ala Lys Ser Asp Val Pro Ile Gln Leu Leu Ser Ala Thr Asn Gln Phe Gln Arg Gln Ala Ala Val Gln Gln Gln Ile Pro Thr Lys Leu Ala Ala Ser Thr Lys Gly Gly Lys Asp Lys Gly Gly Lys Ser Arg Gly Ser Gln Arg Trp Glu Ser Ser Ala Ser Phe Asp Leu Lys Gln Gln Leu Leu Leu Asn Lys Leu Met Gly Lys Asp Glu Ser Thr Ser Arg Asn Arg Arg Ser Leu Ser Pro Ile Leu Pro Gly Arg His Ser Pro Ala Pro Pro Pro Asp Pro Gly Phe Pro Ala Pro Ser Pro Pro Pro Ala Asp Ser Pro Ser Glu Gly Phe Ser Leu Lys Ala Gly Gly Thr Ala Leu Leu Pro Gly Pro Pro Ala Pro Ser Pro Leu Pro Ala Thr Pro Leu Ser Ala Lys Glu Asp Ala Ser Lys Glu Asp Val Ile Phe Phe <210> 9 <211> 1287 <212> PRT
<213> Homo Sapiens <400> 9 Lys Glu Val Gly Ala Gly Ser Ala Asn Gly Val Glu Met Val Gln Gly Pro Val Gln Thr Pro Ala Leu Thr Ile His Arg Arg Lys Arg Arg Arg Ser Cys Pro Pro Asn Arg Ala Ser Tyr Leu Pro Lys Ala Glu Ser Leu Ala Ser Leu Gly Ser His Leu Pro Ala Leu Leu Ser Arg Ala Arg Val Pro Arg Pro Pro Ala Gly Arg Arg Glu Arg Glu Arg Arg Arg Arg Pro Val Ala Lys Ala Pro Ala Arg Leu Arg Gly Glu Tyr Glu Thr Gly Val Lys Met Thr Ser Arg Phe Gly Lys Thr Tyr Ser Arg Lys Gly Gly Asn Gly Ser Ser Lys Phe Asp Glu Val Phe Ser Asn Lys Arg Thr Thr Leu Ser Thr Lys Trp Gly Glu Thr Thr Phe Met Ala Lys Leu Gly Gln Lys Arg Pro Asn Phe Lys Pro Asp Ile Gln Glu Ile Pro Lys Lys Pro Lys Val Glu Glu Glu Ser Thr Gly Asp Pro Phe Gly Phe Asp Ser Asp Asp Glu Ser Leu Pro Val Ser Ser Lys Asn Leu Ala Gln Val Lys Cys Ser Ser Tyr Ser Glu Ser Ser Glu Ala Ala Gln Leu Glu Glu Val Thr Ser Val Leu Glu Ala Asn Ser Lys Ile Ser His Val Val Val Glu Asp Thr Val Val Ser Asp Lys Cys Phe Pro Leu Glu Asp Thr Leu Leu Gly Lys Glu Lys Ser Thr Asn Arg Ile Val Glu Asp Asp Ala Ser Ile Ser Ser Cys Asn Lys Leu Ile Thr Ser Asp Lys Val Glu Asn Phe His Glu Glu His Glu Lys Asn Ser His His Ile His Lys Asn Ala Asp Asp Ser Thr Lys Lys Pro Asn Ala Glu Thr Thr Val Ala Ser Glu Ile Lys Glu Thr Asn Asp Thr Trp Asn Ser Gln Phe Gly Lys Arg Pro Glu Ser Pro Ser Glu Ile Ser Pro Ile Lys Gly Ser Val Arg Thr Gly Leu Phe Glu Trp Asp Asn Asp Phe Glu Asp Ile Arg Ser Glu Asp Cys Ile Leu Ser Leu Asp Ser Asp Pro Leu Leu Glu Met Lys Asp Asp Asp Phe Lys Asn Arg Leu Glu Asn Leu Asn Glu Ala Ile Glu Glu Asp Ile Val Gln Ser Val Leu Arg Pro Thr Asn Cys Arg Thr Tyr Cys Arg Ala Asn Lys Thr Lys Ser Ser Gln Gly Ala Ser Asn Phe Asp Lys Leu Met Asp Gly Thr Ser Gln Ala Leu Ala Lys Ala Asn Ser Glu Ser Ser Lys Asp Gly Leu Asn Gln Ala Lys Lys Gly Gly Val Ser Cys Gly Thr Ser Phe Arg Gly Thr Val Gly Arg Thr Arg Asp Tyr Thr Val Leu His Pro Ser Cys Leu Ser Val Cys Asn Val Thr Ile Gln Asp Thr Met Glu Arg Ser Met Asp Glu Phe Thr Ala Ser Thr Pro Ala Asp Leu Gly Glu Ala Gly Arg Leu Arg Lys Lys Ala Asp Ile Ala Thr Ser Lys Thr Thr Thr Arg Phe Arg Pro Ser Asn Thr Lys Ser Lys Lys Asp Val Lys Leu Glu Phe Phe Gly Phe Glu Asp His Glu Thr Gly Gly Asp Glu Gly Gly Ser Gly Ser Ser Asn Tyr Lys Ile Lys Tyr Phe Gly Phe Asp Asp Leu Ser Glu Ser Glu Asp Asp Glu Asp Asp Asp Cys Gln Val Glu Arg Lys Thr Ser Lys Lys Arg Thr Lys Thr Ala Pro Ser Pro Ser Leu Gln Pro Pro Pro Glu Ser Asn Asp Asn Ser Gln Asp Ser Gln Ser Gly Thr Asn Asn Ala Glu Asn Leu Asp Phe Thr Glu Asp Leu Pro Gly Val Pro Glu Ser Val Lys Lys Pro Ile Asn Lys Gln Gly Asp Lys Ser Lys Glu Asn Thr Arg Lys Ile Phe Ser Gly Pro Lys Arg Ser Pro Thr Lys Ala Val Tyr Asn Ala Arg His Trp Asn His Pro Asp Ser Glu Glu Leu Pro Gly Pro Pro Val Val Lys Pro Gln Ser Val Thr Val Arg Leu Ser Ser Lys Glu Pro Asn Gln Lys Asp Asp Gly Val Phe Lys Ala Pro Ala Pro Pro Ser Lys Val Ile Lys Thr Val Thr Ile Pro Thr Gln Pro Tyr Gln Asp Ile Val Thr Ala Leu Lys Cys Arg Arg Glu Asp Lys Glu Leu Tyr Thr Val Val Gln His Val Lys His Phe Asn Asp Val Val Glu Phe Gly Glu Asn Gln Glu Phe Thr Asp Asp Ile Glu Tyr Leu Leu Ser Gly Leu Lys Ser Thr Gln Pro Leu Asn Thr Arg Cys Leu Ser Val Ile Ser Leu Ala Thr Lys Cys Ala Met Pro Ser Phe Arg Met His Leu Arg Ala His Gly Met Val Ala Met Val Phe Lys Thr Leu Asp Asp Ser Gln His His Gln Asn Leu Ser Leu Cys Thr Ala Ala Leu Met Tyr Ile Leu Ser Arg Asp Arg Leu Asn Met Asp Leu Asp Arg Ala Ser Leu Asp Leu Met Ile Arg Leu Leu Glu Leu Glu Gln Asp Ala Ser Ser Ala Lys Leu Leu Asn Glu Lys Asp Met Asn Lys Ile Lys Glu Lys Ile Arg Arg Leu Cys Glu Thr Val His Asn Lys His Leu Asp Leu Glu Asn Ile Thr Thr Gly His Leu Ala Met Glu Thr Leu Leu Ser Leu Thr Ser Lys Arg Ala Gly Asp Trp Phe Lys Glu Glu Leu Arg Leu Leu Gly Gly Leu Asp His Ile Val Asp Lys Val Lys Glu Cys Val Asp His Leu Ser Arg Asp Glu Asp Glu Glu Lys Leu Val Ala Ser Leu Trp Gly Ala Glu Arg Cys Leu Arg Val Leu Glu Ser Val Thr Val His Asn Pro Glu Asn Gln Ser Tyr Leu Ile Ala Tyr Lys Asp Ser Gln Leu Ile Val Ser Ser Ala Lys Ala Leu Gln His Cys Glu Glu Leu Ile Gln Gln Tyr Asn Arg Ala Glu Asp Ser Ile Cys Leu Ala Asp Ser Lys Pro Leu Pro His Gln Asn Val Thr Asn His Val Gly Lys Ala Val Glu Asp Cys Met Arg Ala Ile Ile Gly Val Leu Leu Asn Leu Thr Asn Asp Asn Glu Trp Gly Ser Thr Lys Thr Gly Glu Gln Asp Gly Leu Ile Gly Thr Ala Leu Asn Cys Val Leu Gln Val Pro Lys Tyr Leu Pro Gln Glu Gln Arg Phe Asp Ile Arg Val Leu Gly Leu Gly Leu Leu Ile Asn Leu Val Glu Tyr Ser Ala Arg Asn Arg His Cys Leu Val Asn Met Glu Thr Ser Cys Ser Phe Asp Ser Ser Ile Cys Ser Gly Glu Gly Asp Asp Ser Leu Arg Ile Gly Gly Gln Val His Ala Val Gln Ala Leu Val Gln Leu Phe Leu Glu Arg Glu Arg Ala Ala Gln Leu Ala Glu Ser Lys Thr Asp Glu Leu Ile Lys Asp Ala Pro Thr Thr Gln His Asp Lys Ser Gly Glu Trp Gln Glu Thr Ser Gly Glu Ile Gln Trp Val Ser Thr Glu Lys Thr Asp Gly Thr Glu Glu Lys His Lys Lys Glu Glu Glu Asp Glu Glu Leu Asp Leu Asn Lys Ala Leu Gln His Ala Gly Lys His Met Glu Asp Cys Ile Val Ala Ser Tyr Thr Ala Leu Leu Leu Gly Cys Leu Cys Gln Glu Ser Pro Ile Asn Val Thr Thr Val Arg Glu Tyr Leu Pro Glu Gly Asp Phe Ser Ile Met Thr Glu Met Leu Lys Lys Phe Leu Ser Phe Met Asn Leu Thr Cys Ala Val Gly Thr Thr Gly Gln Lys Ser Ile Ser Arg Val Ile Glu Tyr Leu Glu His Cys <210>10 <211>591 <212>PRT

<213>Mus musculus <300>
<301> Schreiber, K. L.
<302> Class II histocompatibility molecules associate with calnexin duringassembly in the endoplasmatic reticulum <303> Int. Immunol.

<304> 1994 <305> 6 <306> 101-111 <313> 1 TO 591 <400> 10 Met Glu Gly Lys Trp Leu Leu Cys Leu Leu Leu Val Leu Gly Thr Ala Ala Val Glu Ala His Asp Gly His Asp Asp Asp Ala Ile Asp Ile Glu Asp Asp Leu Asp Asp Val Ile Glu Glu Val Glu Asp Ser Lys Ser Lys Ser Asp Ala Ser Thr Pro Pro Ser Pro Lys Val Thr Tyr Lys Ala Pro Val Pro Thr Gly Glu Val Tyr Phe Ala Asp Ser Phe Asp Arg Gly Ser Leu Ser Gly Trp Ile Leu Ser Lys Ala Lys Lys Asp Asp Thr Asp Asp Glu Ile Ala Lys Tyr Asp Gly Lys Trp Glu Val Asp Glu Met Lys Glu Thr Lys Leu Pro Gly Asp Lys Gly Leu Val Leu Met Ser Arg Ala Lys His His Ala Ile Ser Ala Lys Leu Asn Lys Pro Phe Leu Phe Asp Thr Lys Pro Leu Ile Val Gln Tyr Glu Val Asn Phe Gln Asn Gly Ile Glu Cys Gly Gly Ala Tyr Val Lys Leu Leu Ser Lys Thr Ala Glu Leu Ser Leu Asp Gln Phe His Asp Lys Thr Pro Tyr Thr Ile Met Phe Gly Pro Asp Lys Cys Gly Glu Asp Tyr Lys Leu His Phe Ile Phe Arg His Lys Asn Pro Lys Thr Gly Val Tyr Glu Glu Lys His Ala Lys Arg Pro Asp Ala Asp Leu Lys Thr Tyr Phe Thr Asp Lys Lys Thr His Leu Tyr Thr Leu Ile Leu Asn Pro Asp Asn Ser Phe Glu Ile Leu Val Asp Gln Ser Val Val Asn Ser Gly Asn Leu Leu Asn Asp Met Thr Pro Pro Val Asn Pro Ser Arg Glu Ile Glu Asp Pro Glu Asp Arg Lys Pro Glu Asp Trp Asp Glu Arg Pro Lys Ile Ala Asp Pro Asp Ala Val Lys Pro Asp Asp Trp Asp Glu Asp Ala Pro Ser Lys Ile Pro Asp Glu Glu Ala Thr Lys Pro Glu Gly Trp Leu Asp Asp Glu Pro Glu Tyr Ile Pro Asp Pro Asp Ala Glu Lys Pro Glu Asp Trp Asp Glu Asp Met Asp Gly Glu Trp Glu Ala Pro Gln Ile Ala Asn Pro Lys Cys Glu Ser Ala Pro Gly Cys Gly Val Trp Gln Arg Pro Met Ile Asp Asn Pro Asn Tyr Lys Gly Lys Trp Lys Pro Pro Met Ile Asp Asn Pro Asn Tyr Gln Gly Ile Trp Lys Pro Arg Lys Ile Pro Asn Pro Asp Phe Phe Glu Asp Leu Glu Pro Phe Lys Met Thr Pro Phe Ser Ala Ile Gly Leu Glu Leu Trp Ser Met Thr Ser Asp Ile Phe Phe Asp Asn Phe Ile Ile Ser Gly Asp Arg Arg Val Val Asp Asp Trp Ala Asn Asp Gly Trp Gly Leu Lys Lys Ala Ala Asp Gly Ala Ala Glu Pro Gly Val Val Leu Gln Met Leu Glu Ala Ala Glu Glu Arg Pro Trp Leu Trp Val Val Tyr Ile Leu Thr Val Ala Leu Pro Val Phe Leu Val Ile Leu Phe Cys Cys Ser Gly Lys Lys Gln Ser Asn Ala Met Glu Tyr Lys Lys Thr Asp Ala Pro Gln Pro Asp Val Lys Asp Glu Glu Gly Lys Glu Glu Glu Lys Asn Lys Arg Asp Glu Glu Glu Glu Glu Glu Lys Leu Glu Glu Lys Gln Lys Ser Asp Ala Glu Glu Asp Gly Val Thr Gly Ser Gln Asp Glu Glu Asp Ser Lys Pro Lys Ala Glu Glu Asp Glu Ile Leu Asn Arg Ser Pro Arg Asn Arg Lys Pro Arg Arg Glu <210> 11 <211> 592 <212> PRT
<213> Homo sapiens <400> 11 Met Glu Gly Lys Trp Leu Leu Cys Met Leu Leu Val Leu Gly Thr Ala Ile Val Glu Ala His Asp Gly His Asp Asp Asp Val Ile Asp Ile Glu Asp Asp Leu Asp Asp Val Ile Glu Glu Val Glu Asp Ser Lys Pro Asp Thr Thr Ala Pro Pro Ser Ser Pro Lys Val Thr Tyr Lys Ala Pro Val Pro Thr Gly Glu Val Tyr Phe Ala Asp Ser Phe Asp Arg Gly Thr Leu Ser Gly Trp Ile Leu Ser Lys Ala Lys Lys Asp Asp Thr Asp Asp Glu Ile Ala Lys Tyr Asp Gly Lys Trp Glu Val Glu Glu Met Lys Glu Ser Lys Leu Pro Gly Asp Lys Gly Leu Val Leu Met Ser Arg Ala Lys His His Ala Ile Ser Ala Lys Leu Asn Lys Pro Phe Leu Phe Asp Thr Lys Pro Leu Ile Val Gln Tyr Glu Val Asn Phe Gln Asn Gly Ile Glu Cys Gly Gly Ala Tyr Val Lys Leu Leu Ser Lys Thr Pro Glu Leu Asn Leu Asp Gln Leu His Asp Lys Thr Pro Tyr Thr Ile Met Phe Gly Pro Asp Lys Cys Gly Glu Asp Tyr Lys Leu His Phe Ile Phe Arg His Lys Asn Pro Lys Thr Gly Ile Tyr Glu Glu Lys His Ala Lys Arg Pro Asp Ala Asp Leu Lys Thr Tyr Phe Thr Asp Lys Lys Thr His Leu Tyr Thr Leu Ile Leu Asn Pro Asp Asn Ser Phe Glu Ile Leu Val Asp Gln Ser Val Val Asn Ser Gly Asn Leu Leu Asn Asp Met Thr Pro Pro Val Asn Pro Ser Arg Glu Ile Glu Asp Pro Glu Asp Arg Lys Pro Glu Asp Trp Asp Glu Arg Pro Lys Ile Pro Asp Pro Glu Ala Val Lys Pro Asp Asp Trp Asp Glu Asp Ala Pro Ala Lys Ile Pro Asp Glu Glu Ala Thr Lys Pro Glu Gly Trp Leu Asp Asp Glu Pro Glu Tyr Val Pro Asp Pro Asp Ala Glu Lys Pro Glu Asp Trp Asp Glu Asp Met Asp Gly Glu Trp Glu Ala Pro Gln Ile Ala Asn Pro Arg Cys Glu Ser Ala Pro Gly Cys Gly Val Trp Gln Arg Pro Val Ile Asp Asn Pro Asn Tyr Lys Gly Lys Trp Lys 370 . 375 380 Pro Pro Met Ile Asp Asn Pro Ser Tyr Gln Gly Ile Trp Lys Pro Arg Lys Ile Pro Asn Pro Asp Phe Phe Glu Asp Leu Glu Pro Phe Arg Met Thr Pro Phe Ser Ala Ile Gly Leu Glu Leu Trp Ser Met Thr Ser Asp Ile Phe Phe Asp Asn Phe Ile Ile Cys Ala Asp Arg Arg Ile Val Asp Asp Trp Ala Asn Asp Gly Trp Gly Leu Lys Lys Ala Ala Asp Gly Ala Ala Glu Pro Gly Val Val Gly Gln Met Ile Glu Ala Ala Glu Glu Arg Pro Trp Leu Trp Val Val Tyr Ile Leu Thr Val Ala Leu Pro Val Phe Leu Val Ile Leu Phe Cys Cys Ser Gly Lys Lys Gln Thr Ser Gly Met Glu Tyr Lys Lys Thr Asp Ala Pro Gln Pro Asp Val Lys Glu Glu Glu Glu Glu Lys Glu Glu Glu Lys Asp Lys Gly Asp Glu Glu Glu Glu Gly Glu Glu Lys Leu Glu Glu Lys Gln Lys Ser Asp Ala Glu Glu Asp Gly Gly Thr Val Ser Gln Glu Glu Glu Asp Arg Lys Pro Lys Ala Glu Glu Asp Glu Ile Leu Asn Arg Ser Pro Arg Asn Arg Lys Pro Arg Arg Glu <210> 12 <211> 2441 <212> PRT
<213> Mus musculus <300>
<301> Chrivia, J. C.
<302> Phosphorylated CREB binds specifically to the nuclear protein CBP
<303> Nature <304> 1993 <305> 365 <306> 855-859 <313> 1 TO 2441 <400> 12 Met Ala Glu Asn Leu Leu Asp Gly Pro Pro Asn Pro Lys Arg Ala Lys Leu Ser Ser Pro Gly Phe Ser Ala Asn Asp Asn Thr Asp Phe Gly Ser Leu Phe Asp Leu Glu Asn Asp Leu Pro Asp Glu Leu Ile Pro Asn Gly Glu Leu Ser Leu Leu Asn Ser Gly Asn Leu Val Pro Asp Ala Ala Ser Lys His Lys Gln Leu Ser Glu Leu Leu Arg Gly Gly Ser Gly Ser Ser Ile Asn Pro Gly Ile Gly Asn Val Ser Ala Ser Ser Pro Val Gln Gln Gly Leu Gly Gly Gln Ala Gln Gly Gln Pro Asn Ser Thr Asn Met Ala Ser Leu Gly Ala Met Gly Lys Ser Pro Leu Asn Gln Gly Asp Ser Ser Thr Pro Asn Leu Pro Lys Gln Ala Ala Ser Thr Ser Gly Pro Thr Pro Pro Ala Ser Gln Ala Leu Asn Pro Gln Ala Gln Lys Gln Val Gly Leu Val Thr Ser Ser Pro Ala Thr Ser Gln Thr Gly Pro Gly Ile Cys Met Asn Ala Asn Phe Asn Gln Thr His Pro Gly Leu Leu Asn Ser Asn Ser Gly His Ser Leu Met Asn Gln Ala Gln Gln Gly Gln Ala Gln Val Met Asn Gly Ser Leu Gly Ala Ala Gly Arg Gly Arg Gly Ala Gly Met Pro Tyr Pro Ala Pro Ala Met Gln Gly Ala Thr Ser Ser Val Leu Ala Glu Thr Leu Thr Gln Val Ser Pro Gln Met Ala Gly His Ala Gly Leu Asn Thr Ala Gln Ala Gly Gly Met Thr Lys Met Gly Met Thr Gly Thr Thr Ser Pro Phe Gly Gln Pro Phe Ser Gln Thr Gly Gly Gln Gln Met Gly Ala Thr Gly Val Asn Pro Gln Leu Ala Ser Lys Gln Ser Met Val Asn Ser Leu Pro Ala Phe Pro Thr Asp Ile Lys Asn Thr Ser Val Thr Thr Val Pro Asn Met Ser Gln Leu Gln Thr Ser Val Gly Ile Val Pro Thr Gln Ala Ile Ala Thr Gly Pro Thr Ala Asp Pro Glu Lys Arg Lys Leu Ile Gln Gln Gln Leu Val Leu Leu Leu His Ala His Lys Cys Gln Arg Arg Glu Gln Ala Asn Gly Glu Val Arg Ala Cys Ser Leu Pro His Cys Arg Thr Met Lys Asn Val Leu Asn His Met Thr His Cys Gln Ala Pro Lys Ala Cys Gln Val Ala His Cys Ala Ser Ser Arg Gln Ile Ile Ser His Trp Lys Asn Cys Thr Arg His Asp Cys Pro Val Cys Leu Pro Leu Lys Asn Ala Ser Asp Lys Arg Asn Gln Gln Thr Ile Leu Gly Ser Pro Ala Ser Gly Ile Gln Asn Thr Ile Gly Ser Val Gly Ala Gly Gln Gln Asn Ala Thr Ser Leu Ser Asn Pro Asn Pro Ile Asp Pro Ser Ser Met Gln Arg Ala Tyr Ala Ala Leu Gly Leu Pro Tyr Met Asn Gln Pro Gln Thr Gln Leu Gln Pro Gln Val Pro Gly Gln Gln Pro Ala Gln Pro Pro Ala His Gln Gln Met Arg Thr Leu Asn Ala Leu Gly Asn Asn Pro Met Ser Val Pro Ala Gly Gly Ile Thr Thr Asp Gln Gln Pro Pro Asn Leu Ile Ser Glu Ser Ala Leu Pro Thr Ser Leu Gly Ala Thr Asn Pro Leu Met Asn Asp Gly Ser Asn Ser Gly Asn Ile Gly Ser Leu Ser Thr Ile Pro Thr Ala Ala Pro Pro Ser Ser Thr Gly Val Arg Lys Gly Trp His Glu His Val Thr Gln Asp Leu Arg Ser His Leu Val His Lys Leu Val Gln Ala Ile Phe Pro Thr Pro Asp Pro Ala Ala Leu Lys Asp Arg Arg Met Glu Asn Leu Val Ala Tyr Ala Lys Lys Val Glu Gly Asp Met Tyr Glu Ser Ala Asn Ser Arg Asp Glu Tyr Tyr His Leu Leu Ala Glu Lys Ile Tyr Lys Ile Gln Lys Glu Leu Glu Glu Lys Arg Arg Thr Arg Leu His Lys Gln Gly Ile Leu Gly Asn Gln Pro Ala Leu Pro Ala Ser Gly Ala Gln Pro Pro Val Ile Pro Pro Ala Gln Ser Val Arg Pro Pro Asn Gly Pro Leu Pro Leu Pro Val Asn Arg Met Gln Val Ser Gln Gly Met Asn Ser Phe Asn Pro Met Ser Leu Gly Asn Val Gln Leu Pro Gln Ala Pro Met Gly Pro Arg Ala Ala Ser Pro Met Asn His Ser Val Gln Met Asn Ser Met Ala Ser Val Pro Gly Met Ala Ile Ser Pro Ser Arg Met Pro Gln Pro Pro Asn Met Met Gly Thr His Ala Asn Asn Ile Met Ala Gln Ala Pro Thr Gln Asn Gln Phe Leu Pro Gln Asn Gln Phe Pro Ser Ser Ser Gly Ala Met Ser Val Asn Ser Val Gly Met Gly Gln Pro Ala Ala Gln Ala Gly Val Ser Gln Gly Gln Glu Pro Gly Ala Ala Leu Pro Asn Pro Leu Asn Met Leu Ala Pro Gln Ala Ser Gln Leu Pro Cys Pro Pro Val Thr Gln Ser Pro Leu His Pro Thr Pro Pro Pro Ala Ser Thr g50 855 860 Ala Ala Gly Met Pro Ser Leu Gln His Pro Thr Ala Pro Gly Met Thr Pro Pro Gln Pro Ala Ala Pro Thr Gln Pro Ser Thr Pro Val Ser Ser Gly Gln Thr Pro Thr Pro Thr Pro Gly Ser Val Pro Ser Ala Ala Gln Thr Gln Ser Thr Pro Thr Val Gln Ala Ala Ala Gln Ala Gln Val Thr Pro Gln Pro Gln Thr Pro Val Gln Pro Pro Ser Val Ala Thr Pro Gln Ser Ser Gln Gln Gln Pro Thr Pro Val His Thr Gln Pro Pro Gly Thr Pro Leu Ser Gln Ala Ala Ala Ser Ile Asp Asn Arg Val Pro Thr Pro Ser Thr Val Thr Ser Ala Glu Thr Ser Ser Gln Gln Pro Gly Pro Asp Val Pro Met Leu Glu Met Lys Thr Glu Val Gln Thr Asp Asp Ala Glu Pro Glu Pro Thr Glu Ser Lys Gly Glu Pro Arg Ser Glu Met Met Glu Glu Asp Leu Gln Gly Ser Ser Gln Val Lys Glu Glu Thr Asp Thr Thr Glu Gln Lys Ser Glu Pro Met Glu Val Glu Glu Lys Lys Pro Glu Val Lys Val Glu Ala Lys Glu Glu Glu Glu Asn Ser Ser Asn Asp Thr Ala Ser Gln Ser Thr Ser Pro Ser Gln Pro Arg Lys Lys Ile Phe Lys Pro Glu Glu Leu Arg Gln Ala Leu Met Pro Thr Leu Glu Ala Leu Tyr Arg Gln Asp Pro Glu Ser Leu Pro Phe Arg Gln Pro Val Asp Pro Gln Leu Leu Gly Ile Pro Asp Tyr Phe Asp Ile Val Lys Asn Pro Met Asp Leu Ser Thr Ile Lys Arg Lys Leu Asp Thr Gly Gln Tyr Gln Glu Pro Trp Gln Tyr Val Asp Asp Val Arg Leu Met Phe Asn Asn Ala Trp Leu Tyr Asn Arg Lys Thr Ser Arg Val Tyr Lys Phe Cys Ser Lys Leu Ala Glu Val Phe Glu Gln Glu Ile Asp Pro Val Met Gln Ser Leu Gly Tyr Cys Cys Gly Arg Lys Tyr Glu Phe Ser Pro Gln Thr Leu Cys Cys Tyr Gly Lys Gln Leu Cys Thr Ile Pro Arg Asp Ala Ala Tyr Tyr Ser Tyr Gln Asn Arg Tyr His Phe Cys Gly Lys Cys Phe Thr Glu Ile Gln Gly Glu Asn Val Thr Leu Gly Asp Asp Pro Ser Gln Pro Gln Thr Thr Ile Ser Lys Asp Gln Phe Glu Lys Lys Lys Asn Asp Thr Leu Asp Pro Glu Pro Phe Val Asp Cys Lys Glu Cys Gly Arg Lys Met His Gln Ile Cys Val Leu His Tyr Asp Ile Ile Trp Pro Ser Gly Phe Val Cys Asp Asn Cys Leu Lys Lys Thr Gly Arg Pro Arg Lys Glu Asn Lys Phe Ser Ala Lys Arg Leu Gln Thr Thr Arg Leu Gly Asn His Leu Glu Asp Arg Val Asn Lys Phe Leu Arg Arg Gln Asn His Pro Glu Ala Gly Glu Val Phe Val Arg Val Val Ala Ser Ser Asp Lys Thr Val Glu Val Lys Pro Gly Met Lys Ser Arg Phe Val Asp Ser Gly Glu Met Ser Glu Ser Phe Pro Tyr Arg Thr Lys Ala Leu Phe Ala Phe Glu Glu Ile Asp Gly Val Asp Val Cys Phe Phe Gly Met His Val Gln Asp Thr Ala Leu Ile Ala Pro His Gln Ile Gln Gly Cys Val Tyr Ile Ser Tyr Leu Asp Ser Ile His Phe Phe Arg Pro Arg Cys Leu Arg Thr Ala Val Tyr His Glu Ile Leu Ile Gly Tyr Leu Glu Tyr Val Lys Lys Leu Val Tyr Val Thr Ala His Ile Trp Ala Cys Pro Pro Ser Glu Gly Asp Asp Tyr Ile Phe His Cys His Pro Pro Asp Gln Lys Ile Pro Lys Pro Lys Arg Leu Gln Glu Trp Tyr Lys Lys Met Leu Asp Lys Ala Phe Ala Glu Arg Ile Ile Asn Asp Tyr Lys Asp Ile Phe Lys Gln Ala Asn Glu Asp Arg Leu Thr Ser Ala Lys Glu Leu Pro Tyr Phe Glu Gly Asp Phe Trp Pro Asn Val Leu Glu Glu Ser Ile Lys Glu Leu Glu Gln Glu Glu Glu Glu Arg Lys Lys Glu Glu Ser Thr Ala Ala Ser Glu Thr Pro Glu Gly Ser Gln Gly Asp Ser Lys Asn Ala Lys Lys Lys Asn Asn Lys Lys Thr Asn Lys Asn Lys Ser Ser Ile Ser Arg Ala Asn Lys Lys Lys Pro Ser Met Pro Asn Val Ser Asn Asp Leu Ser Gln Lys Leu Tyr Ala Thr Met Glu Lys His Lys Glu Val Phe Phe Val Ile His Leu His Ala Gly Pro Val Ile Ser Thr Gln Pro Pro Ile Val Asp Pro Asp Pro Leu Leu Ser Cys Asp Leu Met Asp Gly Arg Asp Ala Phe Leu Thr Leu Ala Arg Asp Lys His Trp Glu Phe Ser Ser Leu Arg Arg Ser Lys Trp Ser Thr Leu Cys Met Leu Val Glu Leu His Thr Gln Gly Gln Asp Arg Phe Val Tyr Thr Cys Asn Glu Cys Lys His His Val Glu Thr Arg Trp His Cys Thr Val Cys Glu Asp Tyr Asp Leu Cys Ile Asn Cys Tyr Asn Thr Lys Ser His Thr His Lys Met Val Lys Trp Gly Leu Gly Leu Asp Asp Glu Gly Ser Ser Gln Gly Glu Pro Gln Ser Lys Ser Pro Gln Glu Ser Arg Arg Leu Ser Ile Gln Arg Cys Ile Gln Ser Leu Val His Ala Cys Gln Cys Arg Asn Ala Asn Cys Ser Leu Pro Ser Cys Gln Lys Met Lys Arg Val Val Gln His Thr Lys Gly Cys Lys Arg Lys Thr Asn Gly Gly Cys Pro Val Cys Lys Gln Leu Ile Ala Leu Cys Cys Tyr His Ala Lys His Cys Gln Glu Asn Lys Cys Pro Val Pro Phe Cys Leu Asn Ile Lys His Asn Val Arg Gln Gln Gln Ile Gln His Cys Leu Gln Gln Ala Gln Leu Met Arg Arg Arg Met Ala Thr Met Asn Thr Arg Asn Val Pro Gln Gln Ser Leu Pro Ser Pro Thr Ser Ala Pro Pro Gly Thr Pro Thr Gln Gln Pro Ser Thr Pro Gln Thr Pro Gln Pro Pro Ala Gln Pro Gln Pro Ser Pro Val Asn Met Ser Pro Ala Gly Phe Pro Asn Val Ala Arg Thr Gln Pro Pro Thr Ile Val Ser Ala Gly Lys Pro Thr Asn Gln Val Pro Ala Pro Pro Pro Pro Ala Gln Pro Pro Pro Ala Ala Val Glu Ala Ala Arg Gln Ile Glu Arg Glu Ala Gln Gln Gln Gln His Leu Tyr Arg Ala Asn Ile Asn Asn Gly Met Pro Pro Gly Arg Asp Gly Met Gly Thr Pro Gly Ser Gln Met Thr Pro Val Gly Leu Asn Val Pro Arg Pro Asn Gln Val Ser Gly Pro Val Met Ser Ser Met Pro Pro Gly Gln Trp Gln Gln Ala Pro Ile Pro Gln Gln Gln Pro Met Pro Gly Met Pro Arg Pro Val Met Ser Met Gln Ala Gln Ala Ala Val Ala Gly Pro Arg Met Pro Asn Val Gln Pro Asn Arg Ser Ile Ser Pro Ser Ala Leu Gln Asp Leu Leu Arg Thr Leu Lys Ser Pro Ser Ser Pro Gln Gln Gln Gln Gln Val Leu Asn Ile Leu Lys Ser Asn Pro Gln Leu Met Ala Ala Phe Ile Lys Gln Arg Thr Ala Lys Tyr Val Ala Asn Gln Pro Gly Met Gln Pro Gln Pro Gly Leu Gln Ser Gln Pro Gly Met Gln Pro Gln Pro Gly Met His Gln Gln Pro Ser Leu Gln Asn Leu Asn Ala Met Gln Ala Gly Val Pro Arg Pro Gly Val Pro Pro Pro Gln Pro Ala Met Gly Gly Leu Asn Pro Gln Gly Gln Ala Leu Asn Ile Met Asn Pro Gly His Asn Pro Asn Met Thr Asn Met Asn Pro Gln Tyr Arg Glu Met Val Arg Arg Gln Leu Leu Gln His Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Asn Ser Ala Ser Leu Ala Gly Gly Met Ala Gly His Ser Gln Phe Gln Gln Pro Gln Gly Pro Gly Gly Tyr Ala Pro Ala Met Gln Gln Gln Arg Met Gln Gln His Leu Pro Ile Gln Gly Ser Ser Met Gly Gln Met Ala Ala Pro Met Gly Gln Leu Gly Gln Met Gly Gln Pro Gly Leu Gly Ala Asp Ser Thr Pro Asn Ile Gln Gln Ala Leu Gln Gln Arg Ile Leu Gln Gln Gln Gln Met Lys Gln Gln Ile Gly Ser Pro Gly Gln Pro Asn Pro Met Ser Pro Gln Gln His Met Leu Ser Gly Gln Pro Gln Ala Ser His Leu Pro Gly Gln Gln Ile Ala Thr Ser Leu Ser Asn Gln Val Arg Ser Pro Ala Pro Val Gln Ser Pro Arg Pro Gln Ser Gln Pro Pro His Ser Ser Pro Ser Pro Arg Ile Gln Pro Gln Pro Ser Pro His His Val Ser Pro Gln Thr Gly Thr Pro His Pro Gly Leu Ala Val Thr Met Ala Ser Ser Met Asp Gln Gly His Leu Gly Asn Pro Glu Gln Ser Ala Met Leu Pro Gln Leu Asn Thr Pro Asn Arg Ser Ala Leu Ser Ser Glu Leu Ser Leu Val Gly Asp Thr Thr Gly Asp Thr Leu Glu Lys Phe Val Glu Gly Leu <210> 13 <211> 2442 <212> PRT
<213> Homo sapiens <400> 13 Met Ala Glu Asn Leu Leu Asp Gly Pro Pro Asn Pro Lys Arg Ala Lys Leu Ser Ser Pro Gly Phe Ser Ala Asn Asp Ser Thr Asp Phe Gly Ser Leu Phe Asp Leu Glu Asn Asp Leu Pro Asp Glu Leu Ile Pro Asn Gly Gly Glu Leu Gly Leu Leu Asn Ser Gly Asn Leu Val Pro Asp Ala Ala Ser Lys His Lys Gln Leu Ser Glu Leu Leu Arg Gly Gly Ser Gly Ser Ser Ile Asn Pro Gly Ile Gly Asn Val Ser Ala Ser Ser Pro Val Gln Gln Gly Leu Gly Gly Gln Ala Gln Gly Gln Pro Asn Ser Ala Asn Met Ala Ser Leu Ser Ala Met Gly Lys Ser Pro Leu Ser Gln Gly Asp Ser Ser Ala Pro Ser Leu Pro Lys Gln Ala Ala Ser Thr Ser Gly Pro Thr Pro Ala Ala Ser Gln Ala Leu Asn Pro Gln Ala Gln Lys Gln Val Gly Leu Ala Thr Ser Ser Pro Ala Thr Ser Gln Thr Gly Pro Gly Ile Cys Met Asn Ala Asn Phe Asn Gln Thr His Pro Gly Leu Leu Asn Ser Asn Ser Gly His Ser Leu Ile Asn Gln Ala Ser Gln Gly Gln Ala Gln Val Met Asn Gly Ser Leu Gly Ala Ala Gly Arg Gly Arg Gly Ala Gly Met Pro Tyr Pro Thr Pro Ala Met Gln Gly Ala Ser Ser Ser Val Leu Ala Glu Thr Leu Thr Gln Val Ser Pro Gln Met Thr Gly His Ala Gly Leu Asn Thr Ala Gln Ala Gly Gly Met Ala Lys Met Gly Ile Thr Gly Asn Thr Ser Pro Phe Gly Gln Pro Phe Ser Gln Ala Gly Gly Gln Pro Met Gly Ala Thr Gly Val Asn Pro Gln Leu Ala Ser Lys Gln Ser Met Val Asn Ser Leu Pro Thr Phe Pro Thr Asp Ile Lys Asn Thr Ser Val Thr Asn Val Pro Asn Met Ser Gln Met Gln Thr Ser Val Gly Ile Val Pro Thr Gln Ala Ile Ala Thr Gly Pro Thr Ala Asp Pro Glu Lys Arg Lys Leu Ile Gln Gln Gln Leu Val Leu Leu Leu His Ala His Lys Cys Gln Arg Arg Glu Gln Ala Asn Gly Glu Val Arg Ala Cys Ser Leu Pro His Cys Arg Thr Met Lys Asn Val Leu Asn His Met Thr His Cys Gln Ala Gly Lys Ala Cys Gln Val Ala His Cys Ala Ser Ser Arg Gln Ile Ile Ser His Trp Lys Asn Cys Thr Arg His Asp Cys Pro Val Cys Leu Pro Leu Lys Asn Ala Ser Asp Lys Arg Asn Gln Gln Thr Ile Leu Gly Ser Pro Ala Ser Gly Ile Gln Asn Thr Ile Gly Ser Val Gly Thr Gly Gln Gln Asn Ala Thr Ser Leu Ser Asn Pro Asn Pro Ile Asp Pro Ser Ser Met Gln Arg Ala Tyr Ala Ala Leu Gly Leu Pro Tyr Met Asn Gln Pro Gln Thr Gln Leu Gln Pro Gln Val Pro Gly Gln Gln Pro Ala Gln Pro Gln Thr His Gln Gln Met Arg Thr Leu Asn Pro Leu Gly Asn Asn Pro Met Asn Ile Pro Ala Gly Gly Ile Thr Thr Asp Gln Gln Pro Pro Asn Leu Ile Ser Glu Ser Ala Leu Pro Thr Ser Leu Gly Ala Thr Asn Pro Leu Met Asn Asp Gly Ser Asn Ser Gly Asn Ile Gly Thr Leu Ser Thr Ile Pro Thr Ala Ala Pro Pro Ser Ser Thr Gly Val Arg Lys Gly Trp His Glu His Val Thr Gln Asp Leu Arg Ser His Leu Val His Lys Leu Val Gln Ala Ile Phe Pro Thr Pro Asp Pro Ala Ala Leu Lys Asp Arg Arg Met Glu Asn Leu Val Ala Tyr Ala Lys Lys Val Glu Gly Asp Met Tyr Glu Ser Ala Asn Ser Arg Asp Glu Tyr Tyr His Leu Leu Ala Glu Lys Ile Tyr Lys Ile Gln Lys Glu Leu Glu Glu Lys Arg Arg Ser Arg Leu His Lys Gln Gly Ile Leu Gly Asn Gln Pro Ala Leu Pro Ala Pro Gly Ala Gln Pro Pro Val Ile Pro Gln Ala Gln Pro Val Arg Pro Pro Asn Gly Pro Leu Ser Leu Pro Val Asn Arg Met Gln Val Ser Gln Gly Met Asn Ser Phe Asn Pro Met Ser Leu Gly Asn Val Gln Leu Pro Gln Ala Pro Met Gly Pro Arg Ala Ala Ser Pro Met Asn His Ser Val Gln Met Asn Ser Met Gly Ser Val Pro Gly Met Ala Ile Ser Pro Ser Arg Met Pro Gln Pro Pro Asn Met Met Gly Ala His Thr Asn Asn Met Met Ala Gln Ala Pro Ala Gln Ser Gln Phe Leu Pro Gln Asn Gln Phe Pro Ser Ser Ser Gly Ala Met Ser Val Gly Met Gly Gln Pro Pro Ala Gln Thr Gly Val Ser Gln Gly Gln Val Pro Gly Ala Ala Leu Pro Asn Pro Leu Asn Met Leu Gly Pro Gln Ala Ser Gln Leu Pro Cys Pro Pro Val Thr Gln Ser Pro Leu His Pro Thr Pro Pro Pro Ala Ser Thr Ala Ala Gly Met Pro Ser Leu Gln His Thr Thr Pro Pro Gly Met Thr Pro Pro Gln Pro Ala Ala Pro Thr Gln Pro Ser Thr Pro Val Ser Ser Ser Gly Gln Thr Pro Thr Pro Thr Pro Gly Ser Val Pro Ser Ala Thr Gln Thr Gln Ser Thr Pro Thr Val Gln Ala Ala Ala Gln Ala Gln Val Thr Pro Gln Pro Gln Thr Pro Val Gln Pro Pro Ser Val Ala Thr Pro Gln Ser Ser Gln Gln Gln Pro Thr Pro Val His Ala Gln Pro Pro Gly Thr Pro Leu Ser Gln Ala Ala Ala Ser Ile Asp Asn Arg Val Pro Thr Pro Ser Ser Val Ala Ser Ala Glu Thr Asn Ser Gln Gln Pro Gly Pro Asp Val Pro Val Leu Glu Met Lys Thr Glu Thr Gln Ala Glu Asp Thr Glu Pro Asp Pro Gly Glu Ser Lys Gly Glu Pro Arg Ser Glu Met Met Glu Glu Asp Leu Gln Gly Ala Ser Gln Val Lys Glu Glu Thr Asp Ile Ala Glu Gln Lys Ser Glu Pro Met Glu Val Asp Glu Lys Lys Pro Glu Val Lys Val Glu Val Lys Glu Glu Glu Glu Ser Ser Ser Asn Gly Thr Ala Ser Gln Ser Thr Ser Pro Ser Gln Pro Arg Lys Lys Ile Phe Lys Pro Glu Glu Leu Arg Gln Ala Leu Met Pro Thr Leu Glu Ala Leu Tyr Arg Gln Asp Pro Glu Ser Leu Pro Phe Arg Gln Pro Val Asp Pro Gln Leu Leu Gly Ile Pro Asp Tyr Phe Asp Ile Val Lys Asn Pro Met Asp Leu Ser Thr Ile Lys Arg Lys Leu Asp Thr Gly Gln Tyr Gln Glu Pro Trp Gln Tyr Val Asp Asp Val Trp Leu Met Phe Asn Asn Ala Trp Leu Tyr Asn Arg Lys Thr Ser Arg Val Tyr Lys Phe Cys Ser Lys Leu Ala Glu Val Phe Glu Gln Glu Ile Asp Pro Val Met Gln Ser Leu Gly Tyr Cys Cys Gly Arg Lys Tyr Glu Phe Ser Pro Gln Thr Leu Cys Cys Tyr Gly Lys Gln Leu Cys Thr Ile Pro Arg Asp Ala Ala Tyr Tyr Ser Tyr Gln Asn Arg Tyr His Phe Cys Glu Lys Cys Phe Thr Glu Ile Gln Gly Glu Asn Val Thr Leu Gly Asp Asp Pro Ser Gln Pro Gln Thr Thr Ile Ser Lys Asp Gln Phe Glu Lys Lys Lys Asn Asp Thr Leu Asp Pro Glu Pro Phe Val Asp Cys Lys Glu Cys Gly Arg Lys Met His Gln Ile Cys Val Leu His Tyr Asp Ile Ile Trp Pro Ser Gly Phe Val Cys Asp Asn Cys Leu Lys Lys Thr Gly Arg Pro Arg Lys Glu Asn Lys Phe Ser Ala Lys Arg Leu Gln Thr Thr Arg Leu Gly Asn His Leu Glu Asp Arg Val Asn Lys Phe Leu Arg Arg Gln Asn His Pro Glu Ala Gly Glu Val Phe Val Arg Val Val Ala Ser Ser Asp Lys Thr Val Glu Val Lys Pro Gly Met Lys Ser Arg Phe Val Asp Ser Gly Glu Met Ser Glu Ser Phe Pro Tyr Arg Thr Lys Ala Leu Phe Ala Phe Glu Glu Ile Asp Gly Val Asp Val Cys Phe Phe Gly Met His Val Gln Glu Tyr Gly Ser Asp Cys Pro Pro Pro Asn Thr Arg Arg Val Tyr Ile Ser Tyr Leu Asp Ser Ile His Phe Phe Arg Pro Arg Cys Leu Arg Thr Ala Val Tyr His Glu Ile Leu Ile Gly Tyr Leu Glu Tyr Val Lys Lys Leu Gly Tyr Val Thr Gly His Ile Trp Ala Cys Pro Pro Ser Glu Gly Asp Asp Tyr Ile Phe His Cys His Pro Pro Asp Gln Lys Ile Pro Lys Pro Lys Arg Leu Gln Glu Trp Tyr Lys Lys Met Leu Asp Lys Ala Phe Ala Glu Arg Ile Ile His Asp Tyr Lys Asp Ile Phe Lys Gln Ala Thr Glu Asp Arg Leu Thr Ser Ala Lys Glu SO

Leu Pro Tyr Phe Glu Gly Asp Phe Trp Pro Asn Val Leu Glu Glu Ser Ile Lys Glu Leu Glu Gln Glu Glu Glu Glu Arg Lys Lys Glu Glu Ser Thr Ala Ala Ser Glu Thr Thr Glu Gly Ser Gln Gly Asp Ser Lys Asn Ala Lys Lys Lys Asn Asn Lys Lys Thr Asn Lys Asn Lys Ser Ser Ile Ser Arg Ala Asn Lys Lys Lys Pro Ser Met Pro Asn Val Ser Asn Asp Leu Ser Gln Lys Leu Tyr Ala Thr Met Glu Lys His Lys Glu Val Phe Phe Val Ile His Leu His Ala Gly Pro Val Ile Asn Thr Leu Pro Pro Ile Val Asp Pro Asp Pro Leu Leu Ser Cys Asp Leu Met Asp Gly Arg Asp Ala Phe Leu Thr Leu Ala Arg Asp Lys His Trp Glu Phe Ser Ser Leu Arg Arg Ser Lys Trp Ser Thr Leu Cys Met Leu Val Glu Leu His Thr Gln Gly Gln Asp Arg Phe Val Tyr Thr Cys Asn Glu Cys Lys His His Val Glu Thr Arg Trp His Cys Thr Val Cys Glu Asp Tyr Asp Leu Cys Ile Asn Cys Tyr Asn Thr Lys Ser His Ala His Lys Met Val Lys Trp Gly Leu Gly Leu Asp Asp Glu Gly Ser Ser Gln Gly Glu Pro Gln Ser Lys Ser Pro Gln Glu Ser Arg Arg Val Ser Ile Gln Arg Cys Ile Gln Ser Leu Val His Ala Cys Gln Cys Arg Asn Ala Asn Cys Ser Leu Pro Ser Cys Gln Lys Met Lys Arg Val Val Gln His Thr Lys Gly Cys Lys Arg Lys Thr Asn Gly Gly Cys Pro Val Cys Lys Gln Leu Ile Ala Leu Cys Cys Tyr His Ala Lys His Cys Gln Glu Asn Lys Cys Pro Val Pro Phe Cys Leu Asn Ile Lys His Lys Leu Arg Gln Gln Gln Ile Gln His Arg Leu Gln Gln Ala Gln Leu Met Arg Arg Arg Met Ala Thr Met Asn Thr Arg Asn Val Pro Gln Gln Ser Leu Pro Ser Pro Thr Ser Ala Pro Pro Gly Thr Pro Thr Gln Gln Pro Ser Thr Pro Gln Thr Pro Gln Pro Pro Ala Gln Pro Gln Pro Ser Pro Val Ser Met Ser Pro Ala Gly Phe Pro Ser Val Ala Arg Thr Gln Pro Pro Thr Thr Val Ser Thr Gly Lys Pro Thr Ser Gln Val Pro Ala Pro Pro Pro Pro Ala Gln Pro Pro Pro Ala Ala Val Glu Ala Ala Arg Gln Ile Glu Arg Glu Ala Gln Gln Gln Gln His Leu Tyr Arg Val Asn Ile Asn Asn Ser Met Pro Pro Gly Arg Thr Gly Met Gly Thr Pro Gly Ser Gln Met Ala Pro Val Ser Leu Asn Val Pro Arg Pro Asn Gln Val Ser Gly Pro Val Met Pro Ser Met Pro Pro Gly Gln Trp Gln Gln Ala Pro Leu Pro Gln Gln Gln Pro Met Pro Gly Leu Pro Arg Pro Val Ile Ser Met Gln Ala Gln Ala Ala Val Ala Gly Pro Arg Met Pro Ser Val Gln Pro Pro Arg Ser Ile Ser Pro Ser Ala Leu Gln Asp Leu Leu Arg Thr Leu Lys Ser Pro Ser Ser Pro Gln Gln Gln Gln Gln Val Leu Asn Ile Leu Lys Ser Asn Pro Gln Leu Met Ala Ala Phe Ile Lys Gln Arg Thr Ala Lys Tyr Val Ala Asn Gln Pro Gly Met Gln Pro Gln Pro Gly Leu Gln Ser Gln Pro Gly Met Gln Pro Gln Pro Gly Met His Gln Gln Pro Ser Leu Gln Asn Leu Asn Ala Met Gln Ala Gly Val Pro Arg Pro Gly Val Pro Pro Gln Gln Gln Ala Met Gly Gly Leu Asn Pro Gln Gly Gln Ala Leu Asn Ile Met Asn Pro Gly His Asn Pro Asn Met Ala Ser Met Asn Pro Gln Tyr Arg Glu Met Leu Arg Arg Gln Leu Leu Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gly Ser Ala Gly Met Ala Gly Gly Met Ala Gly His Gly Gln Phe Gln Gln Pro Gln Gly Pro Gly Gly Tyr Pro Pro Ala Met Gln Gln Gln Gln Arg Met Gln Gln His Leu Pro Leu Gln Gly Ser Ser Met Gly Gln Met Ala Ala Gln Met Gly Gln Leu Gly Gln Met Gly Gln Pro Gly Leu Gly Ala Asp Ser Thr Pro Asn Ile Gln Gln Ala Leu Gln Gln Arg Ile Leu Gln Gln Gln Gln Met Lys Gln Gln Ile Gly Ser Pro Gly Gln Pro Asn Pro Met Ser Pro Gln Gln His Met Leu Ser Gly Gln Pro Gln Ala Ser His Leu Pro Gly Gln Gln Ile Ala Thr Ser Leu Ser Asn Gln Val Arg Ser Pro Ala Pro Val Gln Ser Pro Arg Pro Gln Ser Gln Pro Pro His Ser Ser Pro Ser Pro Arg Ile Gln Pro Gln Pro Ser Pro His His Val Ser Pro Gln Thr Gly Ser Pro His Pro Gly Leu Ala Val Thr Met Ala Ser Ser Ile Asp Gln Gly His Leu Gly Asn Pro Glu Gln Ser Ala Met Leu Pro Gln Leu Asn Thr Pro Ser Arg Ser Ala Leu Ser Ser Glu Leu Ser Leu Val Gly Asp Thr Thr Gly Asp Thr Leu Glu Lys Phe Val Glu Gly Leu <210>14 <211>324 <212>PRT

<213>Mus musculus <300>
<301> Metzger, R.
<302> Expression of the mouse and rat proto-oncogene in the brain and peripheral tissues <303> FEBS Lett.
<304> 1995 <305> 3570 <306> 27-32 <313> 1 TO 324 <400> 14 Met Asp Gln Ser Asn Met Thr Ser Leu Ala Glu Glu Lys Ala Met Asn Thr Ser Ser Arg Asn Ala Ser Leu Gly Ser Ser His Pro Pro Ile Pro Ile Val His Trp Val Ile Met Ser Ile Ser Pro Leu Gly Phe Val Glu Asn Gly Ile Leu Leu Trp Phe Leu Cys Phe Arg Met Arg Arg Asn Pro Phe Thr Val Tyr Ile Thr His Leu Ser Met Ala Asp Ile Ser Leu Leu Phe Cys Ile Phe Ile Leu Ser Thr Asp Tyr Ala Leu Asp Tyr Glu Leu Ser Ser Gly His His Tyr Thr Ile Val Thr Leu Ser Val Thr Phe Leu Phe Gly Tyr Asn Thr Gly Leu Tyr Leu Leu Thr Ala Ile Ser Val Glu Arg Cys Leu Ser Val Leu Tyr Pro Ile Trp Tyr Thr Ser His Arg Pro Lys His Gln Ser Ala Phe Val Cys Ala Leu Leu Cys Ala Leu Ser Cys Leu Val Thr Thr Met Glu Tyr Val Met Cys Ile Asp Ser Gly Glu Glu Ser His Ser Arg Ser Asp Cys Arg Ala Val Ile Ile Phe Ile Ala Ile Leu Ser Phe Leu Val Phe Thr Pro Leu Met Leu Val Ser Ser Ser Ile Leu Val Val Lys Ile Arg Lys Asn Thr Trp Ala Ser His Ser Ser Lys Leu Tyr Ile Val Ile Met Val Thr Ile Ile Ile Phe Leu Ile Phe Ala Met Pro Met Arg Val Leu Tyr Leu Leu Tyr Tyr Glu Tyr Trp Ser Ala Phe Gly Asn Leu His Asn Ile Ser Leu Leu Phe Ser Thr Ile Asn Ser Ser Ala Asn Pro Phe Ile Tyr Phe Phe Val Gly Ser Ser Lys Lys Lys Arg Phe Arg Glu Ser Leu Lys Val Val Leu Thr Arg Ala Phe Lys Asp Glu Met Gln Pro Arg Arg Gln Glu Gly Asn Gly Asn Thr Val Ser Ile Glu Thr Val Val <210> 15 <211> 378 <212> PRT
<213> Homo Sapiens <400> 15 Met Val Trp Gly Lys Ile Cys Trp Phe Ser Gln Arg Ala Gly Trp Thr Val Phe Ala Glu Ser Gln Ile Ser Leu Ser Cys Ser Leu Cys Leu His Ser Gly Asp Gln Glu Ala Gln Asn Pro Asn Leu Val Ser Gln Leu Cys Gly Val Phe Leu Gln Asn Glu Thr Asn Glu Thr Ile His Met Gln Met Ser Met Ala Val Gly Gln Gln Ala Leu Pro Leu Asn Ile Ile Ala Pro Lys Ala Val Leu Val Ser Leu Cys Gly Val Leu Leu Asn Gly Thr Val Phe Trp Leu Leu Cys Cys Gly Ala Thr Asn Pro Tyr Met Val Tyr Ile Leu His Leu Val Ala Ala Asp Val Ile Tyr Leu Cys Cys Ser Ala Val Gly Phe Leu Gln Val Thr Leu Leu Thr Tyr His Gly Val Val Phe Phe Ile Pro Asp Phe Leu Ala Ile Leu Ser Pro Phe Ser Phe Glu Val Cys Leu Cys Leu Leu Val Ala Ile Ser Thr Glu Arg Cys Val Cys Val Leu Phe Pro Ile Trp Tyr Arg Cys His Arg Pro Lys Tyr Thr Ser Asn Val Val Cys Thr Leu Ile Trp Gly Leu Pro Phe Cys Ile Asn Ile Val Lys Ser Leu Phe Leu Thr Tyr Trp Lys His Val Lys Ala Cys Val Ile Phe Leu Lys Leu Ser Gly Leu Phe His Ala Ile Leu Ser Leu Val Met Cys Val Ser Ser Leu Thr Leu Leu Ile Arg Phe Leu Cys Cys Ser Gln Gln Gln Lys Ala Thr Arg Val Tyr Ala Val Val Gln Ile Ser Ala Pro Met Phe Leu Leu Trp Ala Leu Pro Leu Ser Val Ala Pro Leu Ile Thr Asp Phe Lys Met Phe Val Thr Thr Ser Tyr Leu Ile Ser Leu Phe Leu Ile Ile Asn Ser Ser Ala Asn Pro Ile Ile Tyr Phe Phe Val Gly Ser Leu Arg Lys Lys Arg Leu Lys Glu Ser Leu Arg Val Ile Leu Gln Arg Ala Leu Ala Asp Lys Pro Glu Val Gly Arg Asn Lys Lys Ala Ala Gly Ile Asp Pro Met Glu Gln Pro His Ser Thr Gln His Val Glu Asn Leu Leu Pro Arg Glu His Arg Val Asp Val Glu Thr <210>16 <211>732 <212>PRT

<213>Homo sapiens <400> 16 Met Glu Arg Gln Val Leu Leu Ser Glu Pro Glu Glu Ala Ala Ala Leu Tyr Arg Gly Leu Ser Arg Gln Pro Ala Leu Ser Ala Ala Cys Leu Gly Pro Glu Val Thr Thr Gln Tyr Gly Gly Gln Tyr Arg Thr Val His Thr Glu Trp Thr Gln Arg Asp Leu Glu Arg Met Glu Asn Ile Arg Phe Cys Arg Gln Tyr Leu Val Phe His Asp Gly Asp Ser Val Val Phe Ala Gly Pro Ala Gly Asn Ser Val Glu Thr Arg Gly Glu Leu Leu Ser Arg Glu Ser Pro Ser Gly Ser Met Lys Ala Val Leu Arg Lys Ala Gly Gly Thr Gly Pro Gly Glu Glu Lys Gln Phe Leu Glu Val Trp Glu Lys Asn Arg Lys Leu Lys Ser Phe Asn Leu Ser Val Leu Glu Lys His Gly Pro Val Tyr Glu Asp Asp Cys Phe Gly Cys Leu Ser Trp Ser His Ser Glu Thr His Leu Leu Tyr Val Ala Glu Arg Lys Arg Pro Lys Ala Glu Ser Phe Phe Gln Thr Lys Ala Leu Asp Val Ser Ala Ser Asp Asp Glu Ile Ala Arg Leu Lys Lys Pro Asp Gln Pro Ile Lys Gly Asp Gln Phe Val Phe Tyr Glu Asp Trp Gly Glu Asn Met Val Ser Lys Ser Ile Pro Val Leu Cys Val Leu Asp Val Glu Ser Gly Asn Ile Ser Val Leu Glu Gly Val Pro Glu Asn Val Ser Pro Gly Gln Ala Phe Trp Ala Pro Gly Asp Ala Gly Val Val Phe Val Gly Trp Trp His Glu Pro Phe Arg Leu Gly Ile Arg Phe Cys Thr Asn Arg Arg Ser Ala Leu Tyr Tyr Val Asp Leu Ile Gly Gly Lys Cys Glu Leu Leu Ser Asp Asp Ser Leu Ala Val Ser Ser Pro Arg Leu Ser Pro Asp Gln Cys Arg Ile Val Tyr Leu Gln Tyr Pro Ser Leu Ile Pro His His Gln Cys Ser Gln Leu Cys Leu Tyr Asp Trp Tyr Thr Lys Val Thr Ser Val Val Val Asp Val Val Pro Arg Gln Leu Gly Glu Asn Phe Ser Gly Ile Tyr Cys Ser Leu Leu Pro Leu Gly Cys Trp Ser Ala Asp Ser Gln Arg Val Val Phe Asp Ser Ala Gln Arg Ser Arg Gln Asp Leu Phe Ala Val Asp Thr Gln Val Gly Thr Val Thr Ser Leu Thr Ala Gly Gly Ser Gly Gly Ser Trp Lys Leu Leu Thr Ile Asp Gln Asp Leu Met Val Ala Gln Phe Ser Thr Pro Ser Leu Pro Pro Thr Leu Lys Val Gly Phe Leu Pro Ser Ala Gly Lys Glu Gln Ser Val Leu Trp Val Ser Leu Glu Glu Ala Glu Pro Ile Pro Asp Ile His Trp Gly Ile Arg Val Leu Gln Pro Pro Pro Glu Gln Glu Asn Val Gln Tyr Ala Gly Leu Asp Phe Glu Ala Ile Leu Leu Gln Pro Gly Ser Pro Pro Asp Lys Thr Gln Val Pro Met Val Val Met Pro His Gly Gly Pro His Ser Ser Phe Val Thr Ala Trp Met Leu Phe Pro Ala Met Leu Cys Lys Met Gly Phe Ala Val Leu Leu Val Asn Tyr Arg Gly Ser Thr Gly Phe Gly Gln Asp Ser Ile Leu Ser Leu Pro Gly Asn Val Gly His Gln Asp Val Lys Asp Val Gln Phe Ala Val Glu Gln Val Leu Gln Glu Glu His Phe Asp Ala Ser His Val Ala Leu Met Gly Gly Ser His Gly Gly Phe Ile Ser Cys His Leu Ile Gly Gln Tyr Pro Glu Thr Tyr Arg Ala Cys Val Ala Arg Asn Pro Val Ile Asn Ile Ala Ser Met Leu Gly Ser Thr Asp Ile Pro Asp Trp Cys Val Val Glu Ala Gly Phe Pro Phe Ser Ser Asp Cys Leu Pro Asp Leu Ser Val Trp Ala Glu Met Leu Asp Lys Ser Pro Ile Arg Tyr Ile Pro Gln Val Lys Thr Pro Leu Leu Leu Met Leu Gly Gln Glu Asp Arg Arg Val Pro Phe Lys Gln Gly Met Glu Tyr Tyr Arg Ala Leu Lys Thr Arg Asn Val Pro Val Arg Leu Leu Leu Tyr Pro Lys Ser Thr His Ala Leu Ser Glu Val Glu Val Glu Ser Asp Ser Phe Met Asn Ala Val Leu Trp Leu Arg Thr His Leu Gly Ser <210> 17 <211> 400 <212> PRT

<213> Homo Sapiens <300>
<301> Duprez, ER.
<302> Direct Submissin <303> Inserm U-301 <304> 1996 <309> 1996-11-26 <400> 17 Met Thr Thr Lys Asn Leu Glu Thr Lys Val Thr Val Thr Ser Ser Pro Ile Arg Gly Ala Gly Asp Gly Met Glu Thr Glu Glu Pro Pro Lys Ser Val Glu Val Thr Ser Gly Val Gln Ser Arg Lys His His Ser Leu Gln Ser Pro Trp Lys Lys Ala Val Pro Ser Glu Ser Pro Gly Val Leu Gln Leu Gly Lys Met Leu Thr Glu Lys Ala Met Glu Val Lys Ala Val Arg Ile Leu Val Pro Lys Ala Ala Ile Thr His Asp Ile Pro Asn Lys Asn Thr Lys Val Lys Ser Leu Gly His His Lys Gly Glu Phe Leu Gly Gln Ser Glu Gly Val Ile Glu Pro Asn Lys Glu Leu Ser Glu Val Lys Asn Val Leu Glu Lys Leu Lys Asn Ser Glu Arg Arg Leu Leu Gln Asp Lys Glu Gly Leu Ser Asn Gln Leu Arg Val Gln Thr Glu Val Asn Arg Glu Leu Lys Lys Leu Leu Val Ala Ser Val Gly Asp Asp Leu Gln Tyr His Phe Glu Arg Leu Ala Arg Glu Lys Asn Gln Leu Ile Leu Glu Asn Glu Ala Leu Gly Arg Asn Thr Ala Gln Leu Ser Glu Gln Leu Glu Arg Met Ser Ile Gln Cys Asp Val Trp Arg Ser Lys Phe Leu Ala Ser Arg Val Met Ala Asp Glu Leu Thr Asn Ser Arg Ala Ala Leu Gln Arg Gln Asn Arg Asp Ala His Gly Ala Ile Gln Asp Leu Leu Ser Glu Arg Glu Gln Phe Arg Gln Glu Met Ile Ala Thr Gln Lys Leu Leu Glu Glu Leu Leu Val Ser Leu Gln Trp Gly Arg Glu Gln Thr Tyr Ser Pro Ser Val Gln Pro His Ser Thr Ala Glu Leu Ala Leu Thr Asn His Lys Leu Ala Lys Ala Val Asn Ser His Leu Leu Gly Asn Val Gly Ile Asn Asn Gln Lys Lys Ile Pro Ser Thr Val Glu Phe Cys Ser Thr Pro Ala Glu Lys Met Ala Glu Thr Val Leu Arg Ile Leu Asp Pro Val Thr Cys Lys Glu Ser Ser Pro Asp Asn Pro Phe Phe Glu Ser Ser Pro Thr Thr Leu Leu Ala Thr Lys Lys Asn Ile Gly Arg Phe His Pro Tyr Thr Arg Tyr Glu Asn Ile Thr Phe Asn Cys Cys Asn His Cys Arg Gly Glu Leu Ile Ala Leu <210>18 <211>319 <212>PRT

<213>Mus musculus <300>
<301> Zou, Y.

<302> CARP, a cardiac ankyrin repea protein, is downstream in the Nkx2-5 homeobox gene pathway <303> Development <304> 1996 <305> 124 <306> 793-804 <313> 1 TO 319 <400> 18 Met Met Val Leu Arg Val Glu Glu Leu Val Thr Gly Lys Lys Asn Ser Asn Gly Ala Ala Gly Glu Phe Leu Pro Gly Glu Phe Arg Asn Gly Glu Tyr Glu Ala Ala Val Ala Leu Glu Lys Gln Glu Asp Leu Lys Thr Leu Pro Ala Asn Ser Val Lys Gln Gly Glu Glu Gln Arg Lys Ser Glu Lys Leu Arg Glu Ala Glu Leu Lys Lys Lys Lys Leu Glu Gln Arg Ser Lys Leu Glu Asn Leu Glu Asp Leu Glu Ile Ile Val Gln Leu Lys Lys Arg Lys Lys Tyr Lys Lys Thr Lys Val Pro Val Val Lys Glu Pro Glu Pro Glu Ile Met Thr Glu Pro Val Asp Val Pro Arg Phe Leu Lys Ala Ala Leu Glu Asn Lys Leu Pro Val Val Glu Lys Leu Val Ser Asp Lys Asn Ser Pro Asp Val Cys Asp Glu Tyr Lys Arg Thr Ala Leu His Arg Ala Cys Leu Glu Gly His Leu Ala Ile Val Glu Lys Leu Met Glu Ala Gly Ala Gln Ile Glu Phe Arg Asp Met Leu Glu Ser Thr Ala Ile His Trp Ala Cys Arg Gly Gly Asn Ala Asp Val Leu Lys Leu Leu Leu Asn Lys Gly Ala Lys Ile Ser Ala Arg Asp Lys Leu Leu Ser Thr Ala Leu His Val Ala Val Arg Thr Gly His Tyr Glu Cys Ala Glu His Leu Ile Ala Cys Glu Ala Asp Leu Asn Ala Lys Asp Arg Glu Gly Asp Thr Pro Leu His Asp Ala Val Arg Leu Asn Arg Tyr Lys Met Ile Arg Leu Leu Met Thr Phe Gly Ala Asp Leu Lys Val Lys Asn Cys Ala Gly Lys Thr Pro Met Asp Leu Val Leu His Trp Gln Ser Gly Thr Lys Ala Ile Phe Asp Ser Pro Lys Glu Asn Ala Tyr Lys Asn Ser Arg Ile Ala Thr Phe <210> 19 <211> 319 <212> PRT
<213> Homo Sapiens <400> 19 Met Met Val Leu Lys Val Glu Glu Leu Val Thr Gly Lys Lys Asn Gly Asn Gly Glu Ala Gly Glu Phe Leu Pro Glu Asp Phe Arg Asp Gly Glu Tyr Glu Ala Ala Val Thr Leu Glu Lys Gln Glu Asp Leu Lys Thr Leu Leu Ala His Pro Val Thr Leu Gly Glu Gln Gln Trp Lys Ser Glu Lys Gln Arg Glu Ala Glu Leu Pro Lys Lys Lys Leu Glu Gln Arg Ser Lys Leu Glu Asn Leu Glu Asp Leu Glu Ile Ile Ile Gln Leu Lys Lys Arg Lys Lys Tyr Arg Lys Thr Lys Val Pro Val Val Lys Glu Pro Glu Pro Glu Ile Ile Thr Glu Pro Val Asp Val Pro Thr Phe Leu Lys Ala Ala Leu Glu Asn Lys Leu Pro Val Val Glu Lys Phe Leu Ser Asp Lys Asn Asn Pro Asp Val Cys Asp Glu Tyr Lys Arg Thr Ala Leu His Arg Ala Cys Leu Glu Gly His Leu Ala Ile Val Glu Lys Leu Met Glu Ala Gly Ala Gln Ile Glu Phe Arg Asp Met Leu Glu Ser Thr Ala Ile His Trp Ala Ser Arg Gly Gly Asn Leu Asp Val Leu Lys Leu Leu Leu Asn Lys Gly Ala Lys Ile Ser Ala Arg Asp Lys Leu Leu Ser Thr Ala Leu His Val Ala Val Arg Thr Gly His Tyr Glu Cys Ala Glu His Leu Ile Ala Cys Glu Ala Asp Leu Asn Ala Lys Asp Arg Glu Gly Asp Thr Pro Leu His Asp Ala Val Arg Leu Asn Arg Tyr Lys Met Ile Arg Leu Leu Ile Met Tyr Gly Ala Asp Leu Asn Ile Lys Asn Cys Ala Gly Lys Thr Pro Met Asp Leu Val Leu His Trp Gln Asn Gly Thr Lys Ala Ile Phe Asp Ser Leu Arg Glu Asn Ser Tyr Lys Thr Ser Arg Ile Ala Thr Phe <210> 20 <211> 490 <212> PRT
<213> Homo sapiens <300>
<301> Field, L. L.

<302> Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31 <303> Genomics <304> 1996 <305> 33 <306> 1-8 <313> 1 TO 490 <400> 20 Met Gly Pro Val Met Pro Pro Ser Lys Lys Pro Glu Ser Ser Gly Ile Ser Val Ser Ser Gly Leu Ser Gln Cys Tyr Gly Gly Ser Gly Phe Ser Lys Ala Leu Gln Glu Asp Asp Asp Leu Asp Phe Ser Leu Pro Asp Ile Arg Leu Glu Glu Gly Ala Met Glu Asp Glu Glu Leu Thr Asn Leu Asn Trp Leu His Glu Ser Lys Asn Leu Leu Lys Ser Phe Gly Glu Ser Val Leu Arg Ser Val Ser Pro Val Gln Asp Leu Asp Asp Asp Thr Pro Pro Ser Pro Ala His Ser Asp Met Pro Tyr Asp Ala Arg Gln Asn Pro Asn Cys Lys Pro Pro Tyr Ser Phe Ser Cys Leu Ile Phe Met Ala Ile Glu Asp Ser Pro Thr Lys Arg Leu Pro Val Lys Asp Ile Tyr Asn Trp Ile Leu Glu His Phe Pro Tyr Phe Ala Asn Ala Pro Thr Gly Trp Lys Asn Ser Val Arg His Asn Leu Ser Leu Asn Lys Cys Phe Lys Lys Val Asp Lys Glu Arg Ser Gln Ser Ile Gly Lys Gly Ser Leu Trp Cys Ile Asp Pro Glu Tyr Arg Gln Asn Leu Ile Gln Ala Leu Lys Lys Thr Pro Tyr His Pro His Pro His Val Phe Asn Thr Pro Pro Thr Cys Pro Gln Ala Tyr Gln Ser Thr Ser Gly Pro Pro Ile Trp Pro Gly Ser Thr Phe Phe Lys Arg Asn Gly Ala Leu Leu Gln Asp Pro Asp Ile Asp Ala Ala Ser Ala Met Met Leu Leu Asn Thr Pro Pro Glu Ile Gln Ala Gly Phe Pro Pro Gly Val Ile Gln Asn Gly Ala Arg Val Leu Ser Arg Gly Leu Phe Pro Gly Val Arg Pro Leu Pro Ile Thr Pro Ile Gly Val Thr Ala Ala Met Arg Asn Gly Ile Thr Ser Cys Arg Met Arg Thr Glu Ser Glu Pro Ser Cys Gly Ser Pro Val Val Ser Gly Asp Pro Lys Glu Asp His Asn Tyr Ser Ser Ala Lys Ser Ser Asn Ala Arg Ser Thr Ser Pro Thr Ser Asp Ser Ile Ser Ser Ser Ser Ser Ser Ala Asp Asp His Tyr Glu Phe Ala Thr Lys Gly Ser Gln Glu Gly Ser Glu Gly Ser Glu Gly Ser Phe Arg Ser His Glu Ser Pro Ser Asp Thr Glu Glu Asp Asp Arg Lys His Ser Gln Lys Glu Pro Lys Asp Ser Leu Gly Asp Ser Gly Tyr Ala Ser Gln His Lys Lys Arg Gln His Phe Ala Lys Ala Arg Lys Val Pro Ser Asp Thr Leu Pro Leu Lys Lys Arg Arg Thr Glu Lys Pro Pro Glu Ser Asp Asp Glu Glu Met Lys Glu Ala Ala Gly Ser Leu Leu His Leu Ala Gly Ile Arg Ser Cys Leu Asn Asn Ile Thr Asn Arg Thr Ala Lys Gly Gln Lys Glu Gln Lys Glu Thr Thr Lys Asn <210>21 <211>212 <212>PRT

<213>Mus musculus <300>
<301> Laufer, W.
<302> GTP-binding protein (rab2) <400> 21 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr Ile Ile Ile Gly Asp Thr Gly Val Gly Lys Ser Cys Leu Leu Leu Gln Phe Thr Asp Lys Arg Phe Gln Pro Val His Asp Leu Thr Ile Gly Val Glu Phe Gly Ala Arg Met Ile Thr Ile Asp Gly Lys Gln Ile Lys Leu Gln Ile Trp Asp Thr Ala Gly Gln Glu Ser Phe Arg Ser Ile Thr Arg Ser Tyr Tyr Arg Gly Ala Ala Gly Ala Leu Leu Val Tyr Asp Ile Thr Arg Arg Asp Thr Phe Asn His Leu Thr Thr Trp Leu Glu Asp Ala Arg Gln His Ser Asn Ser Asn Met Val Ile Met Leu Ile Gly Asn Lys Ser Asp Leu Glu Ser Arg Arg Glu Val Lys Lys Glu Glu Gly Glu Ala Phe Ala Arg Glu His Gly Leu Ile Phe Met Glu Thr Ser Ala Lys Thr Ala Ser Asn Val Glu Glu Ala Phe Ile Asn Thr Ala Lys Glu Ile Tyr Glu Lys Ile Gln Glu Gly Val Phe Asp Ile Asn Asn Glu Ala Asn Gly Ile Lys Ile Gly Pro Gln His Ala Ala Thr Asn Ala Ser His Gly Ser Asn Gln Gly Gly Gln Gln Ala Gly Gly Gly Cys Cys <210> 22 <211> 212 <212> PRT
<213> Homo Sapiens <300>
<301> Tachibana, K.
<302> Nucleotide sequence of a new YPT1-related human cDNA
which belongs to the ras gene superfamily <303> Nucleic Acids Res.
<304> 1988 <305> 16 <306> 10368-<313> 1 TO 212 <400> 22 Met Ala Tyr Ala Tyr Leu Phe Lys Tyr Ile Ile Ile Gly Asp Thr Gly Val Gly Lys Ser Cys Leu Leu Leu Gln Phe Thr Asp Lys Arg Phe Gln Pro Val His Asp Leu Thr Ile Gly Val Glu Phe Gly Ala Arg Met Ile Thr Ile Asp Gly Lys Gln Ile Lys Leu Gln Ile Trp Asp Thr Ala Gly Gln Glu Ser Phe Arg Ser Ile Thr Arg Ser Tyr Tyr Arg Gly Ala Ala Gly Ala Leu Leu Val Tyr Asp Ile Thr Arg Arg Asp Thr Phe Asn His Leu Thr Thr Trp Leu Glu Asp Ala Arg Gln His Ser Asn Ser Asn Met Val Ile Met Leu Ile Gly Asn Lys Ser Asp Leu Glu Ser Arg Arg Glu Val Lys Lys Glu Glu Gly Glu Ala Phe Ala Arg Glu His Gly Leu Met Phe Met Glu Thr Ser Ala Lys Thr Ala Ser Asn Val Glu Glu Ala Phe Ile Asn Thr Ala Lys Glu Ile Tyr Glu Lys Ile Gln Glu Gly Val Phe Asp Ile Asn Asn Glu Ala Asn Gly Ile Lys Ile Gly Pro Gln His Ala Ala Thr Asn Ala Thr His Ala Gly Asn Gln Gly Gly Gln Gln Ala Gly Gly Gly Cys Cys <210> 23 <211> 1712 <212> PRT
<213> Homo Sapiens <300>
<301> Fontoura, B. M.
<302> A conserved biogenesis pathway for nucleoporins:
proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin , nup96 <303> J. Cell Biol.
<304> 1999 <305> 144 <306> 1097-1112 <313> 1 TO 1712 <400> 23 Met Phe Asn Lys Ser Phe Gly Thr Pro Phe Gly Gly Gly Thr Gly Gly Phe Gly Thr Thr Ser Thr Phe Gly Gln Asn Thr Gly Phe Gly Thr Thr Ser Gly Gly Ala Phe Gly Thr Ser Ala Phe Gly Ser Ser Asn Asn Thr Gly Gly Leu Phe Gly Asn Ser Gln Thr Lys Pro Gly Gly Leu Phe Gly Thr Ser Ser Phe Ser Gln Pro Ala Thr Ser Thr Ser Thr Gly Phe Gly Phe Gly Thr Ser Thr Gly Thr Ala Asn Thr Leu Phe Gly Thr Ala Ser Thr Gly Thr Ser Leu Phe Ser Ser Gln Asn Asn Ala Phe Ala Gln Asn Lys Pro Thr Gly Phe Gly Asn Phe Gly Thr Ser Thr Ser Ser Gly Gly Leu Phe Gly Thr Thr Asn Thr Thr Ser Asn Pro Phe Gly Ser Thr Ser Gly Ser Leu Phe Gly Pro Ser Ser Phe Thr Ala Ala Pro Thr Gly Thr Thr Ile Lys Phe Asn Pro Pro Thr Gly Thr Asp Thr Met Val Lys Ala Gly Val Ser Thr Asn Ile Ser Thr Lys His Gln Cys Ile Thr Ala Met Lys Glu Tyr Glu Ser Lys Ser Leu Glu Glu Leu Arg Leu Glu Asp Tyr Gln Ala Asn Arg Lys Gly Pro Gln Asn Gln Val Gly Ala Gly Thr Thr Thr Gly Leu Phe Gly Ser Ser Pro Ala Thr Ser Ser Ala Thr Gly Leu Phe Ser Ser Ser Thr Thr Asn Ser Gly Phe Ala Tyr Gly Gln Asn Lys Thr Ala Phe Gly Thr Ser Thr Thr Gly Phe Gly Thr Asn Pro Gly Gly Leu Phe Gly Gln Gln Asn Gln Gln Thr Thr Ser Leu Phe Ser Lys Pro Phe Gly Gln Ala Thr Thr Thr Gln Asn Thr Gly Phe Ser Phe Gly Asn Thr Ser Thr Ile Gly Gln Pro Ser Thr Asn Thr Met Gly Leu Phe Gly Val Thr Gln Ala Ser Gln Pro Gly Gly Leu Phe Gly Thr Ala Thr Asn Thr Ser Thr Gly Thr Ala Phe Gly Thr Gly Thr Gly Leu Phe Gly Gln Thr Asn Thr Gly Phe Gly Ala Val Gly Ser Thr Leu Phe Gly Asn Asn Lys Leu Thr Thr Phe Gly Ser Ser Thr Thr Ser Ala Pro Ser Phe Gly Thr Thr Ser Gly Gly Leu Phe Gly Phe Gly Thr Asn Thr Ser Gly Asn Ser Ile Phe Gly Ser Lys Pro Ala Pro Gly Thr Leu Gly Thr Gly Leu Gly Ala Gly Phe Gly Thr Ala Leu Gly Ala Gly Gln Ala Ser Leu Phe Gly Asn Asn Gln Pro Lys Ile Gly Gly Pro Leu Gly Thr Gly Ala Phe Gly Ala Pro Gly Phe Asn Thr Thr Thr Ala Thr Leu Gly Phe Gly Ala Pro Gln Ala Pro Val Ala Leu Thr Asp Pro Asn Ala Ser Ala Ala Gln Gln Ala Val Leu Gln Gln His Ile Asn Ser Leu Thr Tyr Ser Pro Phe Gly Asp Ser Pro Leu Phe Arg Asn Pro Met Ser Asp Pro Lys Lys Lys Glu Glu Arg Leu Lys Pro Thr Asn Pro Ala Ala Gln Lys Ala Leu Thr Thr Pro Thr His Tyr Lys Leu Thr Pro Arg Pro Ala Thr Arg Val Arg Pro Lys Ala Leu Gln Thr Thr Gly Thr Ala Lys Ser His Leu Phe Asp Gly Leu Asp Asp Asp Glu Pro Ser Leu Ala Asn Gly Ala Phe Met Pro Lys Lys Ser Ile Lys Lys Leu Val Leu Lys Asn Leu Asn Asn Ser Asn Leu Phe Ser Pro Val Asn Arg Asp Ser Glu Asn Leu Ala Ser Pro Ser Glu Tyr Pro Glu Asn Gly Glu Arg Phe Ser Phe Leu Ser Lys Pro Val Asp Glu Asn His Gln Gln Asp Gly Asp Glu Asp Ser Leu Val Ser His Phe Tyr Thr Asn Pro Ile Ala Lys Pro Ile Pro Gln Thr Pro Glu Ser Ala Gly Asn Lys His Ser Asn Ser Asn Ser Val Asp Asp Thr Ile Val Ala Leu Asn Met Arg Ala Ala Leu Arg Asn Gly Leu Glu Gly Ser Ser Glu Glu Thr Ser Phe His Asp Glu Ser Leu Gln Asp Asp Arg Glu Glu Ile Glu Asn Asn Ser Tyr His Met His Pro Ala Gly Ile Ile Leu Thr Lys Val Gly Tyr Tyr Thr Ile Pro Ser Met Asp Asp Leu Ala Lys Ile Thr Asn Val Phe Gly Glu Cys Ile Val Ser Asp Phe Thr Ile Gly Arg Lys Gly Tyr Gly Ser Ile Tyr Phe Glu Gly Asp Val Asn Leu Thr Asn Leu Asn Leu Asp Asp Ile Val His Ile Arg Arg Lys Glu Val Val Val Tyr Leu Asp Asp Asn Gln Lys Pro Pro Val Gly Glu Gly Leu Asn Arg Lys Ala Glu Val Thr Leu Asp Gly Val Trp Pro Thr Asp Lys Thr Ser Arg Cys Leu Ile Lys Ser Pro Asp Arg Leu Ala Asp Ile Asn Tyr Glu Gly Arg Leu Glu Ala Val Ser Arg Lys Gln Gly Ala Gln Phe Lys Glu Tyr Arg Pro Glu Thr Gly Ser Trp Val Phe Lys Val Ser His Phe Ser Lys Tyr Gly Leu Gln Asp Ser Asp Glu Glu Glu Glu Glu His Pro Ser Lys Thr Ser Thr Lys Lys Leu Lys Thr Ala Pro Leu Pro Pro Ala Ser Gln Thr Thr Pro Leu Gln Met Ala Leu Asn Gly Lys Pro Ala Pro Pro Pro Gln Ser Gln Ser Pro Glu Val Glu Gln Leu Gly Arg Val Val Glu Leu Asp Ser Asp Met Val Asp Ile Thr Gln Glu Pro Val Leu Asp Thr Met Leu Glu Glu Ser Met Pro Glu Asp Gln Glu Pro Val Ser Ala Ser Thr His Ile Ala Ser Ser Leu Gly Ile Asn Pro His Val Leu Gln Ile Met Lys Ala Ser Leu Leu Thr Asp Glu Glu Asp Val Asp Met Ala Leu Asp Gln Arg Phe Ser Arg Leu Pro Ser Lys Ala Asp Thr Ser Gln Glu Ile Cys Ser Pro Arg Leu Pro Ile Ser Ala Ser His Ser Ser Lys Thr Arg Ser Leu Val Gly Gly Leu Leu Gln Ser Lys Phe Thr Ser Gly Ala Phe Leu Ser Pro Ser Val Ser Val Gln Glu Cys Arg Thr Pro Arg Ala Ala Ser Leu Met Asn Ile Pro Ser Thr Ser Ser Trp Ser Val Pro Pro Pro Leu Thr Ser Val Phe Thr Met Pro Ser Pro Ala Pro Glu Val Pro Leu Lys Thr Val Gly Thr Arg Arg Gln Leu Gly Leu Val Pro Arg Glu Lys Ser Val Thr Tyr Gly Lys Gly Lys Leu Leu Met Asp Met Ala Leu Phe Met Gly Arg Ser Phe Arg Val Gly Trp Gly Pro Asn Trp Thr Leu Ala Asn Ser Gly Glu Gln Leu Asn Gly Ser His Glu Leu Glu Asn His Gln Ile Ala Asp Ser Met Glu Phe Gly Phe Leu Pro Asn Pro Val Ala Val Lys Pro Leu Thr Glu Ser Pro Phe Lys Val His Leu Glu Lys Leu Ser Leu Arg Gln Arg Lys Pro Asp Glu Asp Met Lys Leu Tyr Gln Thr Pro Leu Glu Leu Lys Leu Lys His Ser Thr Val His Val Asp Glu Leu Cys Pro Leu Ile Val Pro Asn Leu Gly Val Ala Val Ile His Asp Tyr Ala Asp Trp Val Lys Glu Ala Ser Gly Asp Leu Pro Glu Ala Gln Ile Val Lys His Trp Ser Leu Thr Trp Thr Leu Cys Glu Ala Leu Trp Ala His Leu Lys Glu Leu Asp Ser Gln Leu Asn Glu Pro Arg Glu Tyr Ile Gln Ile Leu Glu Arg Arg Arg Ala Phe Ser Arg Trp Leu Ser Cys Thr Ala Thr Pro Gln Ile Glu Glu Glu Val Ser Leu Thr Gln Lys Asn Ser Pro Val Glu Ala Val Phe Ser Tyr Leu Thr Gly Lys Arg Ile Ser Glu Ala Cys Ser Leu Ala Gln Gln Ser Gly Asp His Arg Leu Ala Leu Leu Leu Ser Gln Phe Val Gly Ser Gln Ser Val Arg Glu Leu Leu Thr Met Gln Leu Val Asp Trp His Gln Leu Gln Ala Asp Ser Phe Ile Gln Asp Glu Arg Leu Arg Ile Phe Ala Leu Leu Ala Gly Lys Pro Val Trp Gln Leu Ser Glu Lys Lys Gln Ile Asn Val Cys Ser Gln Leu Asp Trp Lys Arg Ser Leu Ala Ile His Leu Trp Tyr Leu Leu Pro Pro Thr Ala Ser Ile Ser Arg Ala Leu Ser Met Tyr Glu Glu Ala Phe Gln Asn Thr Ser Asp Ser Asp Arg Tyr Ala Cys Ser Pro Leu Pro Ser Tyr Leu Glu Gly Ser Gly Cys Val Ile Ala Glu Glu Gln Asn Ser Gln Thr Pro Leu Arg Asp Val Cys Phe His Leu Leu Lys Leu Tyr Ser Asp Arg His Tyr Asp Leu Asn Gln Leu Leu Glu Pro Arg Ser Ile Thr Ala Asp Pro Leu Asp Tyr Arg Leu Ser Trp His Leu Trp Glu Val Leu Arg Asp Leu Lys Tyr Thr His Leu Ser Ala Gln Cys Glu Gly Val Leu Gln Ala Ser Tyr Ala Gly Gln Leu Glu Ser Glu Gly Leu Trp Glu Trp Ala Ile Phe Val Leu Leu His Ile Asp Asn Ser Gly Ile Arg Glu Lys Ala Val Arg Glu Leu Leu Thr Arg His Cys Gln Leu Leu Glu Thr Pro Glu Ser Trp Ala Lys Glu Thr Phe Leu Thr Gln Lys Leu Arg Val Pro Ala Lys Trp Ile His Glu Ala Lys Ala Val Arg Ala His Met Glu Ser Asp Lys His Leu Glu Ala Leu Cys Leu Phe Lys Ala Glu His Trp Asn Arg Cys His Lys Leu Ile Ile Arg His Leu Ala Ser Asp Ala Ile Ile Asn Glu Asn Tyr Asp Tyr Leu Lys Gly Phe Leu Glu Asp Leu Ala Pro Pro Glu Arg Ser Ser Leu Ile Gln Asp Trp Glu Thr Ser Gly Leu Val Tyr Leu Asp Tyr Ile Arg Val Ile Glu Met Leu Arg His Ile Gln Gln Val Glu His Phe Asn Asp Ser Asn Ile Val Gln Val Met Thr Trp Ser Ser Tyr Thr Ser Lys <210>24 <211>599 <212>PRT

<213>Mus musculus <300>
<301> De Coignac, A. B.
<302> cDNA cloning and expression analysis of the murine ribonuclease L inhibitor <303> Gene <304> 1998 <305> 209 <306> 149-156 <313> 1 TO 599 <400> 24 Met Ala Asp Lys Leu Thr Arg Ile Ala Ile Val Asn His Asp Lys Cys Lys Pro Lys Lys Cys Arg Gln Glu Cys Lys Lys Ser Cys Pro Val Val Arg Met Gly Lys Leu Cys Ile Glu Val Thr Pro Gln Ser Lys Ile Ala Trp Ile Ser Glu Thr Leu Cys Ile Gly Cys Gly Ile Cys Ile Lys Lys Cys Pro Phe Gly Ala Leu Ser Ile Val Asn Leu Pro Ser Asn Leu Glu Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg Leu Pro Ile Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn Gly Ile Gly Lys Ser Thr Ala Leu Lys Ile Leu Ala Gly Lys Gln Lys Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gln Glu Ile Leu Thr Tyr Phe Arg Gly Ser Glu Leu Lys Asn Tyr Phe Thr Thr Ile Leu Glu Asp Asp Leu Lys Ala Ile Ile Lys Pro Gln Tyr Val Asp Gln Ile Pro Lys Ala Ala Lys Gly Thr Val Gly Ser Ile Leu Asp Arg Lys Asp Glu Thr Lys Thr Gln Ala Ile Val Cys Gln Gln Leu Asp Leu Thr His Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gln Arg Phe Ala Cys Ala Val Val Cys Ile Gln Lys Ala Asp Ile Phe Met Phe Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gln Arg Leu Lys Ala Ala Ile Thr Ile Arg Ser Leu Ile Asn Pro Asp Arg Tyr Ile Ile Val Val Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe Ile Cys Cys Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser Val Arg Glu Gly Ile Asn Ile Phe Leu Asp Gly Tyr Val Pro Thr Glu Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala Ile Val Ala Gly Glu Phe Thr Asp Ser Glu Ile Met Val Met Leu Gly Glu Asn Gly Thr Gly Lys Thr Thr Phe Ile Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gln Lys Ile Ser Pro Lys Ser Thr Gly Ser Val Arg Gln Leu Leu His Glu Lys Ile Arg Asp Ala Tyr Thr His Pro Gln Phe Val Thr Asp Val Met Lys Pro Leu Gln Ile Glu Asn Ile Ile Asp Gln Glu Val Gln Thr Leu Ser Gly Gly Glu Leu Gln Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala Asp Val Tyr Leu Ile Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gln Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe Ile Leu His Ala Lys Lys Thr Ala Phe Val Val Glu His Asp Phe Ile Met Ala Thr Tyr Leu Ala Asp Arg Val Ile Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val Ala Asn Ser Pro Gln Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser Gln Leu Glu Ile Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg Ile Asn Lys Leu Asn Ser Ile Lys Asp Val Glu Gln Lys Lys Ser Gly Asn Tyr Phe Phe Leu Asp Asp <210> 25 <211> 599 <212> PRT
<213> Homo Sapiens <300>
<301> Bisbal, C.
<302> Cloning and characterization of a RNAse L inhibitor. A
new component of the interferon-regulated 2-5A pathway <303> J. Biol. Chem.
<304> 1995 <305> 270 <306> 13308-13317 <313> 1 TO 599 <400> 25 Met Ala Asp Lys Leu Thr Arg Ile Ala Ile Val Asn His Asp Lys Cys Lys Pro Lys Lys Cys Arg Gln Glu Cys Lys Lys Ser Cys Pro Val Val Arg Met Gly Lys Leu Cys Ile Glu Val Thr Pro Gln Ser Lys Ile Ala Trp Ile Ser Glu Thr Leu Cys Ile Gly Cys Gly Ile Cys Ile Lys Lys Cys Pro Phe Gly Ala Leu Ser Ile Val Asn Leu Pro Ser Asn Leu Glu Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg Leu Pro Ile Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn Gly Ile Gly Lys Ser Ala Ala Leu Lys Ile Leu Ala Gly Lys Gln Lys Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gln Glu Ile Leu Thr Tyr Phe Arg Gly Ser Glu Leu Gln Asn Tyr Phe Thr Lys Ile Leu Glu Asp Asp Leu Lys Ala Ile Ile Lys Pro Gln Tyr Val Ala Arg Phe Leu Arg Leu Ala Lys Gly Thr Val Gly Ser Ile Leu Asp Arg Lys Asp Glu Thr Lys Thr Gln Ala Ile Val Cys Gln Gln Leu Asp Leu Thr His Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gln Arg Phe Ala Cys Ala Val Val Cys Ile Gln Lys Ala Asp Ile Phe Met Phe Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gln Arg Leu Lys Ala Ala Ile Thr Ile Arg Ser Leu Ile Asn Pro Asp Arg Tyr Ile Ile Val Val Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe Ile Cys Cys Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser Val Arg Glu Gly Ile Asn Ile Phe Leu Asp Gly Tyr Val Pro Thr Glu Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala Ile Val Ala Gly Glu Phe Thr Asp Ser Glu Ile Met Val Met Leu Gly Glu Asn Gly Thr Gly Lys Thr Thr Phe Ile Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gln Lys Ile Ser Pro Lys Ser Thr Gly Ser Val Arg Gln Leu Leu His Glu Lys Ile Arg Asp Ala Tyr Thr His Pro Gln Phe Val Thr Asp Val Met Lys Pro Leu Gln Ile Glu Asn Ile Ile Asp Gln Glu Val Gln Thr Leu Ser Gly Gly Glu Leu Gln Arg Val Arg Leu Arg Leu Cys Leu Gly Lys Pro Ala Asp Val Tyr Leu Ile Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gln Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe Ile Leu His Ala Lys Lys Thr Ala Phe Val Val Glu His Asp Phe Ile Met Ala Thr Tyr Leu Ala Asp Arg Val Ile Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val Ala Asn Ser Pro Gln Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser Gln Leu Glu Ile Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg Ile Asn Lys Leu Asn Ser Ile Lys Asp Val Glu Gln Lys Lys Ser Gly Asn Tyr Phe Phe Leu Asp Asp <210>26 <211>599 <212>PRT

<213>Mus musculus <400> 26 Met Ala Asp Lys Leu Thr Arg Ile Ala Ile Val Asn His Asp Lys Cys Lys Pro Lys Lys Cys Arg Gln Glu Cys Lys Lys Ser Cys Pro Val Val Arg Met Gly Lys Leu Cys Ile Glu Val Thr Pro Gln Ser Lys Ile Ala Trp Ile Ser Glu Thr Leu Cys Ile Gly Cys Gly Ile Cys Ile Lys Lys Cys Pro Phe Gly Ala Leu Ser Ile Val Asn Leu Pro Ser Asn Leu Glu Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg Leu Pro Ile Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn Gly Ile Gly Lys Ser Thr Ala Leu Lys Ile Leu Ala Gly Lys Gln Lys Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gln Glu Ile Leu Thr Tyr Phe Arg Gly Ser Glu Leu Gln Asn Tyr Phe Thr Lys Ile Leu Glu Asp Asp Leu Lys Ala Ile Ile Lys Pro Gln Tyr Val Asp Gln Ile Pro Lys Ala Ala Lys Gly Thr Val Gly Ser Ile Leu Asp Arg Lys Asp Glu Thr Lys Thr Gln Ala Ile Val Cys Gln Gln Leu Asp Leu Thr His Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gln Arg Phe Ala Cys Ala Val Val Cys Ile Gln Lys Ala Asp Ile Phe Met Phe Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gln Arg Leu Lys Ala Ala Ile Thr Ile Arg Ser Leu Ile Asn Pro Asp Arg Tyr Ile Ile Val Val Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe Ile Cys Cys Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser Val Arg Glu Gly Ile Asn Ile Phe Leu Asp Gly Tyr Val Pro Thr Glu Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala Ile Val Ala Gly Glu Phe Thr Asp Ser Glu Ile Met Val Met Leu Gly Glu Asn Gly Thr Gly Lys Thr Thr Phe Ile Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gln Lys Ile Ser Pro Lys Ser Thr Gly Ser Val Arg Gln Leu Leu His Glu Lys Ile Arg Asp Ala Tyr Thr His Pro Gln Phe Val Thr Asp Val Met Lys Pro Leu Gln Ile Glu Asn Ile Ile Asp Gln Glu Val Gln Thr Leu Ser Gly Gly Glu Leu Gln Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala Asp Val Tyr Leu Ile Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gln Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe Ile Leu His Ala Lys Lys Thr Ala Phe Val Val Glu His Asp Phe Ile Met Ala Thr Tyr Leu Ala Asp Arg Val Ile Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val Ala Asn Ser Pro Gln Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser Gln Leu Glu Ile Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg Ile Asn Lys Leu Asn Ser Ile Lys Asp Val Glu Gln Lys Lys Ser Gly Asn Tyr Phe Phe Leu Asp Asp <210> 27 <211> 599 <212> PRT
<213> Homo sapiens <400> 27 Met Ala Asp Lys Leu Thr Arg Ile Ala Ile Val Asn His Asp Lys Cys Lys Pro Lys Lys Cys Arg Gln Glu Cys Lys Lys Ser Cys Pro Val Val Arg Met Gly Lys Leu Cys Ile Glu Val Thr Pro Gln Ser Lys Ile Ala Trp Ile Ser Glu Thr Leu Cys Ile Gly Cys Gly Ile Cys Ile Lys Lys Cys Pro Phe Gly Ala Leu Ser Ile Val Asn Leu Pro Ser Asn Leu Glu Lys Glu Thr Thr His Arg Tyr Cys Ala Asn Ala Phe Lys Leu His Arg Leu Pro Ile Pro Arg Pro Gly Glu Val Leu Gly Leu Val Gly Thr Asn Gly Ile Gly Lys Ser Thr Ala Leu Lys Ile Leu Ala Gly Lys Gln Lys Pro Asn Leu Gly Lys Tyr Asp Asp Pro Pro Asp Trp Gln Glu Ile Leu Thr Tyr Phe Arg Gly Ser Glu Leu Gln Asn Tyr Phe Thr Lys Ile Leu Glu Asp Asp Leu Lys Ala Ile Ile Lys Pro Gln Tyr Val Asp Gln Ile Pro Lys Ala Ala Lys Gly Thr Val Gly Ser Ile Leu Asp Arg Lys Asp Glu Thr Lys Thr Gln Ala Ile Val Cys Gln Gln Leu Asp Leu Thr His Leu Lys Glu Arg Asn Val Glu Asp Leu Ser Gly Gly Glu Leu Gln Arg Phe Ala Cys Ala Val Val Cys Ile Gln Lys Ala Asp Ile Phe Met Phe Asp Glu Pro Ser Ser Tyr Leu Asp Val Lys Gln Arg Leu Lys Ala Ala Ile Thr Ile Arg Ser Leu Ile Asn Pro Asp Arg Tyr Ile Ile Val Val Glu His Asp Leu Ser Val Leu Asp Tyr Leu Ser Asp Phe Ile Cys Cys Leu Tyr Gly Val Pro Ser Ala Tyr Gly Val Val Thr Met Pro Phe Ser Val Arg Glu Gly Ile Asn Ile Phe Leu Asp Gly Tyr Val Pro Thr Glu Asn Leu Arg Phe Arg Asp Ala Ser Leu Val Phe Lys Val Ala Glu Thr Ala Asn Glu Glu Glu Val Lys Lys Met Cys Met Tyr Lys Tyr Pro Gly Met Lys Lys Lys Met Gly Glu Phe Glu Leu Ala Ile Val Ala Gly Glu Phe Thr Asp Ser Glu Ile Met Val Met Leu Gly Glu Asn Gly Thr Gly Lys Thr Thr Phe Ile Arg Met Leu Ala Gly Arg Leu Lys Pro Asp Glu Gly Gly Glu Val Pro Val Leu Asn Val Ser Tyr Lys Pro Gln Lys Ile Ser Pro Lys Ser Thr Gly Ser Val Arg Gln Leu Leu His Glu Lys Ile Arg Asp Ala Tyr Thr His Pro Gln Phe Val Thr Asp Val Met Lys Pro Leu Gln Ile Glu Asn Ile Ile Asp Gln Glu Val Gln Thr Leu Ser Gly Gly Glu Leu Gln Arg Val Ala Leu Ala Leu Cys Leu Gly Lys Pro Ala Asp Val Tyr Leu Ile Asp Glu Pro Ser Ala Tyr Leu Asp Ser Glu Gln Arg Leu Met Ala Ala Arg Val Val Lys Arg Phe Ile Leu His Ala Lys Lys Thr Ala Phe Val Val Glu His Asp Phe Ile Met Ala Thr Tyr Leu Ala Asp Arg Val Ile Val Phe Asp Gly Val Pro Ser Lys Asn Thr Val Ala Asn Ser Pro Gln Thr Leu Leu Ala Gly Met Asn Lys Phe Leu Ser Gln Leu Glu Ile Thr Phe Arg Arg Asp Pro Asn Asn Tyr Arg Pro Arg Ile Asn Lya Leu Asn Ser Ile Lys Asp Val Glu Gln Lys Lys Ser Gly Asn Tyr Phe Phe Leu Asp Asp <210>28 <211>614 <212>PRT

<213>Mus musculus <300>
<301> Lemaire, L.
<302> High-level expression in male germ cells of murine p68 RNA helicase mRNA
<303> Life Sci.
<304> 1993 <305> 52 <306> 917-926 <313> 1 TO 614 <400> 28 Met Ser Ser Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe Gly Ala Pro Arg Phe Gly Gly Ser Arg Thr Gly Pro Leu Ser Gly Lys Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gln Glu His Pro Asp Leu Ala Arg Arg Thr Ala Gln Glu Val Asp Thr Tyr Arg Arg Ser Lys Glu Ile Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val Ile Ala Arg His Asn Phe Thr Glu Pro Thr Ala Ile Gln Ala Gln Gly Trp Pro Val Ala Leu Ser Gly Leu Asp Met Val Gly Val Ala Gln Thr Gly Ser Gly Lys Thr Leu Ser Tyr Leu Leu Pro Ala Ile Val His Ile Asn His His Pro Phe Leu Glu Arg Gly Asp Gly Pro Ile Cys Leu Val Leu Ala Pro Thr Arg Glu Leu Ala Gln Gln Val Gln Gln Val Ala Ala Glu Tyr Cys Arg Ala Cys Arg Leu Lys Ser Thr Cys Ile Tyr Gly Gly Ala Pro Lys Gly Pro Gln Ile Arg Asp Leu Glu Arg Gly Val Glu Ile Cys Ile Ala Thr Pro Gly Arg Leu Ile Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met Gly Phe Glu Pro Gln Ile Arg Lys Ile Val Asp Gln Ile Arg Pro Asp Arg Gln Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gln Leu Ala Glu Asp Phe Leu Lys Asp Tyr Ile His Ile Asn Ile Gly Ala Leu Glu Leu Ser Ala Asn His Asn Ile Leu Gln Ile Val Asp Val Cys His Asp Val Glu Lys Asp Glu Lys Leu Ile Arg Leu Met Glu Glu Ile Met Ser Glu Lys Glu Asn Lys Thr Ile Val Phe Val Glu Thr Lys Arg Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala Met Gly Ile His Gly Asp Lys Ser Gln Gln Glu Arg Asp Trp Val Leu Asn Glu Phe Lys His Gly Lys Ala Pro Ile Leu Ile Ala Thr Asp Val Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val Ile Asn Tyr Asp Tyr Pro Asn Ser Ser Glu Asp Tyr Ile His Arg Ile Gly Arg Thr Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn Asn Ile Lys Gln Val Ser Asp Leu Ile Ser Val Leu Arg Glu Ala Asn Gln Ala Ile Asn Pro Lys Leu Leu Gln Leu Val Glu Asp Arg Gly Ser Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Asn Leu Leu Lys Arg Asp Phe Gly Ala Lys Thr Gln Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser Phe Gly Ser Asn Phe Val Ser Ala Gly Ile Gln Thr Ser Phe Arg Thr Gly Asn Pro Thr Gly Thr Tyr Gln Asn Gly Tyr Asp Ser Thr Gln Gln Tyr Gly Ser Asn Val Ala Asn Met His Asn Gly Met Asn Gln Gln Ala Tyr Ala Tyr Pro Val Pro Gln Pro Ala Pro Met Ile Gly Tyr Pro Met Pro Thr Gly Tyr Ser Gln <210>29 <211>614 <212>PRT

<213>Homo sapiens <300>
<301> Ford, M. J.
<302> Nuclear protein with sequence homology to translation initiation factor eIF-4A
<303> Nature <304> 1988 <305> 332 <306> 736-738 <313> 1 TO 614 <400> 29 Met Ser Gly Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe Gly Ala Pro Arg Phe Gly Gly Ser Arg Ala Gly Pro Leu Ser Gly Lys Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gln Glu His Pro Asp Leu Ala Arg Arg Thr Ala Gln Glu Val Glu Thr Tyr Arg Arg Ser Lys Glu Ile Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val Ile Ala Arg Gln Asn Phe Thr Glu Pro Thr Ala Ile Gln Ala Gln Gly Trp Pro Val Ala Leu Ser Gly Leu Asp Met Val Gly Val Ala Gln Thr Gly Ser Gly Lys Thr Leu Ser Tyr Leu Leu Pro Ala Ile Val His Ile Asn His Gln Pro Phe Leu Glu Arg Gly Asp Gly Pro Ile Cys Leu Val Leu Ala Pro Thr Arg Glu Leu Ala Gln Gln Val Gln Gln Val Ala Ala Glu Tyr Cys Arg Ala Cys Arg Leu Lys Ser Thr Cys Ile Tyr Gly Gly Ala Pro Lys Gly Pro Gln Ile Arg Asp Leu Glu Arg Gly Val Glu Ile Cys Ile Ala Thr Pro Gly Arg Leu Ile Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met Gly Phe Glu Pro Gln Ile Arg Lys Ile Val Asp Gln Ile Arg Pro Asp Arg Gln Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gln Leu Ala Glu Asp Phe Leu Lys Asp Tyr Ile His Ile Asn Ile Gly Ala Leu Glu Leu Ser Ala Asn His Asn Ile Leu Gln Ile Val Asp Val Cys His Asp Val Glu Lys Asp Glu Lys Leu Ile Arg Leu Met Glu Glu Ile Met Ser Glu Lys Glu Asn Lys Thr Ile Val Phe Val Glu Thr Lys Arg Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala Met Gly Ile His Gly Asp Lys Ser Gln Gln Glu Arg Asp Trp Val Leu Asn Glu Phe Lys His Gly Lys Ala Pro Ile Leu Ile Ala Thr Asp Val Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val Ile Asn Tyr Asp Tyr Pro Asn Ser Ser Glu Asp Tyr Ile His Arg Ile Gly Arg Thr Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn Asn Ile Lys Gln Val Ser Asp Leu Ile Ser Val Leu Arg Glu Ala Asn Gln Ala Ile Asn Pro Lys Leu Leu Gln Leu Val Glu Asp Arg Gly Ser Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Ser Leu Leu Lys Arg Asp Phe Gly Ala Lys Thr Gln Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser Phe Gly Ser Asn Phe Val Ser Ala Gly Ile Gln Thr Ser Phe Arg Thr Gly Asn Pro Thr Gly Thr Tyr Gln Asn Gly Tyr Asp Ser Thr Gln Gln Tyr Gly Ser Asn Val Pro Asn Met His Asn Gly Met Asn Gln Gln Ala Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Pro Met Ile Gly Tyr Pro Met Pro Thr Gly Tyr Ser Gln <210>30 <211>615 <212>PRT

<213>Mus musculus <400> 30 Met Ser Ser Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe Gly Ala Pro Arg Phe Gly Gly Ser Arg Thr Gly Pro Leu Ser Gly Lys Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gln Glu His Pro Asp Leu Ala Arg Arg Thr Ala Gln Glu Val Asp Thr Tyr Arg Arg Ser Lys Glu Ile Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val Ile Ala Arg Gln Asn Phe Thr Glu Pro Thr Ala Ile Gln Ala Gln Gly Trp Pro Val Ala Leu Ser Gly Leu Asp Met Val Gly Val Ala Gln Thr Gly Ser Gly Lys Thr Leu Ser Tyr Leu Leu Pro Ala Ile Val His Ile Asn His Gln Pro Phe Leu Glu Arg Gly Asp Gly Pro Ile Cys Leu Val Leu Ala Pro Thr Arg Glu Leu Ala Gln Gln Val Gln Gln Val Ala Ala Glu Tyr Cys Arg Ala Cys Arg Leu Lys Ser Thr Cys Ile Tyr Gly Gly Ala Pro Lys Gly Pro Gln Ile Arg Asp Leu Glu Arg Gly Val Glu Ile Cys Ile Ala Thr Pro Gly Arg Leu Ile Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met Gly Phe Glu Pro Gln Ile Arg Lys Ile Val Asp Gln Ile Arg Pro Asp Arg Gln Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gln Leu Ala Glu Asp Phe Leu Lys Asp Tyr Ile His Ile Asn Ile Gly Ala Leu Glu Leu Ser Ala Asn His Asn Ile Leu Gln Ile Val Asp Val Cys His Asp Val Glu Lys Asp Glu Lys Leu Ile Arg Leu Met Glu Glu Ile Met Ser Glu Lys Glu Asn Lys Thr Ile Val Phe Val Glu Thr Lys Arg Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala Met Gly Ile His Gly Asp Lys Ser Gln Gln Glu Arg Asp Trp Val Leu Asn Glu Phe Lys His Gly Lys Ala Pro Ile Leu Ile Ala Thr Asp Val Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val Ile Asn Tyr Asp Tyr Pro Asn Ser Ser Glu Asp Tyr Ile His Arg Ile Gly Arg Thr Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn Asn Ile Lys Gln Val Ser Asp Leu Ile Ser Val Leu Arg Glu Ala Asn Gln Ala Ile Asn Pro Lys Leu Leu Gln Leu Val Glu Asp Arg Gly Ser Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Asn Leu Leu Lys Arg Asp Phe Gly Ala Lys Thr Gln Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser Phe Gly Ser Asn Phe Val Ser Ala Gly Ile Gln Thr Ser Phe Arg Thr Gly Asn Pro Thr Gly Thr Tyr Gln Asn Gly Tyr Asp Ser Thr Gln Gln Tyr Gly Ser Asn Val Ala Asn Met His Asn Gly Met Asn Gln Gln Ala Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Ala Pro Met Ile Gly Tyr Pro Met Pro Thr Gly Tyr Ser Gln <210>31 <211>167 <212>PRT

<213>Mus musculus <300>
<301> Aoki, N.
<302> Anagen-specific protein mKAPl3 <400> 31 Met Ser Cys Asn Ser Cys Ser Gly Thr Phe Ser Gln Ser Phe Gly Gly Gln Leu Gln Tyr Pro Ile Ser Ser Cys Gly Ser Ser Tyr Pro Asn Asn Val Phe Tyr Ser Thr Asp Leu Gln Thr Pro Ile Thr His Gln Leu Gly Ser Ser Leu His Ser Gly Cys Gln Glu Thr Phe Cys Glu Pro Thr Asn Cys Gln Thr Ala Tyr Val Val Ser Arg Pro Cys Gln Arg Pro Phe Tyr Ser Gln Arg Ile Arg Gly Pro Cys Arg Pro Cys Gln Ser Thr Phe Ser Gly Ser Leu Gly Phe Gly Ser Arg Gly Phe Gln Ser Phe Gly Cys Gly Tyr Pro Ser Gln Gly Phe Gly Ser His Gly Phe Gln Ser Val Gly Cys Gly Thr Pro Thr Phe Ser Ser Leu Asn Cys Gly Ser Ser Phe Tyr Arg Pro Thr Cys Phe Ser Thr Lys Ser Cys Gln Ser Val Ser Tyr Gln Pro Thr Cys Gly Thr Gly Phe Phe <210>32 <211>150 <212>PRT

<213>Mus musculus <300>
<301> Kuhn, F.
<302> Pmgl and Pmg2 constitute a novel family of KAP genes differentially expressed during skin and mammary gland development <303> Mech. Dev.
<304> 1999 <313> 1 TO 150 <400> 32 Met Ser Tyr Thr Cys Asn Ser Gly Asn Tyr Ser Ser Gln Ser Phe Gly Gly Phe Leu Arg Gln Pro Val Ser Thr Tyr Asn Ser Phe Tyr Pro Thr Ser Asn Val Val Tyr Ser Pro Lys Asn Phe Gln Leu Gly Ser Ser Phe Tyr Asn Gly Gln Gln Glu Thr Phe Ser Glu Pro Leu Glu Gly His Leu Pro Cys Val Gly Ser Ala Ser Phe His Thr Ser Cys Phe Arg Pro Lys Gln Tyr Phe Ser Ser Pro Cys Gln Gly Gly Phe Thr Gly Ser Phe Gly Tyr Gly Asn Thr Gly Phe Gly Ala Phe Gly Phe Gly Ser Ser Gly Ile Arg Ser Gln Gly Cys Gly Ser Asn Phe Tyr Arg Pro Gly Tyr Phe Ser Ser Lys Ser Ile Gln Ser Ser Tyr Tyr Gln Pro Gly Tyr Ser Ser Gly Phe Cys Gly Ser Asn Phe <210>33 <211>469 <212>PRT

<213>Mus musculus <300>
<301> Shibahara, K.
<302> Isolation of a novel gene MA-3 that is induced upon programmed cell death <303> Gene <304> 1995 <305> 166 <306> 297-301 <313> 1 TO 469 <400> 33 Met Asp Ile Glu Asn Glu Gln Thr Leu Asn Val Asn Pro Thr Asp Pro Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp Glu Glu Asn Ala Gly Thr Glu Glu Ile Lys Asn Glu Ile Asn Gly Asn Trp Ile Ser Ala Ser Thr Ile Asn Glu Ala Arg Ile Asn Ala Lys Ala Lys Arg Arg Leu Arg Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp Ser Val Ser Asp Asn Gly Ser Glu Ala Val Arg Ser Gly Val Ala Val Pro Thr Ser Pro Lys Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly Lys Gly Arg Gly Leu Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val Trp Gly Thr Pro Gly Gln Val Tyr Asp Val Glu Glu Val Asp Val Lys Asp Pro Asn Tyr Asp Asp Asp Gln Glu Asn Cys Val Tyr Glu Thr Val Val Leu Pro Leu Asp Glu Thr Ala Phe Glu Lys Thr Leu Thr Pro Ile Ile Gln Glu Tyr Phe Glu His Gly Asp Thr Asn Glu Val Ala Glu Met Leu Arg Asp Leu Asn Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu Ala Val Ser Leu Ala Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr Ser Lys Leu Leu Ser Asp Leu Cys Gly Thr Val Met Ser Thr Asn Asp Val Glu Lys Ser Phe Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala Leu Asp Thr Pro Arg Ala Pro Gln Leu Val Gly Gln Phe Ile Ala Arg Ala Val Gly Asp Gly Ile Leu Cys Asn Thr Tyr Ile Asp Ser Tyr Lys Gly Thr Val Asp Cys Val Gln Ala Arg Ala Ala Leu Asp Lys Ala Thr Val Leu Leu Ser Met Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp Gly Ser Gly Gly Gly Gln Gln Pro Val Asn His Leu Val Lys Glu Ile Asp Met Leu Leu Lys Glu Tyr Leu Leu Ser Gly Asp Ile Ser Glu Ala Glu His Cys Leu Lys Glu Leu Glu Val Pro His Phe His His Glu Leu Val Tyr Glu Ala Ile Val Met Val Leu Glu Ser Thr Gly Glu Ser Ala Phe Lys Met Ile Leu Asp LeuLeuLysSer LeuTrp LysSerSerThr IleThrIl A

e sp Gln Met LysArgGlyTyr GluArg IleTyrAsnGlu IleProAspIle Asn Leu AspValProHis SerTyr SerValLeuGlu ArgPheValGlu Glu Cys PheGlnAlaGly IleIle SerLysGlnLeu ArgAspLeuCys Pro Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly Asp Gly Gly Arg Leu Lys Pro Glu Ser Tyr <210> 34 <211> 458 <212> PRT
<213> Homo Sapiens <400> 34 Met Thr Lys Tyr Pro Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp Glu Glu Asn Ala Gly Thr Glu Glu Val Lys Asn Glu Ile Asn Gly Asn Trp Ile Ser Ala Ser Ser Ile Asn Glu Ala Arg Ile Asn Ala Lys Ala Lys Arg Arg Leu Arg Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp Ser Val Ser Glu Ser Gly Ser Asp Ala Leu Arg Ser Gly Leu Thr Val Pro Thr Ser Pro Lys Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly Lys Gly Arg Gly Leu Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val Trp Gly Thr Pro Gly Gln Val Tyr Asp Val Glu Glu Val Asp Val Lys Asp Pro Asn Tyr Asp Asp Asp Gln Glu Asn Cys Val Tyr Glu Thr Val Val Leu Pro Leu Asp Glu Arg Ala Phe Glu Lys Thr Leu Thr Pro Ile Ile Gln Glu Tyr Phe Glu His Gly Asp Thr Asn Glu Val Ala Glu Met Leu Arg Asp Leu Asn Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu Ala Val Ser Leu Ala Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr Thr Lys Leu Leu Ser Asp Leu Cys Gly Thr Val Met Ser Thr Thr Asp Val Glu Lys Ser Phe Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala Leu Asp Thr Pro Arg Ala Pro Gln Leu Val Gly Gln Phe Ile Ala Arg Ala Val Gly Asp Gly Ile Leu Cys Asn Thr Tyr Ile Asp Ser Tyr Lys Gly Thr Val Asp Cys Val Gln Ala Arg Ala Ala Leu Asp Lys Ala Thr Val Leu Leu Ser Met Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp Gly Ser Gly Gly Gly Gln Gln Ser Val Asn His Leu Val Lys Glu Ile Asp Met Leu Leu Lys Glu Tyr Leu Leu Ser Gly Asp Ile Ser Glu Ala Glu His Cys Leu Lys Glu Leu Glu Val Pro His Phe His His Glu Leu Val Tyr Glu Ala Ile Ile Met Val Leu Glu Ser Thr Gly Glu Ser Thr Phe Lys Met Ile Leu Asp Leu Leu Lys Ser Leu Trp Lys Ser Ser Thr Ile Thr Val Asp Gln Met Lys Arg Gly Tyr Glu Arg Ile Tyr Asn Glu Ile Pro Asp Ile Asn Leu Asp Val Pro His Ser Tyr Ser Val Leu Glu Arg Phe Val Glu Glu Cys Phe Gln Ala Gly Ile Ile Ser Lys Gln Leu Arg Asp Leu Cys Pro Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly Asp Gly Gly Arg Leu Lys Pro Glu Ser Tyr <210>35 <211>171 <212>PRT

<213>Mus musculus <300>
<301> Suk, K.
<302> Enhancement of B-cell translocation gene-1 expresion by prostaglandin E2 in macrophages and the relationship to proliferation <303> Immunology <304> 1997 <305> 91 <306> 121-129 <313> 1 TO 171 <400> 35 Met His Pro Phe Tyr Thr Arg Ala Ala Thr Met Ile Gly Glu Ile Ala Ala Ala Val Ser Phe Ile Ser Lys Phe Leu Arg Thr Lys Gly Leu Thr Ser Glu Arg Gln Leu Gln Thr Phe Ser Gln Ser Leu Gln Glu Leu Leu Ala Glu His Tyr Lys His His Trp Phe Pro Glu Lys Pro Cys Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Leu Ile Gly Gln Ala Ala Gln Arg Ile Gly Leu Ser Ser Gln Glu Leu Phe Arg Leu Leu Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Ala Ser Pro Ala Gly Gly Ser Thr Gln Asn Ser Thr Asn Val Gln Met Val Asp Ser Arg Ile Ser Cys Lys Glu Glu Leu Leu Leu Gly Arg Thr Ser Pro Ser Lys Asn Tyr Asn Met Met Thr Val Ser Gly <210> 36 <211> 171 <212> PRT
<213> Homo Sapiens <400> 36 Met His Pro Phe Tyr Thr Arg Ala Ala Thr Met Ile Gly Glu Ile Ala Ala Ala Val Ser Phe Ile Ser Lys Phe Leu Arg Thr Lys Gly Leu Thr Ser Glu Arg Gln Leu Gln Thr Phe Ser Gln Ser Leu Gln Glu Leu Leu Ala Glu His Tyr Lys His His Trp Phe Pro Glu Lys Pro Cys Lys Gly Ser Gly Tyr Arg Cys Ile Arg Ile Asn His Lys Met Asp Pro Leu Ile Gly Gln Ala Ala Gln Arg Ile Gly Leu Ser Ser Gln Glu Leu Phe Arg Leu Leu Pro Ser Glu Leu Thr Leu Trp Val Asp Pro Tyr Glu Val Ser Tyr Arg Ile Gly Glu Asp Gly Ser Ile Cys Val Leu Tyr Glu Ala Ser Pro Ala Gly Gly Ser Thr Gln Asn Ser Thr Asn Val Gln Met Val Asp Ser Arg Ile Ser Cys Lys Glu Glu Leu Leu Leu Gly Arg Thr Ser Pro Ser Lys Asn Tyr Asn Met Met Thr Val Ser Gly <210>37 <211>226 <212>PRT

<213>Mus musculus <300>
<301> Rubinstein, E.
<302> Molecular cloning of the mouse equivalent of CD9 <303> Thromb. Res.
<304> 1993 <305> 71 <306> 377-383 <313> 1 TO 226 <400> 37 Met Pro Val Lys Gly Gly Ser Lys Cys Ile Lys Tyr Leu Leu Phe Gly Phe Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly Leu Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu Asn Asn His Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly Ala Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu Leu Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Val Trp Gly Tyr Thr His Lys Asp Glu Val Ile Lys Glu Leu Gln Glu Phe Tyr Lys Asp Thr Tyr Gln Lys Leu Arg Ser Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys Ala Ile HisMetAlaLeu AspCys CysGlyIleAla GlyPro GluGlnPhe Leu IleSerAspThr CysPro LysLysGlnLeu LeuGlu PheGlnVal Ser LysProCysPro GluAla IleSerGluVal PheAsn LysPheHis Asn IleIleGlyAla ValGly IleGlyIleAla ValVal IlePheGly Met Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg Arg Ser Arg Glu Met Val <210> 38 <211> 228 <212> PRT
<213> Homo sapiens <300>
<301> Higashihara, M.
<302> Purification and partial characterization of CD9 antigen of human platelets <303> FEBS Lett.
<304> 1990 <305> 264(2) <306> 270-274 <313> 1 TO 228 <400> 38 Met Pro Val Lys Gly Gly Thr Lys Cys Ile Lys Tyr Leu Leu Phe Gly Phe Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly Leu Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu Thr Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly Ala Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu Leu Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Ile Trp Gly Tyr Ser His Lys Asp Glu Val Ile Lys Glu Val Gln Glu Phe Tyr Lys Asp Thr Tyr Asn Lys Leu Lys Thr Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys Ala Ile His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu Gln Phe Ile Ser Asp Ile Cys Pro Lys Lys Asp Val Leu Glu Thr Phe Thr Val Lys Ser Cys Pro Asp Ala Ile Lys Glu Val Phe Asp Asn Lys Phe His Ile Ile Gly Ala Val Gly Ile Gly Ile Ala Val Val Met Ile Phe Gly Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg Arg Asn Arg Glu Met Val <210>39 <211>358 <212>PRT

<213>Mus musculus <300>
<301> Kaestner, K. H.
<302> Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA
<303> J. Biol. Chem.
<304> 1989 <305> 264 <306> 14755-14761 <313> 1 TO 358 <400> 39 Met Pro Ala His Ile Leu Gln Glu Ile Ser Gly Ala Tyr Ser Ala Thr Thr Thr Ile Thr Ala Pro Pro Ser Gly Gly Gln Gln Asn Gly Gly Glu Lys Phe Glu Lys Ser Ser His His Trp Gly Ala Asp Val Arg Pro Glu Leu Lys Asp Asp Leu Tyr Asp Pro Thr Tyr Gln Asp Asp Glu Gly Pro Pro Pro Lys Leu Glu Tyr Val Trp Arg Asn Ile Ile Leu Met Ala Leu Leu His Leu Gly Ala Leu Tyr Gly Ile Thr Leu Val Pro Ser Cys Lys Leu Tyr Thr Cys Leu Phe Ala Tyr Leu Tyr Tyr Val Ile Ser Ala Leu Gly Ile Thr Ala Gly Ala His Arg Leu Trp Ser His Arg Thr Tyr Lys Ala Arg Leu Pro Leu Arg Leu Phe Leu Ile Ile Ala Asn Thr Met Ala Phe Gln Asn Asp Val Tyr Glu Trp Ala Arg Asp His Arg Ala His His Lys Phe Ser Glu Thr His Ala Asp Pro His Asn Ser Arg Arg Gly Phe Phe Phe Ser His Val Gly Trp Leu Leu Val Arg Lys His Pro Ala Val Lys Glu Lys Gly Gly Lys Leu Asp Met Ser Asp Leu Lys Ala Glu Lys Leu Val Met Phe Gln Arg Arg Tyr Tyr Lys Pro Asp Leu Leu Leu Met Cys Phe Val Leu Pro Thr Leu Val Pro Trp Tyr Cys Trp Gly Glu Thr Phe Val Asn Ser Leu Cys Val Ser Thr Phe Leu Arg Tyr Ala Val Val Leu Asn Ala Thr Trp Leu Val Asn Ser Ala Ala His Leu Tyr Gly Tyr Arg Pro Tyr Asp Lys Asn Ile Ser Ser Arg Glu Asn Ile Leu Val Ser Met Gly Ala Val Gly Glu Arg Phe His Asn Tyr His His Ala Phe Pro Tyr Asp Tyr Ser Ala Ser Glu Tyr Arg Trp His Ile Asn Phe Thr Thr Phe Phe Ile Asp Cys Met Ala Leu Leu Gly Leu Ala Tyr Asp Arg Lys Arg Val Ser Arg Ala Ala Val Leu Ala Arg Ile Lys Arg Thr Gly Asp Gly Ser Cys Lys Ser Gly <210> 40 <211> 359 <212> PRT
<213> Homo sapiens <300>
<301> Zhang, L.
<302> Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites <303> Biochem. J.
<304> 1999 <305> 340 <306> 255-264 <313> 1 TO 359 <400> 40 Met Pro Ala His Leu Leu Gln Asp Asp Ile Ser Ser Ser Tyr Thr Thr Thr Thr Thr Ile Thr Ala Pro Pro Ser Arg Val Leu Gln Asn Gly Gly Asp Lys Leu Glu Thr Met Pro Leu Tyr Leu Glu Asp Asp Ile Arg Pro Asp Ile Lys Asp Asp Ile Tyr Asp Pro Thr Tyr Lys Asp Lys Glu Gly Pro Ser Pro Lys Val Glu Tyr Val Trp Arg Asn Ile Ile Leu Met Ser Leu Leu His Leu Gly Ala Leu Tyr Gly Ile Thr Leu Ile Pro Thr Cys Lys Phe Tyr Thr Trp Leu Trp Gly Val Phe Tyr Tyr Phe Val Ser Ala Leu Gly Ile Thr Ala Gly Ala His Arg Leu Trp Ser His Arg Ser Tyr Lys Ala Arg Leu Pro Leu Arg Leu Phe Leu Ile Ile Ala Asn Thr Met Ala Phe Gln Asn Asp Val Tyr Glu Trp Ala Arg Asp His Arg Ala His His Lys Phe Ser Glu Thr His Ala Asp Pro His Asn Ser Arg Arg Gly Phe Phe Phe Ser His Val Gly Trp Leu Leu Val Arg Lys His Pro Ala Val Lys Glu Lys Gly Ser Thr Leu Asp Leu Ser Asp Leu Glu Ala Glu Lys Leu Val Met Phe Gln Arg Arg Tyr Tyr Lys Pro Gly Leu Leu Leu Met Cys Phe Ile Leu Pro Thr Leu Val Pro Trp Tyr Phe Trp Gly Glu Thr Phe Gln Asn Ser Val Phe Val Ala Thr Phe Leu Arg Tyr Ala Val Val Leu Asn Ala Thr Trp Leu Val Asn Ser Ala Ala His Leu Phe Gly Tyr Arg Pro Tyr Asp Lys Asn Ile Ser Pro Arg Glu Asn Ile Leu Val Ser Leu Gly Ala Val Gly Glu Gly Phe His Asn Tyr His His Ser Phe Pro Tyr Asp Tyr Ser Ala Ser Glu Tyr Arg Trp His Ile Asn Phe Thr Thr Phe Phe Ile Asp Cys Met Ala Ala Leu Gly Leu Ala Tyr Asp Arg Lys Lys Val Ser Lys Ala Ala Ile Leu Ala Arg Ile Lys Arg Thr Gly Asp Gly Asn Tyr Lys Ser Gly <210>41 <211>198 <212>PRT

<213>Mus musculus <300>
<301> Tsuzuki, S.
<302> Molecular cloning, enomic organisation, promoter activity, and tissue-specific expression of the mouse ryudocan gene <303> J. Biochem.
<304> 1997 <305> 122 <306> 17-24 <313> 1 TO 198 <400> 41 Met Ala Pro Ala Cys Leu Leu Ala Pro Leu Leu Leu Leu Leu Leu Gly Gly Phe Pro Leu Val Pro Gly Glu Ser Ile Arg Glu Thr Glu Val Ile Asp Pro Gln Asp Leu Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro Asp Asp Glu Asp Ala Gly Gly Ser Asp Asp Phe Glu Leu Ser Gly Ser Gly Asp Leu Asp Asp Thr Glu Glu Pro Arg Pro Phe Pro Glu Val Ile Glu Pro Leu Val Pro Leu Asp Asn His Ile Pro Glu Asn Ala Gln Pro Gly Ile Arg Val Pro Ser Glu Pro Lys Glu Leu Glu Glu Asn Glu Val Ile Pro Lys Arg Ala Pro Ser Asp Val Gly Asp Asp Met Ser Asn Lys Val Ser Met Ser Ser Thr Ala Gln Gly Ser Asn Ile Phe Glu Arg Thr Glu Val Leu Ala Ala Leu Ile Val Gly Gly Val Val Gly Ile Leu Phe Ala Val Phe Leu Ile Leu Leu Leu Val Tyr Arg Met Lys Lys Lys Asp Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro Ile Tyr Lys Lys Ala Pro Thr Asn Glu Phe Tyr Ala <210> 42 <211> 198 <212> PRT
<213> Homo Sapiens <300>
<301> Kojima, T.
<302> Human ryudocan core protein: molecular cloning and characterization of the cDNA, and chromosomal localization of the gene <303> Biochem. Biophys. Res. Commun.
<304> 1993 <305> 190 <306> 814-822 <313> 1 TO 198 <400> 42 Met Ala Pro Ala Arg Leu Phe Ala Leu Leu Leu Phe Phe Val Gly Gly Val Ala Glu Ser Ile Arg Glu Thr Glu Val Ile Asp Pro Gln Asp Leu Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro Asp Asp Glu Asp Val Val Gly Pro Gly Gln Glu Ser Asp Asp Phe Glu Leu Ser Gly Ser Gly Asp Leu Asp Asp Leu Glu Asp Ser Met Ile Gly Pro Glu Val Val His Pro Leu Val Pro Leu Asp Asn His Ile Pro Glu Arg Ala Gly Ser Gly Ser Gln Val Pro Thr Glu Pro Lys Lys Leu Glu Glu Asn Glu Val Ile Pro Lys Arg Ile Ser Pro Val Glu Glu Ser Glu Asp Val Ser Asn Lys Val Ser Met Ser Ser Thr Val Gln Gly Ser Asn Ile Phe Glu Arg Thr Glu Val Leu Ala Ala Leu Ile Val Gly Gly Ile Val Gly Ile Leu Phe Ala Val Phe Leu Ile Leu Leu Leu Met Tyr Arg Met Lys Lys Lys Asp Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro Ile Tyr Lys Lys Ala Pro Thr Asn Glu Phe Tyr Ala <210>43 <211>706 <212>PRT

<213>Mus musculus <300>
<301> Nielsen, A. L.
<302> Murine helix-loop-helix transcriptional activator proteins to the E-box motif of the Akv murine leukemia virus enhancer identified by cDNA cloning <303> Mol. Cell. Biol.
<304> 1992 <305> 12 <306> 3449-3459 <313> 1 TO 706 <400> 43 Met Asn Pro Gln Gln Gln Arg Met Ala Ala Ile Gly Thr Asp Lys Glu Leu Ser Asp Leu Leu Asp Phe Ser Ala Met Phe Ser Pro Pro Val Asn Ser Gly Lys Thr Arg Pro Thr Thr Leu Gly Ser Ser Gln Phe Ser Gly Ser Gly Met Asp Glu Arg Gly Gly Thr Thr Ser Trp Gly Thr Ser Gly Gln Pro Ser Pro Ser Tyr Asp Ser Ser Arg Gly Phe Thr Asp Ser Pro His Tyr Ser Asp His Leu Asn Asp Ser Arg Leu Gly Thr His Glu Gly Leu Ser Pro Thr Pro Phe Met Asn Ser Asn Leu Ile Gly Lys Thr Ser Glu Arg Gly Ser Phe Ser Leu Tyr Ser Arg Asp Ser Ala Leu Ser Gly Cys Gln Ser Ser Leu Leu Arg Ala Ser Ser Arg Thr Trp Glu Pro Ala Gln Leu Ser Ser Ser Gly Lys Pro Gly Thr Pro Tyr Tyr Ser Phe Ser Ala Thr Ser Ser Arg Arg Arg Pro Leu His Asp Ser Val Ala Leu Asp Pro Leu Gln Ala Lys Lys Val Arg Lys Val Pro Pro Gly Leu Pro Ser Ser Val Tyr Ala Pro Ser Pro Asn Ser Asp Asp Phe Asn Arg Glu Ser Pro Ser Tyr Pro Ser Pro Lys Pro Pro Thr Ser Met Phe Ala Ser Thr Phe Phe Met Gln Asp Gly Thr His Ser Ser Ser Asp Leu Trp Ser Ser Ser Asn Gly Met Ser Gln Pro Gly Phe Gly Gly Ile Leu Gly Thr Ser Thr Ser His Met Ser Gln Ser Ser Ser Tyr Gly Ser Leu His Ser His Asp Arg Leu Ser Tyr Pro Pro His Ser Val Ser Pro Thr Asp Ile Asn Thr Ser Leu Pro Pro Met Ser Ser Phe His Arg Gly Ser Thr Ser Ser Ser Pro Tyr Val Ala Ala Ser His Thr Pro Pro Ile Asn Gly Ser Asp Ser Ile Leu Gly Thr Arg Gly Asn Ala Ala Gly Ser Ser Gln Thr Gly Asp Ala Leu Gly Lys Ala Leu Ala Ser Ile Tyr Ser Pro Asp His Thr Ser Ser Ser Phe Pro Ser Asn Pro Ser Thr Pro Val Gly Ser Pro Ser Pro Leu Thr Gly Thr Ser Gln Trp Pro Arg Ala Gly Gly Gln Ala Pro Ser Ser Pro Ser Tyr Glu Asn Ser Leu His Ser Leu Lys Asn Arg Val Glu Gln Gln Leu His Glu His Leu Gln Asp Ala Met Ser Phe Leu Lys Asp Val Cys Glu Gln Ser Arg Met Glu Asp Arg Leu Asp Arg Leu Asp Asp Ala Ile His Val Leu Arg Asn His Ala Val Gly Pro Ser Thr Ser Leu Pro Thr Ser His Ser Asp Ile His Ser Leu Leu Gly Pro Ser His Asn Ala Ser Ile Gly Asn Leu Asn Ser Asn Tyr Gly Gly Ser Ser Leu Val Thr Asn Ser Arg Ser Ala Ser Met Val Gly Thr His Arg Glu Asp Ser Val Ser Leu Asn Gly Asn His Ser Val Leu Ser Ser Thr Val Ala Ala Ser Asn Thr Glu Leu Asn His Lys Thr Pro Glu Asn Phe Arg Gly Gly Val Gln Asn Gln Ser Gly Ser Val Val Pro Thr Glu Ile Lys Thr Glu Asn Lys Glu Lys Asp Glu Asn Leu His Glu Pro Pro Ser Ser Asp Asp Met Lys Ser Asp Asp Glu Ser Ser Gln Lys Asp Ile Lys Val Ser Ser Arg Gly Arg Thr Ser Ser Thr Asn Glu Asp Glu Asp Leu Asn Pro Glu Gln Lys Ile Glu Arg Glu Lys Glu Arg Arg Met Ala Asn Asn Ala Arg Glu Arg Leu Arg Val Arg Asp Ile Asn Glu Ala Phe Lys Glu Leu Gly Arg Met Cys Gln Leu His Leu Lys Ser Glu Lys Pro Gln Thr Lys Leu Leu Ile Leu His Gln Ala Val Ala Val Ile Leu Ser Leu Glu Gln Gln Val Arg Glu Arg Asn Leu Asn Pro Lys Ala Ala Cys Leu Lys Arg 660 . 665 670 Arg Glu Glu Glu Lys Val Ser Ala Ala Ser Ala Glu Pro Pro Ser Thr Leu Pro Gly Ala His Pro Gly Leu Ser Glu Ser Thr Asn Pro Met Gly His Leu <210>44 <211>682 <212>PRT

<213>Homo sapiens <400> 44 Met Asn Pro Gln Gln Gln Arg Met Ala Ala Ile Gly Thr Asp Lys Glu Leu Ser Asp Leu Leu Asp Phe Ser Ala Met Phe Ser Pro Pro Val Asn Ser Gly Lys Thr Arg Pro Thr Thr Leu Gly Ser Ser Gln Phe Ser Gly Ser Gly Ile Asp Glu Arg Gly Gly Thr Thr Ser Trp Gly Thr Ser Gly Gln Pro Ser Pro Ser Tyr Asp Ser Ser Arg Gly Phe Thr Asp Ser Pro His Tyr Ser Asp His Leu Asn Asp Ser Arg Leu Gly Ala His Glu Gly Leu Ser Pro Thr Pro Phe Met Asn Ser Asn Leu Met Gly Lys Thr Ser Glu Arg Gly Ser Phe Ser Leu Tyr Ser Arg Asp Thr Gly Leu Pro Gly Cys Gln Ser Ser Leu Leu Arg Gln Asp Leu Gly Leu Gly Ser Pro Ala Gln Leu Ser Ser Ser Gly Lys Pro Gly Thr Ala Tyr Tyr Ser Phe Ser Ala Thr Ser Ser Arg Arg Arg Pro Leu His Asp Ser Ala Ala Leu Asp Pro Leu Gln Ala Lys Lys Val Arg Lys Val Pro Pro Gly Leu Pro Ser Ser Val Tyr Ala Pro Ser Pro Asn Ser Asp Asp Phe Asn Arg Glu Ser Pro Ser Tyr Pro Ser Pro Lys Pro Pro Thr Ser Met Phe Ala Ser Thr Phe Phe Met Gln Asp Gly Thr His Asn Ser Ser Asp Leu Trp Ser Ser Ser Asn Gly Met Ser Gln Pro Gly Phe Gly Gly Ile Leu Gly Thr Ser Thr Ser His Met Ser Gln Ser Ser Ser Tyr Gly Asn Leu His Ser His Asp Arg Leu Ser Tyr Pro Pro His Ser Val Ser Pro Thr Asp Ile Asn Thr Ser Leu Pro Pro Met Ser Ser Phe His Arg Gly Ser Thr Ser Ser Ser Pro Tyr Val Ala Ala Ser His Thr Pro Pro Ile Asn Gly Ser Asp Ser Ile Leu Gly Thr Arg Gly Asn Ala Ala Gly Ser Ser Gln Thr Gly Asp Ala Leu Gly Lys Ala Leu Ala Ser Ile Tyr Ser Pro Asp His Thr Ser Ser Ser Phe Pro Ser Asn Pro Ser Thr Pro Val Gly Ser Pro Ser Pro Leu Thr Gly Thr Ser Gln Trp Pro Arg Pro Gly Gly Gln Ala Pro Ser Ser Pro Ser Tyr Glu Asn Ser Leu His Ser Leu Gln Ser Arg Met Glu Asp Arg Leu Asp Arg Leu Asp Asp Ala Ile His Val Leu Arg Asn His Ala Val Gly Pro Ser Thr Ser Leu Pro Ala Gly His Ser Asp Ile His Ser Leu Leu Gly Pro Ser His Asn Ala Pro Ile Gly Ser Leu Asn Ser Asn Tyr Gly Gly Ser Ser Leu Val Ala Ser Ser Arg Ser Ala Ser Met Val Gly Thr His Arg Glu Asp Ser Val Ser Leu Asn Gly Asn His Ser Val Leu Ser Ser Thr Val Thr Thr Ser Ser Thr Asp Leu Asn His Lys Thr Gln Glu Asn Tyr Arg Gly Gly Leu Gln Ser Gln Ser Gly Thr Val Val Thr Thr Glu Ile Lys Thr Glu Asn Lys Glu Lys Asp Glu Asn Leu His Glu Pro Pro Ser Ser Asp Asp Met Lys Ser Asp Asp Glu Ser Ser Gln Lys Asp Ile Lys Val Ser Ser Arg Gly Arg Thr Ser Ser Thr Asn Glu Asp Glu Asp Leu Asn Pro Glu Gln Lys Ile Glu Arg Glu Lys Glu Arg Arg Met Ala Asn Asn Ala Arg Glu Arg Leu Arg Val Arg Asp Ile Asn Glu Ala Phe Lys Glu Leu Gly Arg Met Cys Gln Leu His Leu Lys Ser Glu Lys Pro Gln Thr Lys Leu Leu Ile Leu His Gln Ala Val Ala Val Ile Leu Ser Leu Glu Gln Gln Val Arg Glu Arg Asn Leu Asn Pro Lys Ala Ala Cys Leu Lys Arg Arg Glu Glu Glu Lys Val Ser Ala Val Ser Ala Glu Pro Pro Thr Thr Leu Pro Gly Thr His Pro Gly Leu Ser Glu Thr Thr Asn Pro Met Gly His Met <210>45 <211>167 <212>PRT

<213>Mus musculus <300>
<301> Zeng, Q.
<302> Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatase homologues to PRL-1 <303> Biochem. Biophys. Res. Commun.
<304> 1998 <305> 244 <306> 421-427 <313> 1 TO 167 <400> 45 Met Asn Arg Pro Ala Pro Val Glu Ile Ser Tyr Glu Asn Met Arg Phe Leu Ile Thr His Asn Pro Thr Asn Ala Thr Leu Asn Lys Phe Thr Glu Glu Leu Lys Lys Tyr Gly Val Thr Thr Leu Val Arg Val Cys Asp Ala Thr Tyr Asp Lys Ala Pro Val Glu Lys Glu Gly Ile His Val Leu Asp Trp Pro Phe Asp Asp Gly Ala Pro Pro Pro Asn Gln Ile Val Asp Asp Trp Leu Asn Leu Leu Lys Thr Leu Phe Arg Glu Glu Pro Gly Cys Cys Val Ala Val His Cys Val Ala Gly Ile Gly Arg Ala Pro Val Leu Val Ala Leu Ala Leu Ile Glu Cys Gly Met Lys Tyr Glu Asp Ala Val Gln Phe Ile Arg Gln Lys Arg Arg Gly Ala Phe Asn Ser Lys Gln Leu Leu Tyr Leu Glu Lys Tyr Arg Pro Lys Met Arg Leu Arg Phe Arg Asp Thr Asn Gly His Cys Cys Val Gln <210> 46 <211> 167 <212> PRT
<213> Homo Sapiens <300>

<301> Montagna, M.
<302> A 100-kb physical and transcriptional map around the EDH17B2 gene: identification of three novel genes and a pseudogene of a human homologue of the rat PRL-1 tyrosine phosphatase <303> Hum. Genet.
<304> 1995 <305> 96 <306> 532-538 <400> 46 Met Asn Arg Pro Ala Pro Val Glu Ile Ser Tyr Glu Asn Met Arg Phe Leu Ile Thr His Asn Pro Thr Asn Ala Thr Leu Asn Lys Phe Thr Glu Glu Leu Lys Lys Tyr Gly Val Thr Thr Leu Val Arg Val Cys Asp Ala Thr Tyr Asp Lys Ala Pro Val Glu Lys Glu Gly Ile His Val Leu Asp Trp Pro Phe Asp Asp Gly Ala Pro Pro Pro Asn Gln Ile Val Asp Asp Trp Leu Asn Leu Leu Lys Thr Lys Phe Arg Glu Glu Pro Gly Cys Cys Val Ala Val His Cys Val Ala Gly Leu Gly Arg Ala Pro Val Leu Val Ala Leu Ala Leu Ile Glu Cys Gly Met Lys Tyr Glu Asp Ala Val Gln Phe Ile Arg Gln Lys Arg Arg Gly Ala Phe Asn Ser Lys Gln Leu Leu Tyr Leu Glu Lys Tyr Arg Pro Lys Met Arg Leu Arg Phe Arg Asp Thr Asn Gly His Cys Cys Val Gln <210> 47 <211> 532 <212> PRT

<213> Mus musculus <300>
<301> Inoue, T.
<302> Isolation of complementary DNAs encoding a cerebellum-enriched nuclear factor I family that activates ranscription from the mouse myelin basic protein promoter <303> J. Biol. Chem.
<304> 1990 <305> 265 <306> 19065-19070 <313> 1 TO 532 <400> 47 Met Lys Leu Ala Asp Ser Val Met Ala Gly Lys Ala Ser Asp Gly Ser Ile Lys Trp Gln Leu Cys Tyr Asp Ile Ser Ala Arg Thr Trp Trp Met Asp Glu Phe His Pro Phe Ile Glu Ala Leu Leu Pro His Val Arg Ala Phe Ala Tyr Thr Trp Phe Asn Leu Gln Ala Arg Lys Arg Lys Tyr Phe Lys Lys His Glu Lys Arg Met Ser Lys Glu Glu Glu Arg Ala Val Lys Asp Glu Leu Leu Ser Glu Lys Pro Glu Val Lys Gln Lys Trp Ala Ser Arg Leu Leu Ala Lys Leu Arg Lys Asp Ile Arg Pro Glu Tyr Arg Glu Asp Phe Val Leu Thr Val Thr Gly Lys Lys Pro Pro Cys Cys Val Leu Ser Asn Pro Asp Gln Lys Gly Lys Met Arg Arg Ile Asp Cys Leu Arg Gln Ala Asp Lys Val Trp Arg Leu Asp Leu Val Met Val Ile Leu Phe Lys Gly Ile Pro Leu Glu Ser Thr Asp Gly Glu Arg Leu Val Lys Ser Pro Gln Cys Ser Asn Pro Gly Leu Cys Val Gln Pro His His Ile Gly Val Ser Val Lys Glu Leu Asp Leu Tyr Leu Ala Tyr Phe Val His Ala Ala Asp Ser Ser Gln Ser Glu Ser Pro Ser Gln Pro Ser Glu Ala Asp Ile Lys Asp Gln Pro Glu Asn Gly His Leu Gly Phe Gln Asp Ser Phe Val Thr Ser Gly Val Phe Ser Val Thr Glu Leu Val Arg Val Ser Gln Thr Pro Ile Ala Ala Gly Thr Gly Pro Asn Phe Ser Leu Ser Asp Leu Glu Ser Ser Ser Tyr Tyr Ser Met Ser Pro Gly Ala Met Arg Arg Ser Leu Pro Ser Thr Ser Ser Thr Ser Ser Thr Lys Arg Leu Lys Ser Val Glu Asp Glu Met Asp Ser Pro Gly Glu Glu Pro Phe Tyr Thr Gly Gln Gly Arg Ser Pro Gly Ser Gly Ser Gln Ser Ser Gly Trp His Glu Val Glu Pro Gly Leu Pro Ser Pro Ser Thr Leu Lys Lys Ser Glu Lys Ser Gly Phe Ser Ser Pro Ser Pro Ser Gln Thr Ser Ser Leu Gly Thr Ala Phe Thr Gln His His Arg Pro Val Ile Thr Gly Pro Arg Ala Ser Pro His Ala Thr Pro Ser Thr Leu His Phe Pro Thr Ser Pro Ile Ile Gln Gln Pro Gly Pro Tyr Phe Ser His Pro Ala Ile Arg Tyr His Pro Gln Glu Thr Leu Lys Glu Phe Val Gln Leu Val Cys Pro Asp Ala Gly Gln Gln Ala Gly Gln Val Gly Phe Leu Asn Pro Asn Gly Ser Ser Gln Gly Lys Val His Asn Pro Phe Leu Pro Thr Pro Met Leu Pro Pro Pro Pro Pro Pro Pro Met Ala Arg Pro Val Pro Leu Pro Met Pro Asp Thr Lys Pro Pro Thr Thr Ser Thr Glu Gly Gly Ala Ala Ser Pro Thr Ser Pro Thr Tyr Ser Thr Pro Ser Thr Ser Pro Ala Asn Arg Phe Val Ser Val Gly Pro Arg Asp Pro Ser Phe Val Asn Ile Pro Gln Gln Thr Gln Ser Trp Tyr Leu Gly <210> 48 <211> 433 <212> PRT
<213> Homo sapiens <300>
<301> Amemiy, K.
<302> Nuclear factor 1 <400> 48 Met Asp Glu Phe His Pro Phe Ile Glu Ala Leu Leu Pro His Val Arg Ala Phe Ser Tyr Thr Trp Phe Asn Leu Gln Ala Arg Lys Arg Lys Tyr Phe Lys Lys His Glu Lys Arg Met Ser Lys Asp Glu Glu Arg Ala Val Lys Asp Glu Leu Leu Gly Glu Lys Pro Glu Ile Lys Gln Lys Trp Ala Ser Arg Leu Leu Ala Lys Leu Arg Lys Asp Ile Arg Pro Glu Phe Arg Glu Asp Phe Val Leu Thr Ile Thr Gly Lys Lys Pro Pro Cys Cys Val Leu Ser Asn Pro Asp Gln Lys Gly Lys Ile Arg Arg Ile Asp Cys Leu Arg Gln Ala Asp Lys Val Trp Arg Leu Asp Leu Val Met Val Ile Leu Phe Lys Gly Ile Pro Leu Glu Ser Thr Asp Gly Glu Arg Leu Tyr Lys Ser Pro Gln Cys Ser Asn Pro Gly Leu Cys Val Gln Pro His His Ile Gly Val Thr Ile Lys Glu Leu Asp Leu Tyr Leu Ala Tyr Phe Val His Thr Pro Glu Ser Gly Gln Ser Asp Ser Ser Asn Gln Gln Gly Asp Ala Asp Ile Lys Pro Leu Pro Asn Gly His Leu Ser Phe Gln Asp Cys Phe Val Thr Ser Gly Val Trp Asn Val Thr Glu Leu Val Arg Val Ser Gln Thr Pro Val Ala Thr Ala Ser Gly Pro Asn Phe Ser Leu Ala Asp Leu Glu Ser Pro Ser Tyr Tyr Asn Ile Asn Gln Val Thr Leu Gly Arg Arg Ser Ile Thr Ser Pro Pro Ser Thr Ser Thr Thr Lys Arg Pro Lys Ser Ile Asp Asp Ser Glu Met Glu Ser Pro Val Asp Asp Val Phe Tyr Pro Gly Thr Gly Arg Ser Pro Ala Ala Gly Ser Ser Gln Ser Ser Gly Trp Pro Asn Asp Val Asp Ala Gly Pro Ala Ser Leu Lys Lys Ser Gly Lys Leu Asp Phe Cys Ser Ala Leu Ser Ser Gln Gly Ser Ser Pro Arg Met Ala Phe Thr His His Pro Leu Pro Val Leu Ala Gly Val Arg Pro Gly Ser Pro Arg Ala Thr Ala Ser Ala Leu His Phe Pro Ser Thr Ser Ile Ile Gln Gln Ser Ser Pro Tyr Phe Thr His Pro Thr Ile Arg Tyr His His His His Gly Gln Asp Ser Leu Lys Glu Phe Val Gln Phe Val Cys Ser Asp Gly Ser Gly Gln Ala Thr Gly Gln His Ser Gln Arg Gln Ala Pro Pro Leu Pro Thr Gly Leu Ser Ala Ser Asp Pro Gly Thr Ala Thr Phe <210>49 <211>829 <212>DNA

<213>Mus musculus <400> 49 caattctcct acgggctcca gactcagact ggtggaccca aacgcactcc ccttactaag 60 agggtcgcgg ccccacagga tggatcccct agagccccag aaacttctgg accacctcca 120 gtggatcatc cacctccttc aagtaaggct tccaggcctc cgcccatggg gagctgtcct 180 gctactggtg tggagccccc aagttcccca gtcattgagt ctgaaactct gatagaagac 240 gtgctgagac ctctggaaca ggcattggag gactgccatg gtcacacaaa gaaacaggta 300 tgtgatgata tcagccgacg cttggcgctg cttcaagaac agtgggctgg agggaagttg 360 tcaaaacctg taaaggaggg gatggcattg ctagtgcaag gaattttaan attcacccag 420 tgggatgcag cagatgacat tcaccgatca ttcatggttg accatgtgac tgaggtcagt 480 cagtggatgg tgggagtaaa aagattaatt gcagaaaagg aagagtctat cttcagagga 540 gaccaaagaa gagaaattta cagtggaacc tgagaaccag acaataccag gcttccaaca 600 gccatcataa tgcctgtggc tccccagact cacttcacct gacttcctat gccttagtgt 660 ggaaggcttc ttnttccttt ttaccaccag ggagactatt ggtcttgtgg gtcttgacca 720 aagatcctat ntagaccact gcaagatcac ttgttatgta catttcaata aacatctcaa 780 taaaatctca atggtgggaa gtgggtagga aagatgaaaa aaaaaaaag 829 <210> 50 <211> 875 <212> DNA
<213> Homo sapiens <300>
<301> Lanz, R. B.
<302> A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex <303> Cell <304> 1999 <305> 97 <306> 17-27 <313> 1 TO 875 <400> 50 cgcttggcgg agctgtacgt gaagccgggc aacaaggaac gcggctggaa cgacccgccg 60 cagttctcat acgggctgca gacccaggcc ggcggaccca ggcgctcgct gcttaccaag 120 agggtagccg caccccagga tggatccccc agagtccccg catcagagac ttctcctggg 180 cctcccccaa tggggcctcc acctccttca agtaaggctc ccaggtcccc acctgtgggg 240 agtggtcctg cctctggcgt ggagcccaca agtttcccag tcgagtctga ggctgtgatg 300 gaggatgtgc tgagaccttt ggaacaggca ttggaagact gccgtggcca cacaaggaag 360 caggtatgtg atgacatcag ccgacgcctg gcactgctgc aggaacagtg ggctggagga 420 aagttgtcaa tacctgtaaa gaagagaatg gctctactgg tgcaagagct ttcaagccac 480 cggtgggacg cagcagatga catccaccgc tccctcatgg ttgaccatgt gactgaggtc 540 agtcagtgga tggtaggagt taaaagatta attgcagaaa agaggagtct gttttcagag 600 gaggcagcca atgaagagaa atctgcagcc acagctgaga agaaccatac cataccaggc 660 ttccagcagg cttcataatc ctcggttccc cagactcacc ggacaccatc tcctatgcct 720 tggagacctt ctgtcacttg gctcccttct taccaccacc aagactgtcc cactgggcct 780 gacccaccta tgagggaaga agtcccacct gggccagagg gagttcatgt gttactcata 840 acatgcattt caataaaaac atctctgcgg tggtg 875 <210>51 <211>182 <212>PRT

<213>Mus musculus <300>
<301> Schleef, M.
<302> Subtractive cDNA cloning as a tool to analyse secondary effects of a muscle disease. Characterisation of affected genes in the myotonic ADR mouse <303> Neuromuscul. Disord.
<304> 1994 <305> 4 <306> 205-217 <313> 1 TO 182 <400> 51 Met Gln Asp Ile Met Asp Arg Pro Pro Arg Ser Pro Lys Glu Pro Leu Ile Ser Gly Trp Leu Phe Phe Arg Tyr Met Ala Ile Gly Gly Tyr Val Gly Ala Ala Thr Val Gly Ala Ala Ala Trp Trp Phe Leu Tyr Ala Glu Asp Gly Pro His Val Ser Tyr His Gln Leu Thr His Phe Met Gln Cys Thr Glu His Asn Pro Glu Phe Asp Gly Leu Asp Cys Glu Val Phe Glu Ala Pro Glu Pro Met Thr Met Ala Leu Ser Glu Leu Val Thr Ile Glu Met Cys Asn Ala Leu Asn Ser Leu Ser Glu Asn Gln Ser Leu Leu Arg Met Pro Pro Trp Val Asn Ile Trp Leu Leu Gly Ser Ile Cys Leu Ser Met Ser Leu His Phe Leu Ile Leu Tyr Val Asp Pro Leu Pro Met Ile Phe Lys Leu Arg Ala Leu Asp Phe Thr Gln Trp Leu Met Val Leu Lys Ile Ser Leu Pro Val Ile Gly Leu Asp Glu Leu Leu Lys Phe Ile Ala Arg Asn Tyr Leu Glu Gly <210> 52 <211> 1001 <212> PRT
<213> Homo sapiens <400> 52 Met Glu Ala Ala His Ala Lys Thr Thr Glu Glu Cys Leu Ala Tyr Phe Gly Val Ser Glu Thr Thr Gly Leu Thr Pro Asp Gln Val Lys Arg Asn Leu Glu Lys Tyr Gly Leu Asn Glu Leu Pro Ala Glu Glu Gly Lys Thr Leu Trp Glu Leu Val Ile Glu Gln Phe Glu Asp Leu Leu Val Arg Ile Leu Leu Leu Ala Ala Cys Ile Ser Phe Val Leu Ala Trp Phe Glu Glu Gly Glu Glu Thr Ile Thr Ala Phe Val Glu Pro Phe Val Ile Leu Leu Ile Leu Ile Ala Asn Ala Ile Val Gly Val Trp Gln Glu Arg Asn Ala Glu Asn Ala Ile Glu Ala Leu Lys Glu Tyr Glu Pro Glu Met Gly Lys Val Tyr Arg Ala Asp Arg Lys Ser Val Gln Arg Ile Lys Ala Arg Asp Ile Val Pro Gly Asp Ile Val Glu Val Ala Val Gly Asp Lys Val Pro Ala Asp Ile Arg Ile Leu Ala Ile Lys Ser Thr Thr Leu Arg Val Asp Gln Ser Ile Leu Thr Gly Glu Ser Val Ser Val Ile Lys His Thr Glu Pro Val Pro Asp Pro Arg Ala Val Asn Gln Asp Lys Lys Asn Met Leu Phe Ser Gly Thr Asn Ile Ala Ala Gly Lys Ala Leu Gly Ile Val Ala Thr Thr Gly Val Gly Thr Glu Ile Gly Lys Ile Arg Asp Gln Met Ala Ala Thr Glu Gln Asp Lys Thr Pro Leu Gln Gln Lys Leu Asp Glu Phe Gly Glu Gln Leu Ser Lys Val Ile Ser Leu Ile Cys Val Ala Val Trp Leu Ile Asn Ile Gly His Phe Asn Asp Pro Val His Gly Gly Ser Trp Phe Arg Gly Ala Ile Tyr Tyr Phe Lys Ile Ala Val Ala Leu Ala Val Ala Ala Ile Pro Glu Gly Leu Pro Ala Val Ile Thr Thr Cys Leu Ala Leu Gly Thr Arg Arg Met Ala Lys Lys Asn Ala Ile Val Arg Ser Leu Pro Ser Val Glu Thr Leu Gly Cys Thr Ser Val Ile Cys Ser Asp Lys Thr Gly Thr Leu Thr Thr Asn Gln Met Ser Val Cys Lys Met Phe Ile Ile Asp Lys Val Asp Gly Asp Ile Cys Leu Leu Asn Glu Phe Ser Ile Thr Gly Ser Thr Tyr Ala Pro Glu Gly Glu Val Leu Lys Asn Asp Lys Pro Val Arg Pro Gly Gln Tyr Asp Gly Leu Val Glu Leu Ala Thr Ile Cys Ala Leu Cys Asn Asp Ser Ser Leu Asp Phe Asn Glu Ala Lys Gly Val Tyr Glu Lys Val Gly Glu Ala Thr Glu Thr Ala Leu Thr Thr Leu Val Glu Lys Met Asn Val Phe Asn Thr Asp Val Arg Ser Leu Ser Lys Val Glu Arg Ala Asn Ala Cys Asn Ser Val Ile Arg Gln Leu Met Lys Lys Glu Phe Thr Leu Glu Phe Ser Arg Asp Arg Lys Ser Met Ser Val Tyr Cys Ser Pro Ala Lys Ser Ser Arg Ala Ala Val Gly Asn Lys Met Phe Val Lys Gly Ala Pro Glu Gly Val Ile Asp Arg Cys Asn Tyr Val Arg Val Gly Thr Thr Arg Val Pro Leu Thr Gly Pro Val Lys Glu Lys Ile Met Ala Val Ile Lys Glu Trp Gly Thr Gly Arg Asp Thr Leu Arg Cys Leu Ala Leu Ala Thr Arg Asp Thr Pro Pro Lys Arg Glu Glu Met Val Leu Asp Asp Ser Ala Arg Phe Leu Glu Tyr Glu Thr Asp Leu Thr Phe Val Gly Val Val Gly Met Leu Asp Pro Pro Arg Lys Glu Val Thr Gly Ser Ile Gln Leu Cys Arg Asp Ala Gly Ile Arg Val Ile Met Ile Thr Gly Asp Asn Lys Gly Thr Ala Ile Ala Ile Cys Arg Arg Ile Gly Ile Phe Gly Glu Asn Glu Glu Val Ala Asp Arg Ala Tyr Thr Gly Arg Glu Phe Asp Asp Leu Pro Leu Ala Glu Gln Arg Glu Ala Cys Arg Arg Ala Cys Cys Phe Ala Arg Val Glu Pro Ser His Lys Ser Lys Ile Val Glu Tyr Leu Gln Ser Tyr Asp Glu Ile Thr Ala Met Thr Gly Asp Gly Val Asn Asp Ala Pro Ala Leu Lys Lys Ala Glu Ile Gly Ile Ala Met Gly Ser Gly Thr Ala Val Ala Lys Thr Ala Ser Glu Met Val Leu Ala Asp Asp Asn Phe Ser Thr Ile Val Ala Ala Val Glu Glu Gly Arg Ala Ile Tyr Asn Asn Met Lys Gln Phe Ile Arg Tyr Leu Ile Ser Ser Asn Val Gly Glu Val Val Cys Ile Phe Leu Thr Ala Ala Leu Gly Leu Pro Glu Ala Leu Ile Pro Val Gln Leu Leu Trp Val Asn Leu Val Thr Asp Gly Leu Pro Ala Thr Ala Leu Gly Phe Asn Pro Pro Asp Leu Asp Ile Met Asp Arg Pro Pro Arg Ser Pro Lys Glu Pro Leu Ile Ser Gly Trp Leu Phe Phe Arg Tyr Met Ala Ile Gly Gly Tyr Val Gly Ala Ala Thr Val Gly Ala Ala Ala Trp Trp Phe Leu Tyr Ala Glu Asp Gly Pro His Val Asn Tyr Ser Gln Leu Thr His Phe Met Gln Cys Thr Glu Asp Asn Thr His Phe Glu Gly Ile Asp Cys Glu Val Phe Glu Ala Pro Glu Pro Met Thr Met Ala Leu Ser Val Leu Val Thr Ile Glu Met Cys Asn Ala Leu Asn Ser Leu Ser Glu Asn Gln Ser Leu Leu Arg Met Pro Pro Trp Val Asn Ile Trp Leu Leu Gly Ser Ile Cys Leu Ser Met Ser Leu His Phe Leu Ile Leu Tyr Val Asp Pro Leu Pro Met Ile Phe Lys Leu Arg Ala Leu Asp Leu Thr Gln Trp Leu Met Val Leu Lys Ile Ser Leu Pro Val Ile Gly Leu Asp Glu Ile Leu Lys Phe Val Ala Arg Asn Tyr Leu Glu Asp Pro Glu Asp Glu Arg Arg Lys <210>53 <211>89 <212>PRT

<213>Mus musculus <400> 53 Met Pro Ser Glu Leu Glu Lys Ala Leu Ser Asn Leu Ile Asp Val Tyr His Aan Tyr Ser Asn Ile Gln Gly Asn His His Ala Leu Tyr Lys Asn Asp Phe Lys Lys Met Val Thr Thr Glu Cys Pro Gln Phe Val Gln Asn Ile Asn Ile Glu Asn Leu Phe Arg Glu Leu Asp Ile Asn Ser Asp Asn Ala Ile Asn Phe Glu Glu Phe Leu Ala Met Val Ile Lys Val Gly Val Ala Ser His Lys Asp Ser His Lys Glu <210> 54 <211> 93 <212> PRT
<213> Homo sapiens <300>
<301> Dorin, J. R.
<302> A clue to the basic defect in cystic fibrosis from cloning the CF antigen gene <303> Nature <304> 1987 <305> 326 <306> 614-617 <313> 1 TO 93 <400> 54 Met Leu Thr Glu Leu Glu Lys Ala Leu Asn Ser Ile Ile Asp Val Tyr His Lys Tyr Ser Leu Ile Lys Gly Asn Phe His Ala Val Tyr Arg Asp Asp Leu Lys Lys Leu Leu Glu Thr Glu Cys Pro Gln Tyr Ile Arg Lys Lys Gly Ala Asp Val Trp Phe Lys Glu Leu Asp Ile Asn Thr Asp Gly Ala Val Asn Phe Gln Glu Phe Leu Ile Leu Val Ile Lys Met Gly Val Ala Ala His Lys Lys Ser His Glu Glu Ser His Lys Glu <210> 55 <211> 134 <212> PRT
<213> Homo sapiens <400> 55 Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser Ser Arg Ser Cys Gly Asp Tyr Leu Arg Tyr Pro Ala Ser Ser Arg Gly Phe Ser Tyr Pro Ser Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gln Leu Gly Ser Ser Leu Tyr Arg Gly Cys Gln Glu Ile Cys Trp Glu Pro Thr Ser Cys Gln Thr Ser Tyr Val Glu Ser Ser Pro Cys Gln Thr Ser Cys Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro Cys Lys Thr Thr Tyr Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys Arg Ser Leu Gly Tyr Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly Ser Ser Gly Val Arg Ser Leu Gly Tyr Gly Ser <210>56 <211>306 <212>PRT

<213>Mus musculus <400> 56 Met Ala Ser Ser Gly Ser Val Gln Gln Leu Pro Leu Val Leu Leu Met Leu Leu Leu Ala Ser Ala Ala Arg Ala Arg Leu Tyr Phe Arg Ser Gly Gln Thr Cys Tyr His Pro Ile Arg Gly Asp Gln Leu Ala Leu Leu Gly Arg Arg Thr Tyr Pro Arg Pro His Glu Tyr Leu Ser Pro Ala Asp Leu Pro Lys Asn Trp Asp Trp Arg Asn Val Asn Gly Val Asn Tyr Ala Ser Val Thr Arg Asn Gln His Ile Pro Gln Tyr Cys Gly Ser Cys Trp Ala His Gly Ser Thr Ser Ala Met Ala Asp Arg Ile Asn Ile Lys Arg Lys Gly Ala Trp Pro Ser Ile Leu Leu Ser Val Gln Asn Val Ile Asp Cys Gly Asn Ala Gly Ser Cys Glu Gly Gly Asn Asp Leu Pro Val Trp Glu Tyr Ala His Lys His Gly Ile Pro Asp Glu Thr Cys Asn Asn Tyr Gln Ala Lys Asp Gln Asp Cys Asp Lys Phe Asn Gln Cys Gly Thr Cys Thr Glu Phe Lys Glu Cys His Thr Ile Gln Asn Tyr Thr Leu Trp Arg Val Gly Asp Tyr Gly Ser Leu Ser Gly Arg Glu Lys Met Met Ala Glu Ile Tyr Ala Asn Gly Pro Ile Ser Cys Gly Ile Met Ala Thr Glu Met Met Ser Asn Tyr Thr Gly Gly Ile Tyr Ala Glu His Gln Asp Gln Ala Val Ile Asn His Ile Ile Ser Val Ala Gly Trp Gly Val Ser Asn Asp Gly Ile Glu Tyr Trp Ile Val Arg Asn Ser Trp Gly Glu Pro Trp Gly Glu Lys Gly Trp Met Arg Ile Val Thr Ser Thr Tyr Lys Gly Gly Thr Gly Asp Ser Tyr Asn Leu Ala Ile Glu Ser Ala Cys Thr Phe Gly Asp Pro Ile Val <210> 57 <211> 303 <212> PRT
<213> Homo sapiens <400> 57 Met Ala Arg Arg Gly Pro Gly Trp Arg Pro Leu Leu Leu Leu Val Leu Leu Ala Gly Ala Ala Gln Gly Gly Leu Tyr Phe Arg Arg Gly Gln Thr Cys Tyr Arg Pro Leu Arg Gly Asp Gly Leu Ala Pro Leu Gly Arg Thr Thr Tyr Pro Arg Pro His Glu Tyr Leu Ser Pro Ala Asp Leu Pro Lys Ser Trp Asp Trp Arg Asn Val Asp Gly Val Asn Tyr Ala Ser Ile Thr Arg Asn Gln His Ile Pro Gln Tyr Cys Gly Ser Cys Trp Ala His Ala Ser Thr Ser Ala Met Ala Asp Arg Ile Asn Ile Lys Arg Lys Gly Ala Trp Pro Ser Thr Leu Leu Ser Val Gln Asn Val Ile Asp Cys Gly Asn Ala Gly Ser Cys Glu Gly Gly Asn Asp Leu Ser Val Trp Asp Tyr Ala His Gln His Gly Ile Pro Asp Glu Thr Cys Asn Asn Tyr Gln Ala Lys Asp Gln Glu Cys Asp Lys Phe Asn Gln Cys Gly Thr Cys Asn Glu Phe Lys Glu Cys His Ala Ile Arg Asn Tyr Thr Leu Trp Arg Val Gly Asp Tyr Gly Ser Leu Ser Gly Arg Glu Lys Met Met Ala Glu Ile Tyr Ala Asn Gly Pro Ile Ser Cys Gly Ile Met Ala Thr Glu Arg Leu Ala Asn Tyr Thr Gly Gly Ile Tyr Ala Glu Tyr Gln Asp Thr Thr Tyr Ile Asn His Val Val Ser Val Ala Gly Trp Gly Ile Ser Asp Gly Thr Glu Tyr Trp Ile Val Arg Asn Ser Trp Gly Glu Pro Trp Gly Glu Arg Gly Trp Leu Arg Ile Val Thr Ser Thr Tyr Lys Asp Gly Lys Gly Ala Arg Tyr Asn Leu Ala Ile Glu Glu His Cys Thr Phe Gly Asp Pro Ile Val <210> 58 <211> 469 <212> PRT
<213> Homo sapiens <400> 58 Met Asp Ile Glu Asn Glu Gln Thr Leu Asn Val Asn Pro Thr Asp Pro Asp Asn Leu Ser Asp Ser Leu Phe Ser Gly Asp Glu Glu Asn Ala Gly Thr Glu Glu Ile Lys Asn Glu Ile Asn Gly Asn Trp Ile Ser Ala Ser Thr Ile Asn Glu Ala Arg Ile Asn Ala Lys Ala Lys Arg Arg Leu Arg Lys Asn Ser Ser Arg Asp Ser Gly Arg Gly Asp Ser Val Ser Asp Asn Gly Ser Glu Ala Val Arg Ser Gly Val Ala Val Pro Thr Ser Pro Lys Gly Arg Leu Leu Asp Arg Arg Ser Arg Ser Gly Lys Gly Arg Gly Leu Pro Lys Lys Gly Gly Ala Gly Gly Lys Gly Val Trp Gly Thr Pro Gly Gln Val Tyr Asp Val Glu Glu Val Asp Val Lys Asp Pro Asn Tyr Asp Asp Asp Gln Glu Asn Cys Val Tyr Glu Thr Val Val Leu Pro Leu Asp Glu Thr Ala Phe Glu Lys Thr Leu Thr Pro Ile Ile Gln Glu Tyr Phe Glu His Gly Asp Thr Asn Glu Val Ala Glu Met Leu Arg Asp Leu Asn Leu Gly Glu Met Lys Ser Gly Val Pro Val Leu Ala Val Ser Leu Ala Leu Glu Gly Lys Ala Ser His Arg Glu Met Thr Ser Lys Leu Leu Ser Asp Leu Cys Gly Thr Val Met Ser Thr Asn Asp Val Glu Lys Ser Phe Asp Lys Leu Leu Lys Asp Leu Pro Glu Leu Ala Leu Asp Thr Pro Arg Ala Pro Gln Leu Val Gly Gln Phe Ile Ala Arg Ala Val Gly Asp Gly Ile Leu Cys Asn Thr Tyr Ile Asp Ser Tyr Lys Gly Thr Val Asp Cys Val Gln Ala Arg Ala Ala Leu Asp Lys Ala Thr Val Leu Leu Ser Met Ser Lys Gly Gly Lys Arg Lys Asp Ser Val Trp Gly Ser Gly Gly Gly Gln Gln Pro Val Asn His Leu Val Lys Glu Ile Asp Met Leu Leu Lys Glu Tyr Leu Leu Ser Gly Asp Ile Ser Glu Ala Glu His Cys Leu Lys Glu Leu Glu Val Pro His Phe His His Glu Leu Val Tyr Glu Ala Ile Val Met Val Leu Glu Ser Thr Gly Glu Ser Ala Phe Lys Met Ile Leu Asp Leu Leu Lys Ser Leu Trp Lys Ser Ser Thr Ile Thr Ile Asp Gln Met Lys Arg Gly Tyr Glu Arg Ile Tyr Asn Glu Ile Pro Asp Ile Asn Leu Asp Val Pro His Ser Tyr Ser Val Leu Glu Arg Phe Val Glu Glu Cys Phe Gln Ala Gly Ile Ile Ser Lys Gln Leu Arg Asp Leu Cys Pro Ser Arg Gly Arg Lys Arg Phe Val Ser Glu Gly Asp Gly Gly Arg Leu Lys Pro Glu Ser Tyr <210>59 <211>418 <212>PRT

<213>Mus musculus <400> 59 Met Ala Phe Ile Ala Ala Leu Gly Leu Leu Met Ala Arg Ile Cys Pro Ala Val Leu Ser Phe Pro Asp Gly Thr Leu Gly Met Asp Ala Ala Val Gln Glu Asp His Asp Asn Gly Thr Gln Leu Asp Ser Leu Thr Leu Ala Ser Ile Asn Thr Asp Phe Ala Phe Ser Leu Tyr Lys Glu Leu Val Leu Lys Asn Pro Asp Thr Asn Ile Val Phe Ser Pro Leu Ser Ile Ser Ala Ala Leu Ala Leu Val Ser Leu Gly Ala Lys Gly Asn Thr Leu Glu Glu Ile Leu Glu Gly Leu Lys Phe Asn Leu Thr Glu Thr Ser Glu Ala Asp Ile His Gln Gly Phe Gly His Leu Leu Gln Arg Leu Asn Gln Pro Lys Asp Gln Val Gln Ile Ser Thr Gly Ser Ala Leu Phe Ile Glu Lys Arg Gln Gln Ile Leu Thr Glu Phe Gln Glu Lys Ala Lys Thr Leu Tyr Gln Ala Glu Ala Phe Thr Ala Asp Phe Gln Gln Pro Arg Gln Ala Lys Lys Leu Ile Asn Asp Tyr Val Arg Lys Gln Thr Gln Gly Met Ile Lys Glu Leu Val Ser Asp Leu Asp Lys Arg Thr Leu Met Val Leu Val Asn Tyr Ile Tyr Phe Lys Ala Lys Trp Lys Val Pro Phe Asp Pro Leu Asp Thr Phe Lys Ser Glu Phe Tyr Ala Gly Lys Arg Arg Pro Val Ile Val Pro Met Met Ser Met Glu Asp Leu Thr Thr Pro Tyr Phe Arg Asp Glu Glu Leu Ser Cys Thr Val Val Glu Leu Lys Tyr Thr Gly Asn Ala Ser Ala Leu Phe Ile Leu Pro Asp Gln Gly Arg Met Gln Gln Val Glu Ala Ser Leu Gln Pro Glu Thr Leu Arg Lys Trp Lys Asn Ser Leu Lys Pro Arg Met Ile Asp Glu Leu His Leu Pro Lys Phe Ser Ile Ser Thr Asp Tyr Ser Leu Glu Asp Val Leu Ser Lys Leu Gly Ile Arg Glu Val Phe Ser Thr Gln Ala Asp Leu Ser Ala Ile Thr Gly Thr Lys Asp Leu Arg Val Ser Gln Val Val His Lys Ala Val Leu Asp Val Ala Glu Thr Gly Thr Glu Ala Ala Ala Ala Thr Gly Val Lys Phe Val Pro Met Ser Ala Lys Leu Tyr Pro Leu Thr Val Tyr Phe Asn Arg Pro Phe Leu Ile Met Ile Phe Asp Thr Glu Thr Glu Ile Ala Pro Phe Ile Ala Lys Ile Ala Asn Pro Lys <210> 60 <211> 423 <212> PRT
<213> Homo Sapiens <400> 60 Met Glu Arg Met Leu Pro Leu Leu Thr Leu Gly Leu Leu Ala Ala Gly Phe Cys Pro Ala Val Leu Cys His Pro Asn Ser Pro Leu Asp Glu Glu Asn Leu Thr Gln Glu Asn Gln Asp Arg Gly Thr His Val Asp Leu Gly Leu Ala Ser Ala Asn Val Asp Phe Ala Phe Ser Leu Tyr Lys Gln Leu Val Leu Lys Ala Pro Asp Lys Asn Val Ile Phe Ser Pro Leu Ser Ile Ser Thr Ala Leu Ala Phe Leu Ser Leu Gly Ala His Asn Thr Thr Leu Thr Glu Ile Leu Lys Gly Leu Lys Phe Asn Leu Thr Glu Thr Ser Glu Ala Glu Ile His Gln Ser Phe Gln His Leu Leu Arg Thr Leu Asn Gln Ser Ser Asp Glu Leu Gln Leu Ser Met Gly Asn Ala Met Phe Val Lys Glu Gln Leu Ser Leu Leu Asp Arg Phe Thr Glu Asp Ala Lys Arg Leu Tyr Gly Ser Glu Ala Phe Ala Thr Asp Phe Gln Asp Ser Ala Ala Ala Lys Lys Leu Ile Asn Asp Tyr Val Lys Asn Gly Thr Arg Gly Lys Ile Thr Asp Leu Ile Lys Asp Leu Asp Ser Gln Thr Met Met Val Leu Val Asn Tyr Ile Phe Phe Lys Ala Lys Trp Glu Met Pro Phe Asp Pro Gln Asp Thr His Gln Ser Arg Phe Tyr Leu Ser Lys Lys Lys Trp Val Met Val Pro Met Met Ser Leu His His Leu Thr Ile Pro Tyr Phe Arg Asp Glu Glu Leu Ser Cys Thr Val Val Glu Leu Lys Tyr Thr Gly Asn Ala Ser Ala Leu Phe Ile Leu Pro Asp Gln Asp Lys Met Glu Glu Val Glu Ala Met Leu Leu Pro Glu Thr Leu Lys Arg Trp Arg Asp Ser Leu Glu Phe Arg Glu Ile Gly Glu Leu Tyr Leu Pro Lys Phe Ser Ile Ser Arg Asp Tyr Asn Leu Asn Asp Ile Leu Leu Gln Leu Gly Ile Glu Glu Ala Phe Thr Ser Lys Ala Asp Leu Ser Gly Ile Thr Gly Ala Arg Asn Leu Ala Val Ser Gln Val Val His Lys Ala Val Leu Asp Val Phe Glu Glu Gly Thr Glu Ala Ser Ala Ala Thr Ala Val Lys Ile Thr Leu Leu Ser Ala Leu Val Glu Thr Arg Thr Ile Val Arg Phe Asn Arg Pro Phe Leu Met Ile Ile Val Pro Thr Asp Thr Gln Asn Ile Phe Phe Met Ser Lys Val Thr Asn Pro Lys Gln Ala <210>61 <211>542 <212>DNA

<213>Mus musculus <400> 61 agcagktata tgtttattga tcctttgctc ctacctcttt attctggttg gtggtgttcc 60 tcttttgtgt gaggttggtc agctgggaac taaaagaaag gctactttgt tctaagtagg 120 agtgccaggg gaaaggatct gctctgaccc acagacccca tgcagctgca gaagtgaggg 180 ctctaactct gtgccagatg tggacaaagt gaggagatcc tgcagggggg cagtgcctgg 240 aggcaaagcc tggagaagtg aaagagtgag gcagactggg caccaagtag tcctagatgc 300 tgcggataga cacggggcag caagctttcc tcttggtcca tatgggttgg cctgtaaggt 360 tgcacagtcc catcaaraca gcaaggctga agggagacat aaccagagtc taaactggga 420 ctgagcttac ttgatggggc ccangctttt gggtggaggc asatacaggg agagagcagg 480 ggtgggggac aaaanaaatt tcangctcaa gaacatgggc tngtgctcca aaaaatcttg 540 ga 542 <210>62 <211>2035 <212>DNA

<213>Mus musculus <400> 62 cacgagcaca gaggctggca gctggctggt ttcagctctg cagactgcag aacacagaag 60 atggctttca ttgcagctct ggggctcttg atggctggga tctgccctgc tgtcctctgc 120 ttcccagatg gcacgttggg aatggatgct gcagtccaag aagaccatga caatgggaca 180 caactggaca gtctcacatt ggcctccatc aacactgact ttgccttcag cctctacaag 240 gagctggttt tgaagaatcc agataaaaat attgtcttct ccccacttag catctcagcg 300 gccttggctg tcatgtccct gggagcaaag ggcaacaccc tggaagagat tctagaaggt 360 ctcaagttca atcttacaga gacctctgag gcagacatcc accagggctt tgggcacctc 420 ctacagaggc tcaaccagcc aaaggaccag gtacagatca gcacgggtag tgccctgttt 480 attgaaaagc gccagcagat cctgacagaa ttccaggaga aggcaaagac tctgtaccag 540 gctgaggcct tcacagcaga cttccagcag cctcgacagg ccaaaaagct catcaatgac 600 tatgtgagga aacagaccca ggggatgatc aaggaactgg tctcagacct ggataaaagg 660 acattgatgg tgctggtgaa ttatatctac tttaaagcca aatggaaggt gccctttgac 720 cctcttgaca cgttcaagtc tgagttctac tgcggcaaga ggaggcccgt gatagtgccc 780 atgatgagca tggaggacct gaccacaccc tacttccgag atgaggagct gtcctgcact 840 gtggtggagc tgaagtacac aggaaatgcc agcgccctgt tcatcctccc tgaccagggc 900 aggatgcagc aggtggaagc cagcttacaa ccagagaccc tgaggaagtg gaagaattct 960 ctgaaaccca ggatgataga tgagctccac ctgcccaagt tctccatctc caccgactac 1020 agcctggagg atgtcctttc aaagctgggc atcagggaag tcttctccac acaggctgac 1080 ctgtctgcaa tcacaggaac caaggatctg agagtgtctc aggtggtcca caaggctgtg 1140 ctggatgtgg ctgagacagg cacagaagca gctgctgcca ctggagtcaa atttgtccca 1200 atgtctgcga aactgtaccc tctgactgta tatttcaatc ggcctttcct gataatgatc 1260 tttgacacag aaactgaaat tgcccccttt atagccaaga tagccaaccc caaatgagac 1320 tagaactccc caagtgttga cgcttcttcc cgggagccag gcattgagcc tgtctgtggg 1380 tctccatgtg cattttggct tccatgctct gcttggcctt ggcatgcctg gattagatag 1440 tgactaactg tgttataacc tcatgtacag acatccctgt gggaagtcag tgccgtgctc 1500 ccagacttct tggtagcact agcccatgtt cctgagcctg aaatttgtct tgtcccctac 1560 ccctgctctc tccctgtatc tgcctccacc caaaagcctg ggccccatca agtaagctca 1620 gtcccagttt agactctggt tatgtctccc ttcagccttg ctgtcttgat gggactgtgc 1680 aaccttacag gccaacccat atggaccaag aggaaagctt ggctggcccg tgtctatccg 1740 cagcatctag gactacttgg tgcccagtct gcctcactct ttcatttctc caggctttgc 1800 ctccaggcac tgcccccctg caggatctcc tcactttgtc cacatctggc acagagttag 1860 agccctcact tctgcagctg catggggtct gtgggtcaga gcagatcctt tcccctggca 1920 ctcctactta gaacaaagta gcctttcttt tagttcccag ctgaccaacc tcacacaaaa 1980 gaggaacacc aaccagaata aagaggtagg agcaaaggat caataaacat gtaac 2035 <210>63 <211>120 <212>DNA

<213>Mus musculus <400> 63 accacagtcc atgccatcac tgccacccag aagactgtgg atggcccctc tggaaagctg 60 tggcgtgatg gccgtggggc tgcccagaac atcatccctg catccactgg tgctgccaag 120 <210>64 <211>1310 <212>DNA

<213>Mus musculus <400> 64 actgcagaac acagaagatg gctttcattg cagctctggg gctcttgatg gctaggatct 60 gccctgctgt cctctccttc ccagatggca cgttgggaat ggatgctgca gtccaagaag 120 accatgacaa tgggacacaa ctggacagtc tcacattggc ctccatcaac actgactttg 180 ccttcagcct ctacaaggag ctggttttga agaatccaga tacaaatatt gtcttctccc 240 cacttagcat ctcagcggcc ttggccctcg tgtccctggg agcaaagggc aacaccctgg 300 aagagattct agaaggtctc aagttcaatc ttacagagac ctctgaggca gacatccacc 360 agggctttgg gcacctccta cagaggctca accagccaaa ggaccaggta cagatcagca 420 cgggtagtgc cctgtttatt gaaaagcgcc agcagatcct gacagaattc caggagaagg 480 caaagactct gtaccaggct gaggccttca cagcagactt ccagcagcct cgacaggcca 540 aaaagctcat caatgactat gtgaggaaac agacccaggg gatgatcaag gaactggtct 600 cagacctgga taaaaggaca ttgatggtgc tggtgaatta tatctacttt aaagccaaat 660 ggaaggtgcc ctttgaccct cttgacacgt tcaagtctga gttctacgcg ggcaagagga 720 ggcccgtgat agtgcccatg atgagcatgg aggacctgac cacaccctac ttccgagatg 780 aggagctgtc ctgcactgtg gtggagctga agtacacagg aaatgccagc gccctgttca 840 tcctccctga ccagggcagg atgcagcagg tggaagccag cttacaacca gagaccctga 900 ggaagtggaa gaattctctg aaacccagga tgatagatga gctccacctg cccaagttct 960 ccatctccac cgactacagc ctggaggatg tcctttcaaa gctgggcatc agggaagtct 1020 tctccacaca ggctgacctg tctgcaatca caggaaccaa ggatctgaga gtctctcagg 1080 tggtccacaa ggctgtgctg gatgtggctg agacaggcac agaagcagct gctgccactg 1140 gagtcaaatt tgtcccaatg tctgcgaaac tgtaccctct gactgtatat ttcaatcggc 1200 ctttcctgat aatgatcttt gacacagaaa ctgaaattgc cccctttata gccaagatag 1260 ccaaccccaa atgagactag aactccccaa gtgttgacgc ttcttcccgg 1310 <210> 65 <211> 20 <212> DNA
<213> Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Universal primer <220>
<223> Description of Artificial Sequence: Universal Primer <400> 65 agcgtggtcg cggccgaggt 20 <210> 66 <211> 21 <212> DNA
<213> Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Universal primer <220>
<223> Description of Artificial Sequence: Universal Primer <400> 66 tccagttgtg tcccattgtc a 21 <210> 67 <211> 21 <212> DNA
<213> Mus musculus <400> 67 ctgtcctctg cttcccagat g 21 <210>68 <211>21 <212>DNA

<213>Mus musculus <400> 68 tccagttgtg tcccattgtc a 21 <210>69 <211>19 <212>DNA

<213>Mus musculus <400> 69 atcaacggga agcccatca 19 <210>70 <211>20 <212>DNA

<213>Mus musculus <400> 70 gacatactca gcaccggcct 20 <210>71 <211>30 <212>DNA

<213>Mus musculus <400> 71 actgcagaac acagaagatg gctttcattg 30 <210>72 <211>30 <212>DNA

<213>Mus musculus <400> 72 ccgggaagaa gcgtcaacac ttggggagtt 30 <210> 73 <211> 30 <212> DNA
<213> Homo Sapiens <400> 73 aactcagctg aactcacatc tcccgtcaac 30 <210> 74 <211> 30 <212> DNA
<213> Homo Sapiens <400> 74 gtctgaaaga actagcctgt ccagccagta 30 <210> 75 <211> 22 <212> DNA
<213> Homo Sapiens <400> 75 catgggtgtg aaccatgaga ag 22 <210> 76 <211> 21 <212> DNA
<213> Homo Sapiens <400> 76 ctaagcagtt ggtggtgcag g 21 <210> 77 <211> 19 <212> DNA
<213> Homo Sapiens <400> 77 gaggccattt ccagcgact 19 <210> 78 <211> 20 <212> DNA
<213> Homo sapiens <400> 78 gaataacccg acatggcgtc 20 <210> 79 <211> 43 <212> DNA
<213> Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Antisense primer that fuses the T7 RNA polymerase promoter with a region homologous to human MRPB
<220>
<223> Description of Artificial Sequence: Antisense primer that fuses the T7 RNA polmerase promoter with a region homolgous to human MRP8 <400> 79 taatacgact cactataggg cccacgccca tctttatcac cag 43 <210> 80 <211> 43 <212> DNA
<213> Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Sense primer that fuses the T3 RNA polymerase promoter with a region homologous to human MRPe <220>
<223> Description of Artificial Sequence: Sense primer that fuses the T3 RNA polmerase promoter with a region homolgous to human MRPe <400> 80 aattaaccct cactaaaggg ggaatttcca tgccgtctac agg 43 <210>81 <211>42 <212>DNA

<213>Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Antisense primer that fuses the T3 RNA polymerase promoter with a region homologous to human p68 helicase <220>
<223> Description of Artificial Sequence: Antisense primer that fuses the T3 RNA polmerase promoter with a region homolgous to human p68 helicase <400> 81 aattaaccct cactaaaggg ggcaacatta cttccatatt gc 42 <210> 82 <211> 41 <212> DNA
<213> Artificial Sequence <220>
<223> Beschreibung der kunstlichen Sequenz:Sense primer that fuses the T7 RNA polymerase promoter with a region homologous to human p68 helicase <220>
<223> Description of Artificial Sequence: Antisense primer that fuses the T7 RNA polmerase promoter with a region homolgous to human p68 helicase <400> 82 taatacgact cactataggg cgagacaggg aaaactatga c 41 <210>83 <211>22 <212>DNA

<213>Mus musculus <400> 83 ccttatctct gtgcttcggg as 22 <210> 84 <211> 21 <212> DNA
<213> Mus musculus <400> 84 cgacctgaac ctctgtcttc g 21 <210> 85 <211> 15 <212> PRT
<213> Homo sapiens <400> 85 Arg Glu Phe Gln Arg Gly Thr Cys Ser Arg Pro Asp Thr Glu Cys <210> 86 <211> 16 <212> PRT
<213> Homo Sapiens <400> 86 Arg Glu Tyr Gln Arg Gly Asn Cys Asn Arg Gly Glu Asn Asp Cys Arg <210> 87 <211> 15 <212> PRT
<213> Homo Sapiens <400> 87 Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala <210> 88 <211> 16 <212> PRT
<213> Homo Sapiens <400> 88 Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Ser Cys <210> 89 <211> 175 <212> PRT
<213> Homo sapiens <400> 89 Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser Ser Arg Ser Cys Gly Asp Tyr Leu Arg Tyr Pro Ala Ser Ser Arg Gly Phe Ser Tyr Pro Ser Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gln Leu Gly Ser Ser Leu Tyr Arg Gly Cys Gln Glu Ile Cys Trp Glu Pro Thr Ser Cys Gln Thr Ser Tyr Val Glu Ser Ser Pro Cys Gln Thr Ser Cys Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro Cys Lys Thr Thr Tyr Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys Arg Ser Leu Gly Tyr Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly Ser Ser Gly Val Arg Ser Leu Gly Tyr Gly Ser Cys Gly Phe Pro Ser Leu Gly Tyr Gly Ser Gly Phe Cys Arg Pro Thr Tyr Leu Ala Ser Arg Ser Cys Gln Ser Pro Cys Tyr Arg Pro Ala Tyr Gly Ser Thr Phe Cys Arg Ser Thr Cys <210> 90 <211> 193 <212> PRT
<213> Homo sapiens <400> 90 Met Trp His Ala Asn Ser Glu Ser Ser Gln Cys Asn Ser Ala Glu Leu Thr Ser Pro Ile Asn Met Ser Tyr Asn Cys Cys Ser Gly Asn Phe Ser Ser Arg Ser Cys Gly Gly Tyr Leu His Tyr Pro Ala Ser Ser Cys Gly Phe Ser Tyr Pro Ser Asn Gln Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gln Leu Gly Ser Ser Leu Tyr Arg Gly Cys Gln Gln Thr Cys Trp Glu Pro Thr Ser Cys Gln Thr Ser Tyr Val Glu Ser Ser Pro Cys Gln Thr Ser Cys Tyr Arg Pro Arg Thr Ser Leu Leu Cys Ser Pro Cys Gln Thr Thr Tyr Ser Gly Ser Leu Gly Phe Gly Ser Ser Ser Cys Arg Ser Leu Gly Tyr Gly Ser Arg Ser Cys Tyr Ser Val Gly Cys Gly Ser Ser Gly Phe Arg Ser Leu Gly Tyr Gly Gly Cys Gly Phe Pro Ser Leu Gly Tyr Gly Val Gly Phe Cys Arg Pro Thr Tyr Leu Ala Ser Arg Ser Cys Gln Ser Ser Cys Tyr Arg Pro Thr Cys Gly Ser Gly Phe Tyr Tyr <210> 91 <211> 172 <212> PRT
<213> Homo sapiens <400> 91 Met Ser Tyr Asn Cys Cys Ser Arg Asn Phe Ser Ser Cys Ser His Gly Gly Tyr Leu His Tyr Pro Gly Ser Ser Cys Gly Ser Ser Tyr Pro Ser Asn Leu Val Tyr Ser Thr Asp Leu Cys Ser Pro Ser Thr Cys Gln Leu Gly Ser Ser Leu Tyr Arg Gly Cys Gln Glu Thr Cys Trp Arg Pro Asn Ser Cys Gln Thr Leu Cys Val Glu Ser Ser Pro Cys His Thr Ser Cys Tyr Tyr Pro Arg Thr His Met Leu Cys Asn Ser Cys Leu Thr Met His Val Gly Ser Arg Gly Phe Gly Ser Asn Ser Cys Cys Ser Leu Ser Cys Gly Ser Arg Ser Cys Ser Ser Leu Gly Cys Gly Ser Asn Gly Phe Arg Tyr Leu Asn Tyr Arg Ile His Thr Ser Pro Ser Gln Ser Tyr Arg Ser Arg Phe Cys His Pro Ile Tyr Phe Pro Pro Arg Arg Trp Phe His Ser Ser Cys Tyr Gln Pro Phe Cys Arg Ser Gly Phe Tyr <210> 92 <211> 160 <212> PRT
<213> Homo Sapiens <400> 92 Met Ser Tyr Asn Cys Cys Ser Arg Asn Phe Ser Ser Arg Ser Phe Gly Gly Tyr Leu Tyr Tyr Pro Gly Ser Tyr Pro Ser Ser Leu Val Tyr Ser Thr Ala Leu Cys Ser Pro Ser Thr Cys Gln Leu Arg Ser Ser Leu Tyr Arg Asp Cys Gln Lys Thr Cys Trp Glu Pro Ala Ser Cys Gln Lys Ser Cys Tyr Arg Pro Arg Thr Ser Ile Leu Cys Cys Pro Cys Gln Thr Thr Cys Ser Gly Ser Leu Gly Phe Arg Ser Ser Ser Cys Arg Ser Gln Gly Tyr Gly Ser Arg Cys Cys Tyr Ser Leu Gly Asn Gly Ser Ser Gly Phe Arg Phe Leu Lys Tyr Gly Gly Cys Gly Phe Pro Ser Leu Ser Tyr Gly Ser Arg Phe Cys Tyr Pro Asn Tyr Leu Ala Ser Gly Ala Trp Gln Ser Ser Cys Tyr Arg Pro Ile Cys Gly Ser Arg Phe Tyr Gln Phe Thr Cys <210> 93 <211> 137 <212> PRT
<213> Homo Sapiens <400> 93 Met Ser Tyr Asn Cys Ser Ser Gly Asn Phe Ser Ser Cys Cys Phe Gly Ser Tyr Leu Arg Tyr Pro Val Ser Thr Tyr Asn Leu Phe Tyr Pro Ser Asn Ala Ile Tyr Ser Pro Asn Thr Cys Gln Leu Gly Ser Ser Leu Tyr Asn Gly Cys Gln Glu Thr Tyr Cys Glu Pro Thr Ser Cys Gln Thr Ser Cys Thr Leu Ala Arg Ser Tyr Gln Thr Ser Cys Tyr Cys Pro Lys Asn Ser Ile Phe Cys Ser Pro Arg Gln Thr Asn Tyr Ile Arg Ser Leu Gly Cys Gly Asn Thr Gly Leu Gly Ser Leu Gly Cys Gly Ser Thr Gly Phe Gln Ser Leu Asp Cys Gly Ser Ser Phe Tyr His Pro Thr Thr Phe Ser Ser Arg Asn Phe Gln Ala Thr Cys Tyr <210> 94 <211> 163 <212> PRT
<213> Homo sapiens <400> 94 Met Ser Phe Asn Cys Ser Thr Arg Asn Cys Ser Ser Arg Pro Ile Gly Gly Arg Cys Ile Val Pro Val Ala Gln Val Thr Thr Thr Ser Thr Thr Asp Ala Asp Cys Leu Gly Gly Ile Cys Leu Pro Ser Ser Phe Gln Thr Gly Ser Trp Leu Leu Asp His Cys Gln Glu Thr Cys Cys Glu Pro Thr Ala Cys Gln Pro Thr Cys Tyr Arg Arg Thr Ser Cys Val Ser Asn Pro Cys Gln Val Thr Cys Ser Arg Gln Thr Thr Cys Ile Ser Asn Pro Cys Ser Thr Thr Tyr Ser Arg Pro Leu Thr Phe Val Ser Ser Gly Cys Gln Pro Leu Gly Gly Ile Ser Ser Val Cys Gln Pro Val Gly Gly Ile Ser Thr Val Cys Gln Pro Val Gly Gly Val Ser Thr Val Cys Gln Pro Ala Cys Gly Val Ser Arg Thr Tyr Gln Gln Ser Cys Val Ser Ser Cys Arg Arg Thr Cys <210> 95 <211> 671 <212> DNA
<213> Homo Sapiens <400> 95 aactcacatc tcccgtcaac atgtcctaca actgctgctc tggaaacttc tcctcccgct 60 cctgtggtga ctacctgcgc tacccagcat cctcacgtgg cttttcctac cccagcaatc 120 tggtctacag cactgacctc tgctctccca gcacctgcca gctgggttcc tctctctata 180 ggggctgtca ggagatctgc tgggagccca ccagctgcca gacgtcctat gtggagtcca 240 gcccctgcca gacctcctgc taccgcccca gaacctcctt gctctgcagt ccttgcaaga 300 cgacttactc tgggtctcta ggctttggat ccagcagctg ccgctccctg ggctatggat 360 cgaggagctg ctactcagtg ggctgtgggt ccagtggtgt cagatccctg ggttatggaa 420 gctgtggctt cccttccctc ggctatggat ctggattctg ccgcccaacc tacttggctt 480 ctaggagctg ccagtctcct tgttacagac cagcctatgg atcaaccttc tgcagatcaa 540 cttgctgaat ttccagacct tttaagcaaa gtgtctcagt ctctacgtag agctgttatc 600 ataggcattt ccagcaatgt gagctaaccc ctcttactac tagctcttca tcctttctct 660 ggcatcaagt a 671 <210> 96 <211> 697 <212> DNA
<213> Homo Sapiens <400> 96 atataaatgg tcctgtccag atgtggcatg caaactcaga atcttctcag tgtaactcag 60 ctgaactcac atctcccatc aacatgtcct acaactgctg ctctggaaac ttctcctccc 120 gctcctgtgg tggctacctg cactacccag cctcctcctg tggcttttcc taccccagca 180 accaggtcta cagcactgac ctctgctctc ccagcacgtg ccagctgggt tcctctctct 240 ataggggctg tcagcagacc tgctgggagc ccaccagctg ccagacatcc tatgtggagt 300 ccagcccctg ccagacctcc tgctaccgtc ccagaacctc cttgctctgc agtccctgcc 360 agacaactta ctctgggtct ctaggctttg gatccagcag ctgccgctcc ctgggctatg 420 gatcgaggag ctgctactca gtgggctgtg ggtccagtgg cttcagatcc ctgggttatg 480 gaggctgtgg cttcccttcc ctgggctatg gcgttggatt ctgccgccca acctacttgg 540 cttctaggag ctgccagtct tcttgctaca gaccaacttg tggatcaggc ttctactatt 600 gatcatcttg ttaaattgct gattttgttg gctaatgcct tcaatgcctc tactcataac 660 ctttattgtc ttcatcatgt acagaaagaa ttagcct 697 <210> 97 <211> 637 <212> DNA
<213> Homo Sapiens <400> 97 ctcacatctt cccgtcaaca tgtcctacaa ctgttgctct agaaacttct cctcctgctc 60 ccacgggggt tacttgcact acccaggctc ctcctgtggc tcttcctacc ccagcaacct 120 ggtctacagc actgacctct gctctcccag cacctgccag ctgggttcct ctctctatag 180 gggctgtcag gagacctgct ggaggcccaa cagctgtcag acattgtgtg ttgagtccag 240 cccctgccac acctcctgct actaccccag gactcacatg ctctgcaatt cttgcctgac 300 tatgcatgtt gggtctcggg gttttggatc caatagctgc tgctccctga gctgtggatc 360 caggagctgc tcctcactgg gctgtggatc caatggcttc agatatctga attatagaat 420 ccatacctcc ccttcccaga gttatagatc cagattctgc catccaatct attttccacc 480 tagaaggtgg ttccattcat cttgttatca gccattctgt agatctggtt tctactgact 540 aatgtggtga ctggtaaaac tcatttgaga aatgcatatt ctttagtaag gtcatctgtt 600 aatttcttcc tttgagaagt attctaatat tattgat 637 <210> 98 <211> 603 <212> DNA
<213> Homo sapiens <400> 98 tgaactccca tctctcatca gcatgtccta caactgctgc tctagaaact tctcctcccg 60 ctcctttggg ggctacctgt actacccagg ctcctacccc agcagcctgg tctacagcac 120 tgccctctgc tctcccagca cctgccagct gcgttcctct ctctacaggg actgtcagaa 180 gacctgctgg gagcccgcca gctgccagaa atcctgctac cgccccagga cctccatcct 240 ctgctgtccc tgtcagacga cttgctctgg atctctaggc tttcggtcca gcagctgtcg 300 ctcccagggc tatggatcta ggtgctgcta ctcgctggga aatggatcca gtggcttcag 360 attcctgaaa tatggaggct gtggttttcc ttccctgagt tacggatcca gattctgcta 420 cccaaactac ttggcttctg gagcctggca gtcttcttgt tacagaccaa tctgtggatc 480 tcgcttctat caattcacct gctaaatttc tagatccttt tgagtattgg gatcaaagtc 540 tctactgaat gcagccatta ttttcattct tgccagatcc caatatcttt ttattcttcc 600 acc 603 <210>99 <211>531 <212>DNA

<213>Homo sapiens <400> 99 gagctcagaa ctcctgttaa catgtcttac aactgcagct ctggaaactt ctcctcctgc 60 tgttttggaa gttacctgag gtatccagtt tccacttata atttgttcta ccccagcaat 120 gccatctatt ctccaaatac ctgccaactg ggctcctctc tctacaatgg ctgtcaggag 180 acctactgtg agcccaccag ctgccagaca tcctgcactt tggccagatc ctatcagaca 240 tcctgttact gcccaaagaa ttccatcttc tgcagtcccc gccagactaa ctacataaga 300 tcccttggat gtggaaacac tggccttgga tctcttggtt gtggaagcac tggcttccaa 360 tctctggact gtgggtccag cttctaccac ccaactacct tttcatccag gaatttccag 420 gcaacttgtt actaaccagc ctttgggtct cgcctttttg gatcatctta ctgaatattc 480 tccattctct catgattatt tctgtactct atggaactgc aacactcagc c 531 <210> 100 <211> 609 <212> DNA
<213> Homo Sapiens <400> 100 gcagccctct gtctgacatc atgtccttca actgctccac aagaaattgc tcttccaggc 60 ccattggagg acgctgcatt gttccagtgg cccaagttac cacgacttcc accactgatg 120 ctgactgcct gggcggcatc tgtttgccca gttccttcca gactggctct tggctcctgg 180 accactgtca agagacctgc tgtgagccca ctgcttgcca gccaacctgt taccggcgaa 240 cttcatgtgt ctccaaccct tgccaggtga cttgctctcg acaaactacc tgtatttcca 300 acccctgctc aactacctac agccggccgc tcacctttgt ctctagtgga tgtcagcccc 360 tgggaggcat ctccagtgtc tgccaaccag tgggcggcat ctctactgtc tgccaaccag 420 tgggaggagt ctctactgtc tgccagccag cctgtggggt ctccaggacg tatcagcagt 480 cctgcgtgtc cagctgccga agaacctgct aagtgtgtag gagccagtga gcgaatcaag 540 actccacgac ctgccagctg tttccaggat cttccagcat gctgcttgtc cctgaatagc 600 tcttcatag 609 <210>101 <211>113 <212>PRT

<213>Mus musculus <400> 101 Met Ala Asn Lys Ala Pro Ser Gln Met Glu Arg Ser Ile Thr Thr Ile Ile Asp Thr Phe His Gln Tyr Ser Arg Lys Glu Gly His Pro Asp Thr Leu Ser Lys Lys Glu Phe Arg Gln Met Val Glu Ala Gln Leu Ala Thr Phe Met Lys Lys Glu Lys Arg Asn Glu Ala Leu Ile Asn Asp Ile Met Glu Asp Leu Asp Thr Asn Gln Asp Asn Gln Leu Ser Phe Glu Glu Cys Met Met Leu Met Ala Lys Leu Ile Phe Ala Cys His Glu Lys Leu His Glu Asn Asn Pro Arg Gly His Gly His Ser His Gly Lys Gly Cys Gly Lys <210> 102 <211> 114 <212> PRT
<213> Homo Sapiens <400> 102 Met Thr Cys Lys Met Ser Gln Leu Glu Arg Asn Ile Glu Thr Ile Ile Asn Thr Phe His Gln Tyr Ser Val Lys Leu Gly His Pro Asp Thr Leu Asn Gln Gly Glu Phe Lys Glu Leu Val Arg Lys Asp Leu Gln Asn Phe Leu Lys Lys Glu Asn Lys Asn Glu Lys Val Ile Glu His Ile Met Glu Asp Leu Asp Thr Asn Ala Asp Lys Gln Leu Ser Phe Glu Glu Phe Ile Met Leu Met Ala Arg Leu Thr Trp Ala Ser His Glu Lys Met His Glu Gly Asp Glu Gly Pro Gly His His His Lys Pro Gly Leu Gly Glu Gly Thr Pro <210>103 <211>341 <212>PRT

<213>Mus musculus <400> 103 Met Ala Val Ser Val Thr Pro Ile Arg Asp Thr Lys Trp Leu Thr Leu Glu Val Cys Arg Glu Phe Gln Arg Gly Thr Cys Ser Arg Pro Asp Thr Glu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gln Val Glu Asn Gly Arg Val Ile Ala Cys Phe Aap Ser Leu Lys Gly Arg Cys Ser Arg Glu Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gln Leu Glu Ile Asn Gly Arg Asn Asn Leu Ile Gln Gln Lys Asn Met Ala Met Leu Ala Gln Gln Met Gln Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu Gln Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Ser Ala Ser Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu Val Pro Ala Glu Ile Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn Pro Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gln Lys Leu Met Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gln Arg Gly Asn Cys Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser Thr Met Ile Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr Ile Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro Ala His Leu Gln Ala Lys Ile Lys Ala Ala Gln Tyr Gln Val Asn Gln Ala Ala Ala Ala Gln Ala Ala Ala Thr Ala Ala Ala Met Gly Ile Pro Gln Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu Lys Thr Asn Gly Ala Thr Ala Val Phe Asn Thr Gly Ile Phe Gln Tyr Gln Gln Ala Leu Ala Asn Met Gln Leu Gln Gln His Thr Ala Phe Leu Pro Pro Gly Ser Ile Leu Cys Met Thr Pro Ala Thr Ser Val Asp Thr His Asn Ile Cys Arg Thr Ser Asp <210> 104 <211> 370 <212> PRT
<213> Homo Sapiens <400> 104 Met Ala Val Ser Val Thr Pro Ile Arg Asp Thr Lys Trp Leu Thr Leu Glu Val Cys Arg Glu Phe Gln Arg Gly Thr Cys Ser Arg Pro Asp Thr Glu Cys Lys Phe Ala His Pro Ser Lys Ser Cys Gln Val Glu Asn Gly Arg Val Ile Ala Cys Phe Asp Ser Leu Lys Gly Arg Cys Ser Arg Glu Asn Cys Lys Tyr Leu His Pro Pro Pro His Leu Lys Thr Gln Leu Glu Ile Asn Gly Arg Asn Asn Leu Ile Gln Gln Lys Asn Met Ala Met Leu Ala Gln Gln Met Gln Leu Ala Asn Ala Met Met Pro Gly Ala Pro Leu Gln Pro Val Pro Met Phe Ser Val Ala Pro Ser Leu Ala Thr Asn Ala Ser Ala Ala Ala Phe Asn Pro Tyr Leu Gly Pro Val Ser Pro Ser Leu Val Pro Ala Glu Ile Leu Pro Thr Ala Pro Met Leu Val Thr Gly Asn Pro Gly Val Pro Val Pro Ala Ala Ala Ala Ala Ala Ala Gln Lys Leu Met Arg Thr Asp Arg Leu Glu Val Cys Arg Glu Tyr Gln Arg Gly Asn Cys Asn Arg Gly Glu Asn Asp Cys Arg Phe Ala His Pro Ala Asp Ser Thr Met Ile Asp Thr Asn Asp Asn Thr Val Thr Val Cys Met Asp Tyr Ile Lys Gly Arg Cys Ser Arg Glu Lys Cys Lys Tyr Phe His Pro Pro Ala His Leu Gln Ala Lys Ile Lys Ala Ala Gln Tyr Gln Val Asn Gln Ala Ala Ala Ala Gln Ala Ala Ala Thr Ala Ala Ala Met Gly Ile Pro Gln Ala Val Leu Pro Pro Leu Pro Lys Arg Pro Ala Leu Glu Lys Thr Asn Gly Ala Thr Ala Val Phe Asn Thr Gly Ile Phe Gln Tyr Gln Gln Ala Leu Ala Asn Met Gln Leu Gln Gln His Thr Ala Phe Leu Pro Pro Val Pro Met Val His Gly Ala Thr Pro Ala Thr Val Ser Ala Ala Thr Thr Ser Ala Thr Ser Val Pro Phe Ala Ala Thr Ala Thr Ala Asn Gln Ile Pro Ile Ile Ser Ala Glu His Leu Thr Ser His Lys Tyr Val Thr Gln Met <210>105 <211>419 <212>PRT

<213>Mus musculus <400> 105 Met Aan Lys His Gln Lys Pro Val Leu Thr Gly Gln Arg Phe Lys Thr Arg Lys Arg Asp Glu Lys Glu Lys Phe Glu Pro Thr Val Phe Arg Asp Thr Leu Val Gln Gly Leu Asn Glu Ala Gly Asp Asp Leu Glu Ala Val Ala Lys Phe Leu Asp Ser Thr Gly Ser Arg Leu Asp Tyr Arg Arg Tyr Ala Asp Thr Leu Phe Asp Ile Leu Val Ala Gly Ser Met Leu Ala Pro Gly Gly Thr Arg Ile Asp Asp Gly Asp Lys Thr Lys Met Thr Asn His Cys Val Phe Ser Ala Asn Glu Asp His Glu Thr Ile Arg Asn Tyr Ala Gln Val Phe Asn Lys Leu Ile Arg Arg Tyr Lys Tyr Leu Glu Lys Ala Phe Glu Asp Glu Met Lys Lys Leu Leu Leu Phe Leu Lys Ala Phe Ser Glu Ala Glu Gln Thr Lys Leu Ala Met Leu Ser Gly Ile Leu Leu Gly Asn Gly Thr Leu Pro Ala Thr Ile Leu Thr Ser Leu Phe Thr Asp Ser Leu Val Lys Glu Gly Ile Ala Ala Ser Phe Ala Val Lys Leu Phe Lys Ala Trp Met Ala Glu Lys Asp Ala Asn Ser Val Thr Ser Ser Leu Arg Lys Ala Asn Leu Asp Lys Arg Leu Leu Glu Leu Phe Pro Val Asn Arg Gln Ser Val Asp His Phe Ala Lys Tyr Phe Thr Asp Ala Gly Leu Lys Glu Leu Ser Asp Phe Leu Arg Val Gln Gln Ser Leu Gly Thr Arg Lys Glu Leu Gln Lys Glu Leu Gln Glu Arg Leu Ser Gln Glu Cys Pro Ile Lys Glu Val Val Leu Tyr Val Lys Glu Glu Met Lys Arg Asn Asp Leu Pro Glu Thr Ala Val Ile Gly Leu Leu Trp Thr Cys Ile Met Asn Ala Val Glu Trp Asn Lys Lys Glu Glu Leu Val Ala Glu Gln Ala Leu Lys His Leu Lys Gln Tyr Ala Pro Leu Leu Ala Val Phe Ser Ser Gln Gly Gln Ser Glu Leu Val Leu Leu Gln Lys Val Gln Glu Tyr Cys Tyr Asp Asn Ile His Phe Met Lys Ala Phe Gln Lys Ile Val Val Leu Phe Tyr Lys Ala Asp Val Leu Ser Glu Glu Ala Ile Leu Lys Trp Tyr Lys Glu Ala His Ala Ala Lys Gly Lys Ser Val Phe Leu Asp Gln Met Lys Lys Phe Val Glu Trp Ile Gln Asn Ala Glu Glu Glu Ser Glu Ser Glu Gly Glu Glu Ser <210> 106 <211> 2988 <212> PRT
<213> Homo Sapiens <400> 106 Met Val Glu Gly Asp Thr Val Thr Phe Ser Phe Glu Met Arg Ser Gly Arg Glu His Asn Thr Pro Asp Lys Ala Met Trp Gly Phe Ala Cys Thr Val Arg Ala Gln Glu Ser Ser Glu Asp Val Ser Gly Gly Leu Pro Phe Leu Val Asp Leu Ala Leu Gly Leu Ser Val Leu Ala Cys Ser Met Leu Arg Ile Leu Tyr Asn Gly Pro Glu Ile Thr Lys Glu Glu Glu Ala Cys Gln Glu Leu Leu Arg Ser Lys Leu Leu Gln Arg Glu Val Ile Gln Pro Asp Val Met Glu Glu Met Val Val Ser Cys Val Ile Lys His Leu Asn Leu Val Asp Ala Leu Gln Ser Leu Ile Asn Phe Gln Tyr Gln Glu Glu His Ala Glu Glu Tyr Asp Leu Leu Cys Lys Ile Met Gly Glu Thr Phe Lys Lys Leu Asn Ala Met Glu Arg Gln Leu Gln Asn Lys Met Lys Glu Leu Glu Leu Leu Cys Ser Met Lys Glu Val Ser Phe Asp Gly Asn Asp Leu Glu Asn Met Val Leu Ser Leu Arg Glu Lys Phe Leu Gln Glu Val Asn Ser Leu Ile Gln Lys Pro Ser His Pro Leu Ala Lys Thr Lys Thr Leu Val Lys Ser Leu Met Asn Arg Ala Glu Leu Leu Leu His Val Thr Ile Ala Ala Gln Ser Gly Leu Thr Arg Ser Ile Ser Gly Thr Pro Ala Glu Thr Pro Ala Cys Lys Ser Ala Ser Glu Thr Lys Val Ile Ser His Ala Val Arg Gln Pro Val Phe Leu Arg Ser Met Ser Ala Pro Ser Asp Leu Glu Met Ile Gly Asn Glu Asp Leu Glu Phe Thr Arg Ala Asn Gln Arg Arg Arg His Val Thr Ser His Arg Ser Ser Ser Phe Thr Leu Leu Gln Ser Leu Ala Ile Glu Asp Ser Arg Asp Lys Pro Thr Tyr Ser Val Leu Leu Gly Gln Leu Phe Ala Phe Ile Gly Thr Asn Pro Asp Gln Ala Val Ser Ser Ser Ser Phe Leu Leu Ala Ala Gln Thr Arg Trp Arg Arg Gly Asn Thr Arg Lys Gln Ala Leu Val His Met Arg Glu Leu Leu Thr Ala Ala Val Arg Val Gly Gly Val Thr His Leu Val Gly Pro Val Thr Met Val Leu Gln Gly Gly Pro Arg Ile Glu Glu Leu Thr Cys Gly Gly Met Val Glu Gln Val Gln Glu Ala Phe Gly Glu Thr Met Thr Ser Val Val Ser Leu Cys Ala Arg Tyr Pro Ile Ala Cys Ala Asn Ser Ile Gly Leu Leu Cys Thr Ile Pro Tyr Thr Arg Ser Glu Glu Lys Cys Leu Val Arg Ser Gly Leu Val Gln Leu Met Asp Arg Leu Cys Ser Leu Ser Asn Gln Thr Glu Ser Ser Ser Ser Glu Lys Gln Thr Lys Lys Gln Lys Val Ala Thr Met Ala Trp Ala Ala Phe Gln Val Leu Ala Asn Arg Cys Val Glu Trp Glu Lys Glu Glu Glu Thr Gly Ser Tyr Tyr Val Ala Gln Leu Cys Arg Ala Ala Leu Pro Leu Met Ser Val Glu Asp Cys Gly Asn Val Glu Leu Pro Pro Trp Ser Tyr Ser Val Pro Ser Leu Asn Ser Glu Gln Glu Asp Pro Ser Asp Pro Ala Ser Lys Ile Ala Ser Leu Leu Leu Ala Lys Leu Ala Asp Tyr Val Val Pro Gly Cys Gln Thr Val Leu Ser Pro Thr Ala Ser Glu Pro Asp Thr Thr Leu Thr Lys Thr Ser Pro Lys Asn Ser Leu Lys Gly Asp Lys Asp Pro Gly Glu Glu Ser Glu Ala Val Asp Gly Lys Leu Ser Ile Phe Ile His Lys Arg Glu Asp Gln Ser Ser His Glu Val Leu Gln Pro Leu Leu Ser Ser Ser Glu Gly Arg Pro Phe Arg Leu Gly Thr Gly Ala Asn Met Glu Lys Val Val Lys Met Asp Arg Asp Met Thr Lys Gly Gly Cys Cys Glu Val Ile Thr Glu Glu Ala Ala Ala Ala Leu Arg Lys Ala Thr Lys Trp Ala Gln Ser Gly Leu Ile Val Ser Ile Gly Pro Pro Val Glu Ser Ile Asn Pro Glu Thr Val Ser Gly Leu Ser Thr Gly Asp Lys Lys Lys Thr Ala Gln Thr Ser Ile Cys Arg Glu Arg Asn Ser Glu Leu Ala Arg Thr Asp Pro Val Arg Pro Phe Ile Ser Gly His Val Ala Asn Ser Met Ala Ala Glu Val Ile Ala Leu Leu His Ser Leu Leu Met Ala Pro Glu Ser Asn Ala Ala Gln Ile Trp Thr Thr Thr Ala Glu Lys Val Leu Ser Arg Ala Leu Met Tyr Ile Pro Gln Leu Gly Lys Tyr Ala Glu Ser Ile Leu Glu Asn Gly Ser Ser Ser Gly Arg Lys Leu Ala Lys Leu Gln Arg Ile Ala Arg Gln Ala Val Ala Ala Leu Cys Ala Leu Gly Gly Phe Lys Glu Thr Ile Lys Ile Gly Ser Glu Val Gln Ala Leu Pro Leu His Lys Leu Ser Ile Thr Glu Lys Val Val Gln Ala Val Gln Ser Met Leu Leu Pro Gln Glu Gly Ser Leu Ser Ile His Thr Ser Leu Pro Ala Thr Gly Asp Gly Ser Ala Pro Val Met Ala Val Val Arg Leu Leu Ala Glu Ile Arg Thr Arg Ala Cys Leu Val Met Ala Gln Leu Leu Glu Asp Ser Leu Phe Cys Glu Glu Phe Ile Gln Gln Cys Pro Ala Ala Val Glu Val Leu Asn Leu Val Ala Gln Glu Cys Ser Ala Gly Glu Arg Leu Ala Val Val Glu Val Gln Cys Glu Arg Leu Arg Met Leu Tyr Arg Asp Cys Ala Arg Pro Pro Pro Pro Pro Leu Gln Ala Asp Arg Arg Gln Ala Pro Ser Phe Tyr Trp Glu Ile Glu Ile Val Ser Tyr Gly Asp Thr Asp Asp Asp Thr Gly Pro Ile Val Ser Phe Gly Phe Thr Thr Glu Ala Glu Lys Arg Asp Gly Ala Trp Thr Asn Pro Val Gly Thr Cys Leu Phe His Asn Asn Gly Arg Ala Val His Tyr Asn Gly Ser Ser Leu Leu Gln Trp Lys Ser Val Arg Leu Asp Val Thr Leu Ser Pro Gly Asp Val Ala Gly Ile Gly Trp Glu Arg Thr Glu Gly Thr Pro Pro Pro Pro Gly Gln Pro Ala Lys Gly Arg Val Tyr Phe Thr Tyr Cys Gly Gln Arg Leu Ser Pro Tyr Leu Glu Asp Val Ser Gly Gly Met Trp Pro Val Val His Ile Gln Lys Lys Ala Glu Ile Lys Ile Asn Val Ser Leu Ser Lys Ser Phe Ile Trp Ser Pro Phe Gln Asn Thr Lys Thr Arg Ala Asn Phe Gly Ser Arg Pro Phe Ala Tyr Ala Glu Gly Gln Ala His Arg Asn Ala Ala Asp Leu Cys Thr Asp Leu Ala Glu Glu Ile Ser Ala Asn Phe Glu Ala Leu Pro Phe Ala Met Ala Ser Asp Ser Asp Asn Asp Ala Gly Thr Ser Ile Ala Ser Asp Pro Gly Thr His Gly Pro Pro Cys Arg Ile Ala Ala Val Ala Thr Ala Gln Gln Gln Tyr Asp Ser Asp Thr Ser Cys His Tyr Lys Val Glu Leu Ser Tyr Glu Asn Phe Ile Thr Ser Gly Pro Asp Pro His Pro Pro Pro Ile Ala Asp Asp Glu Ser Asp Asp Asp Asp Asp Asp Asp Ile Pro Gln Glu Asp His Tyr Ala Leu Leu Val Lys Ala Trp Glu Thr Lys Val Phe Pro Thr Ile Arg Arg Arg Phe Arg Asn Glu Ala Glu Arg Lys Ser Gly Leu Asp Gln Ile Lys Gly Ala Leu Gln Leu Gly Met Val Asp Ile Ala Arg Gln Thr Val Glu Phe Leu Tyr Glu Glu Asn Gly Gly Ile Pro Arg Asp Leu Tyr Leu Pro Thr Ile Glu Asp Ile Lys Asp Glu Ala Asn Lys Phe Thr Ile Asp Lys Val Arg Lys Gly Leu Thr Val Val Thr Arg Ser Pro Asp Ser Asn Asn Val Ala Ser Ser Ala Val Gly Thr Ala Leu Pro Lys Phe Ala Ile Arg Gly Met Leu Lys Thr Phe Gly Leu His Gly Val Val Leu Asp Val Asp Ser Val Asn Glu Leu Val Gln Val Glu Thr Tyr Leu Arg Ser Glu Gly Val Leu Val Arg Tyr Trp Tyr Pro Ile Asp Met Leu Glu Arg Pro Pro Ala Gly Tyr Arg Arg Thr Ala Thr Asn Gly Leu Val Thr Leu Asp Asn Thr Asn Leu Gln Ile His Arg Glu Leu Leu Arg Cys Glu Ala Ala Leu Ala Arg Leu Tyr Cys Arg Met Ala Leu Leu Asn Ile Phe Ala Pro Lys Leu Pro His Leu Phe Thr Arg Leu Phe His Ile Pro Ala Ile Arg Asp Ile Thr Leu Glu His Leu Gln Leu Leu Ser Asn Gln Leu Leu Ala Pro Pro Leu Pro Asp Gly Thr Ile Ser Ser Ser Ser Ile Leu Leu Ala Gln Ser Leu Gln His Cys Ile His Ser Gln Asn Cys Ser Ala Thr Asp Leu Phe Tyr Gln Gly Asn Ser Gln Thr Val Arg Glu Trp Leu Asn Val Ala Ile Thr Arg Thr Leu His Gln Gly Glu Glu Ser Leu Leu Glu Leu Thr Lys Gln Ile Cys Ser Phe Leu Gln Thr Ala Pro Glu Gln Phe Pro Ser Glu Glu Phe Pro Ile Ser Glu Ser Lys Val Asn Met Asp Val Asn Phe Pro Gly Ala Ala Phe Val Val Val Ser Cys Lys Glu Ser Gln Ser Gly Phe Arg Lys Asp Ser ' s f DEMANDES OU BREVETS VOLUMlNEUX
LA PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DE
NOTE: Pour les tomes additiot'els, veuillez co~tacter le Bureau canadien des brevets JUMBO APPLlCATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATEiNT CONTAINS MORE
THAN ONE VOLUME
. THlS !S VOLUME OF
WOTE:.For additional voiumes~piease contact'the Canadian Patent Office

Claims (32)

1. Use of at least one polypeptide or variants thereof according to one of SEQ ID No . 1 to SEQ ID
Nr. 4, SEQ ID No. 7 to SEQ ID No. 9, SEQ ID No. 103 to SEQ ID No. 104 or SEQ ID No. 106 or nucleic acids encoding this or variants thereof for the diagnosis and/or prevention and/or treatment of disorders or for the identification of pharmacologically active substances.

2. Use of at least one polypeptide or variants thereof according to one of SEQ ID No. 5 to SEQ ID
No. 6 or SEQ ID No. 10 to SEQ ID No. 48, SEQ ID No.
55 to SEQ ID No. 58, SEQ ID No. 89 to SEQ ID No.
94, SEQ ID No. 105 or SEQ ID No. 109 to SEQ ID No.
114 or nucleic acids encoding this or variants thereof for the diagnosis and/or prevention and/or treatment of skin disorders and/or treatment in wound healing or for the identification of pharmacologically active substances.

3. Use of at least one polypeptide or variants thereof according to one of SEQ ID No. 51 to SEQ ID
No. 54 or SEQ ID No. 101 to SEQ ID No. 102 or nucleic acids encoding this or variants thereof, for the diagnosis and/or prevention and/or treatment in wound healing or for the identification of pharmacologically active substances.

4. Use of at least one nucleic acid or variants thereof according to one of SEQ ID No. 49 or SEQ ID
No. 50, for the diagnosis and/or prevention and/or treatment of skin diseases and/or treatment in wound healing or for the identification of pharmacologically active substances.

5. Use of a nucleic acid according to one of Claims 1 to 4, characterized in that the nucleic acid is a DNA or RNA, preferably a DNA, in particular a double-stranded DNA.

6. Use of a nucleic acid according to one of Claims 1 to 5, characterized in that the sequence of the nucleic acid has at least one intron and/or a polyA sequence.

7. Use of a nucleic acid according to one of Claims 1 to 6 in the form of its antisense sequence.

8. Use of a nucleic acid according to one of Claims 1 to 7, characterized in that the nucleic acid has been prepared synthetically.

9. Use of a polypeptide according to one of Claims 1 to 3, characterized in that the polypeptide has been prepared synthetically.

10. Use of a polypeptide according to one of Claims 1 to 3, characterized in that the polypeptide is a fusion protein.

11. Use of a nucleic acid according to one of Claims 1 to 8 for the preparation of a vector, preferably in the form of a plasmid, shuttle vector, phagemid, cosmid, expression vector or vector having gene therapy activity.

12. Use of a nucleic acid according to one of Claims 1 to 8 for the preparation of a knock-out gene construct or an expression cassette.

13. Host cell, transformed using a vector or a knock-out gene construct according to one of Claims 11 or 12.

14. Host cell according to Claim 13, characterized in that it is a skin cell.

15. Transgenic embryonic non-human stem cell, characterized in that it contains a knock-out gene construct or an expression cassette according to Claim 12.

16. Process for the production of a transgenic non-human mammal, characterized in that an embryonic non-human stem cell according to Claim 15 is regenerated to give a transgenic non-human mammal.

17. Transgenic non-human mammal, characterized in that its genome contains a knock-out gene construct or an expression cassette according to Claim 12.

18. Process for preparing a polypeptide for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, characterized in that a nucleic acid according to one of Claims 1 to 8 is expressed.

19. Process for preparing a fusion protein for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances in a suitable host cell, characterized in that a nucleic acid according to one of Claims 1 to 8 is expressed.

20. Process for producing an antibody, preferably a polyclonal or monoclonal antibody, for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, characterized in that an antibody-producing organism is immunized with a polypeptide or functional equivalents thereof or parts thereof having at least 6 amino acids, preferably having at least 8 amino acids, in particular having at least 12 amino acids according to one of Claims 1 to 3 and 9 or 10.

21. Antibody for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances, characterized in that it is directed against a polypeptide according to one of Claims 1 to 3 and 9 or 10.

22. Use of an antibody according to Claim 21 for the diagnosis and/or prevention and/or treatment of disorders, in particular skin disorders, or treatment in wound healing or for the identification of pharmacologically active substances.

23. Process for preparing a diagnostic for the diagnosis of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries.

24. Diagnostic for the diagnosis of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that it contains at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with suitable additives and auxiliaries.

25. Diagnostic according to Claim 24, characterized in that it contains a probe, preferably a DNA probe.

26. Process for producing a medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries.

27. Medicament for the treatment of disorders, in particular skin disorders and/or disorders in wound healing, characterized in that it contains at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with suitable additives and auxiliaries.

28. Use of a medicament according to Claim 27 for the treatment of disorders, in particular skin disorders and/or disorders in wound healing.

29. Process for preparing a test for the discovery of functional interactors in connection with disorders, in particular skin disorders and/or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is combined with suitable additives and auxiliaries.

30. Test for the identification of functional interactors in connection with disorders, in particular skin disorders and/or disorders in wound healing, characterized in that it contains at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims, if appropriate together with suitable additives and auxiliaries.

31. Process for preparing an array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, characterized in that at least one nucleic acid, at least one polypeptide or at least one antibody according to one of the aforementioned claims is immobilized on a support material.

32. Array immobilized on a support material for analysis in connection with disorders, in particular skin disorders or disorders in wound healing, characterized in that it contains at least one nucleic acid and/or at least one polypeptide and/or at least one antibody according to one of the aforementioned claims.