HUMAN PROTEINS HAVING TRANSMEMBRANE DOMAINS AND cDNAs ENCODING THESE PROTEINS

Abstract: The invention provides human proteins having transmembrane domains and cDNAs coding for these proteins as well as eukaryotic cells expressing said cDNAs. All of the proteins exist in the cell membrane, so that they are considered to be proteins controlling the proliferation and the differentiation of the cells. Accordingly, the proteins can be employed as pharmaceuticals such as carcinostatic agents relating to the control of the proliferation and the differentiation of the cells or as antigens for preparing antibodies against said proteins. The cDNAs can be utilized as probes for the gene diagnosis and gene sources for the gene therapy. Furthermore, the cDNAs can be utilized for large-scale expression of said proteins. Cells, wherein these membrane protein genes are introduced and membrane proteins are expressed in large amounts, can be utilized for detection of the corresponding ligands, screening of novel low-molecular pharmaceuticals, and so on.

Description: DESCRIPTION Human Proteins Having Transmembrane Domains and DNAs Encoding these Proteins TECHNICAL FIELD The present invention relates to human proteins having transmembrane domains and cDNAs coding for these proteins as well as eucaryotic cells expressing said cDNAs . The proteins of the present invention can oe employed as pharmaceuticals or as antigens for preparing antibodies against said proteins . The human cDNAs of the present invention can be utilized as probes for the gene diagnosis and gene sources for the gene therapy. Furtnermore, the cDNAs can be utilized as gene sources for large-scale production of the proteins encoded by said cDNAs . Cells, wherein these membrane protein genes are introduced and membrane proteins are expressed m large amounts, can be utilized for detection of the corresponding ligands, screening of novel low-molecular pharmaceuticals, and so on. BACKGROUND ART Membrane proteins play important roles, as signal receptors, ion channels, transporters, etc. m the material transportation and the information transmission which are mediated by the cell membrane. Examples thereof include receptors for a variety of cytokmes, ion channels for the sodium ion, the potassium ion, the chloride ion, etc., transporters for sacchaπdes and ammo acids, and so on, where the genes of many of them have been cloned already. It has been clarified that abnormalities of these membrane proteins are associated with a number of hitherto-cryptogenic diseases. For instance, a gene of a membrane protein having twelve transmembrane domains was identified as the gene responsible for cystic fibrosis [Rommens, J. M. et al . , Science 245: 1059-1065 (1989) ] . In addition, it has been clarified that several membrane proteins act as receptors when a virus infects the cells. For instance, HIV-1 is revealed to infect into the cells through mediation of a membrane protein fusin having a membrane protein on the T-cell membrane, a CD-4 antigen, and seven transmembrane domains [Feng, Y. et al . , Science 272: 872-877 (1996) ] . Therefore, discovery of a new membrane protein is anticipated to lead to elucidation of the causes of many diseases, so that isolation of a new gene coding for the membrane protein has been desired. Heretofore, owing to difficulty in the purification, many membrane proteins have been isolated by an approach from the gene side. A general method is the so-called expression cloning which comprises transfection of a cDNA library in eucaryotic cells to express cDNAs and then detection of the cells expressing the target membrane protein on the membrane by an immunological technique using an antibody or a physiological technique on the change in the membrane permeability . However, this method is applicable only to cloning of a gene of a membrane protein with a known function. In general, membrane proteins possess hydrophobic transmembrane domains inside the proteins, wherein, after synthesis thereof m the πbosome, these domains remain in the phospholipid membrane to be trapped m the membrane. Accordingly, the evidence of the cDNA for encoding the membrane protein is provided by determination of the whole base sequence of a full-length cDNA followed by detection of highly hydrophobic transmembrane domains m the ammo acid sequence of the protein encoded by said cDNA. DISCLOSURE OF INVENTION The object of the present invention is to provide novel human proteins having transmembrane domains and DNAs coding for said proteins as well as transformation eucaryotic cells that are capable of expressing said cDNAs . As the result of intensive studies, the present inventors have been successful cloning of cDNAs coding for proteins having transmembrane domains from the human full-length cDNA bank, thereby completing the present invention. In other words, the present invention provides human proteins having transmembrane domains, namely proteins containing any of the ammo acid sequences represented by Sequence Nos. 1 to 10. Moreover, the present invention provides DNAs coding for the above-mentioned proteins, exemplified by cDNAs containing any of the base sequences represented by Sequence Nos. 11 to No. 20, as well as transformation eucaryotic cells that are capable of expressing sa d cDNAs. BRIEF DESCRIPTION OF DRAWINGS Figure 1 : A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01244. Figure 2: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01498. Figure 3: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01565. Figure 4 : A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01606. Figure 5: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01737. Figure 6: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP01962. Figure 7: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10435. Figure 8: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10479. Figure 9: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10481. Figure 10: A figure depicting the hydrophobicity/hydrophilicity profile of the protein encoded by clone HP10495. BEST MODE FOR CARRYINC OUT OF THE INVENTION The proteins of the present invention can be obtained, for example, by a method for isolation from human organs, cell lines, etc., a method for preparation of peptides by the chemical synthesis, or a method for production with the recombinant DNA technology using the DNAs coding for the transmembrane domains of the present invention, wherein the method for obtainment by the recombinant DNA technology is employed preferably. For instance, in vitro expression of the proteins can be achieved by preparation of an RNAby in vitro transcription from a vector having one of cDNAs of the present invention, followed by in vitro translation using this RNA as a template. Also, recombination of the translation region into a suitable expression vector by the method known in the art leads to production of a large amount of the encoded protein by using prokaryotic cells such as Escheri chia coli , Bacill us subtilis, etc. , and eucaryotic cells such as yeasts, insect cells, mammalian cells, etc. In the case in which a protein of the present invention is produced by a microorganism such as Escheri chia coli etc., a recombinant expression vector bearing the translation region in the cDNA of the present invention is constructed in an expression vector having an origin, a promoter, a ribosome-binding site, a cDNA-cloning site, a terminator etc., which can be replicated in the microorganism, and, after transformation of the host cells with said expression vector, the thus-obtained transformant is incubated, whereby the protein encoded by said cDNA can be produced on a large scale in the microorganism. In this case, a protein fragment containing an optional region can be obtained by carrying out the expression with inserting an initiation codon and a termination codon in front of and behind an optional translation region. Alternatively, a fusion protein with another protein can be expressed. Only a protein portion coding for said cDNA can be obtained by cleavage of said fusion protein with a suitable protease . In the case in which one of the proteins of the present invention is produced in eucaryotic cells, the protein of the present invention can be produced as a transmembrane protein on the cell-membrane surface, when the translation region of said cDNA is subjected to recombination to an expression vector for eucaryotic cells that has a promoter, a splicing region, a poly(A) insertion site, etc., followed by introduction into the eucaryotic cells. The expression vector is exemplified by pKAl, Ped6dpc2, pCDM8, pSVK3, pMSG, pSVL, pBK-CMV, pBK-RSV, EBV vector, pRS, pYES2, and so on. Examples of eucaryotic cells to be used in general include mammalian culture cells such as simian kidney cells C0S7, Chinese hamster ovary cells CHO, etc., budding yeasts, fission yeasts, silkworm cells, Xenopus laevi s egg cells, and so on, but any eucaryotic cells may be used, provided that they are capable of expressing the present proteins on the membrane surface. The expression vector can be introduced the eucaryotic cells by methods known m the art such as the electroporation method, the potassium phosphate method, the liposome method, the DEAE-dextran method, and so on. After one of the proteins of the present invention is expressed m prokaryotic cells or eucaryotic cells, the ob ective protein can be isolated from the culture and purified by a combination of separation procedures known m the art. Such examples include treatment with a denaturing agent such as urea or a surface-active agent, sonication, enzymatic digestion, salt g-out or solvent precipitation, dialysis, centrifugation, ultraflltration, gel filtration, SDS-PAGE, isoelectric focusing, ion-exchange chromatography, hydrophobic chromatography, affinity chromatography, reverse phase chromatography, and so on. The proteins of the present invention include peptide fragments (more than 5 ammo acid residues) containing any partial ammo acid sequence in the ammo acid sequences represented by Sequence Nos. 1. to 10. These peptide fragments can be utilized as antigens for preparation of antibodies. Hereupon, among the proteins of the present invention, those having the signal sequence are secreted in the form of maturation proteins on the surface of the cells, after the signal sequences are removed. Therefore, these maturation proteins shall come within the scope of the present invention. The N-termmal ammo acid sequences of the maturation proteins can be easily identified by using the method for the cleavage-site determination m a signal sequence [Japanese Patent Kokai Publication No.1996-187100]. Furthermore, some membrane proteins undergo the processing on the cell surface to be converted to the secretory forms. Such proteins or peptides in the secretory forms shall come within the scope of the present invention. When sugar chain-binding sites are present in the amino acid sequences, expression in appropriate eucaryotic cells affords proteins wherein sugar chains are added. Accordingly, such proteins or peptides wherein sugar chains are added shall come within the scope of the present invention. The DNAs of the present invention include all DNAs coding for the above-mentioned proteins. Said DNAs can be obtained by using a method by chemical synthesis, a method by cDNA cloning, and so on. The cDNAs of the present invention can be cloned, for example, from cDNA libraries of the human cell origin. These cDNA are synthesized by using as templates poly (A) + RNAs extracted from human cells. The human cells may be cells delivered from the human body, for example, by the operation or may be the culture cells. The cDNAs can be synthesized by using any method selected from the Okayama-Berg method [Okayama, H. and Berg, P., Mol. Cell. Biol. 2: 161-170 (1982)], the Gubler-Hoffman method [Gubler, U. and Hoffman, J. Gene 25: 263-269 (1983) ] , and so on, but it is preferred to use the capping method [Kato, S. et al . , Gene 150: 243-250 (1994)], as exemplified in Examples, in order to obtain a full-length clone in an effective manner. The primary selection of one of the cDNAs coding for the human proteins having transmembrane domains is carried out by sequencing of a partial base sequence of a cDNA clone selected at random from cDNA libraries, sequencing of the amino acid sequence encoded by the base sequence, and recognition of the presence or absence of a hydrophobic site in the resulting N- terminal amino acid sequence region. Next, the secondary selection is carried out by determination of the whole sequence by the sequencing and the protein expression by in vitro translation. Ascertainment of cDNAs of the present invention for encoding the proteins having secretory signal sequences is carried out by using the signal sequence detection method [Yokoyama-Kobayashi, M. et al., Gene 163: 193-196 (1995)]. In other words, the ascertainment for a coding portion of an inserted cDNA fragment to function as a signal sequence is provided by fusing a cDNA fragment coding for the N-terminus of the target protein with a cDNA coding for the protease domain of urokinase and then expressing the resulting cDNA in COS7 cells to detect the urokinase activity in the cell culture medium. On the other hand, in the case in which the urokinase activity is not detectable in the cell medium, the N-terminal region is judged to remain in the membrane. The cDNAs of the present invention are characterized by containing either of the base sequences represented by Sequence Nos. 11 to 20 or the base sequences represented by Sequence Nos. 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39. Table 1 summarizes the clone number (HP number) , the cells affording the cDNA, the total base number of the cDNA, and the number of the amino acid residues of the encoded protein, for each of the cDNAs . Table 1 Sequence No. HP No. Cell Number of Number of bases amino acids 1, 1 1, 21 HP 0 1 244 Stomach Cancer 979 123 2, 1 2, 22 HP 0 1498 Stomach Cancer 1279 220 3, 1 3, 23 HP 0 1 565 Stomach Cancer 835 81 4, 1 4, 24 HP 0 1606 Stomach Cancer 1 256 301 5, 1 5, 25 HP 0 1 737 Stomach Cancer 1305 383 6, 1 6, 26 HP 0 1 962 Liver 899 1 99 7, 1 7, 27 HP 1 0435 Stomach Cancer 905 229 8, 1 8, 28 HP 1 0479 PMA-U937 841 1 78 9, 1 9, 29 HP 1 048 1 PMA-U937 1451 443 1 o, 20, 30 HP 1 0495 Stomach Cancer 886 1 30 Hereupon, the same clones as the cDNAs of the present invention can be easily obtained by screening of the cDNA libraries constructed from the human cell lines and human tissues utilized in the present invention by the use of an oligonucleotide probe synthesized on the basis of the cDNA base sequence described in any of Sequence Nos. 11 to 21, 23, 25, 27, 29, 31, 35, 37 and 39. In general, the polymorphism due to the individual difference is frequently observed in human genes. Accordingly, any cDNA that is subj ected to insertion or deletion of one or plural nucleotides and/or substitution with other nucleotides in Sequence Nos. 11 to 21, 23, 25, 27, 29, 31, 35, 37 and 39 shall come within the scope of the present invention. In a similar manner, any protein that is formed by these modifications comprising insertion or deletion of one or plural amino acids and/or substitution with other amino acids shall come within the scope of the present invention, as far as the protein possesses the activity of any protein having the ammo acid sequences represented by Sequence Nos. 1 to 10. The cDNAs of the present invention include cDNA fragments (more than 10 bp) containing any partial base sequence m the base sequences represented by Sequence Nos. 11 to 20 or m the base sequences represented by Sequence Nos. 21, 23, 25, 27, 29, 30, 31, 33, 35 and 39. Also, DNA fragments consisting of a sense chain and an anti-sense chain shall come within this scope. These DNA fragments can be utilized as the probes for the gene diagnosis. In addition to the activities and uses described above, the polynucleotides and proteins of tne present invention may exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified below. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or by administration or use of polynucleotides encoding such proteins (such as, for example, m gene therapies or vectors suitable for introduction of DNA) . Research Uses and Utilities The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues m which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or m disease states) ; as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out" known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a "gene chip" or other support, including for examination of expression patterns; to raise anti-protein antibodiesusing DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction) , the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction. The proteins provided by the present invention can similarly be used in assay to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or m a disease state) ; and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, m a receptor-ligand interaction) , the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved m these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled m the art. References disclosing such methods include without limitation "Molecular Cloning: A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E.F. Fπtscn and T. Mamatis eds . , 1989, and "Methods in Enzy ology: Guide to Molecular Cloning Techniques", Academic Press, Berger, S.L. and A.R. Kimmel eds., 1987. Nutritional Uses Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or ammo acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as m the form of powder, pills, solutions, suspensions or capsules . In the case of microorganisms, the protein or polynucleotide of the invention can be added to the medium m or on which the microorganism is cultured. Cytokine and Cell Prolif ration/Diff rentiation Activity A protein of the present invention may exhibit cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either mαucing or inhibiting) activity or may induce production of other cytokmes m certain cell populations. Many protein factors discovered to date, including all known cytokmes, have exhibited activity one or more factor dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+ ιpreBM+), 2E8, RB5, DAI, 123, T1165, HT2, CTLL2, TF-1, Mo7e and CMK. The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for T-cell or thymocyte proliferation include without limitation those described m: Current Protocols m Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies m Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al . , J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al . , J. Immunol. 149:3778-3783, 1992; Bowman et al . , J. Immunol. 152: 1756-1761, 1994. Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human Interferonγ, Schreiber, R.D. In Current Protocols in Immunology . J.E.e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994. Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomiy, K., Davis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al . , Nature 336:690-692, 1988; Greenberger et al . , Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6-Nordan, R. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Acad. Sci. U.S.A. 83: 1857-1861, 1986; Measurement of human Interleukin 11 - Bennett, F., Giannotti, J., Clark, S.C. and Turner, K. J. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9 - Ciarletta, A., Giannotti, J., Clark, S.C. and Turner, K.J. In Current Protocols in Immunology . J.E . e . a. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991. Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans) ; Weinberger et al., Proc. Natl. Acad. Sci. USA 77 : 6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al . , J. Immunol.140:508-512, 1988. Immune stimulating or Suppressing Activity A protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID) ) , e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial orfungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteπa, Leishmania spp . , malaria spp . and various fungal infections such as candidiasis. Of course, m this regard, a protein of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., m the treatment of cancer. Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guilla -Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, yasthenia gravis, graft-versus- host disease and autoimmune inflammatory eye disease. Such a protein of the present invention may also to be useful m the treatment of allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein of the present invention. Using the proteins of the invention it may also be possible to immune responses, m a number of ways. Down regulation may be the form of inhibiting or blocking an immune response already progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance m T cells, or both. Immunosuppression of T cell responses is generally an active, non-antigen-specifIC, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or anergy m T cells, is distinguishable from immunosuppression m that it is generally antigen-specific and persists after exposure to the toleπzmg agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen m the absence of the toleπzmg agent. Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as , for example, B7)), e.g., preventing high level lymphokme synthesis by activated T cells, will be useful m situations of tissue, skin and organ transplantation and m graft-versus-host disease (GVHD) . For example, blockage of T cell function should result m reduced tissue destruction m tissue transplantation. Typically, m tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural lιgand(s) on immune cells (such as a soluble, monomeric form of a peptide having B7-2 activity alone or m conjunction with a monomeric form of a peptide having an activity of another B lymphocyte antigen (e.g., B7-1, B7-3) or blocking antibody) , prior to transplantation can lead to the binding of the molecule to the natural ligand(s) on the immune cells without transmitting the corresponding costimulatory signal. Blocking B lymphocyte antigen function in this matter prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant Moreover, the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens. The efficacy of particular blocking reagents in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease. Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms. Administration of reagents which block costimulation of T cells by disrupting receptor : ligand interactions of B lymphocyte antigens can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856) . Upregulation of an antigen function (preferably a B lymphocyte antigen function) , as a means of up regulating immune responses, may also be useful in therapy. Upregulation of immune responses may be m the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response through stimulating B lymphocyte antigen function may be useful m cases of viral infection. In addition, systemic viral diseases such as influenza, the commoncold, and encephalitis might be alleviated by the administration of stimulatory forms of B lymphocyte antigens systemically . Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulatmg the T cells m vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and remtroducmg the m vitro activated T cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and remtroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells m vivo. In another application, up regulation or enhancement of antigen function (preferably B lymphocyte antigen function) may be useful in the induction of tumor immunity. Tumor cells (e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma) transfected with a nucleic acid encoding at least one peptide of the present invention can be administered to a subject to overcome tumor-specific tolerance m the subject. If desired, the tumor cell can be transfected to express a combination of peptides. For example, tumor cells obtained from a patient can be transfected ex vivo with an expression vector directing the expression of a peptide having B7-2-lιke activity alone, or in conjunction with a peptide having B7-l-lιke activity and/or B7-3-lιke activity. The transfected tumor cells are returned to the patient to result in expression of the peptides on the surface of the transfected cell. Alternatively, gene therapy techniques can be used to target a tumor cell for transfection m vivo. The presence of the peptide of the present invention having the activity of a B lymphocyte antigen (s) on the surface of the tumor cell provides the necessary costimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient amounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domam truncated portion) of an MHC class I α chain protein and β 2 microglobulm protein or an MHC class Ilα chain protein and an MHC class Ilβ chain protein to thereby express MHC class I or MHC class II proteins on the cell surface. Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance m the subject. The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described m: Current Protocols m Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies m Humans); Herrmann et al . , Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al . , J. Immunol. 128:1968-1974, 1982; Handa et al . , J. Immunol. 135:1564-1572, 1985; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al . , J. Immunol. 140:508-512, 1988; Herrmann et al., Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al . , J. Immunol. 128:1968-1974, 1982; Handa et al . , J. Immunol. 135:1564-1572, 1985; Takai et al . , J. Immunol. 137:3494-3500, 1986; Bowmanet al . , J. Virology 61:1992-1998; Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al . , Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994. Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J.J. and Brunswick, M. In Current Protocols in Immunology . J.E . e . a . Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994. Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Thl and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al . , J. Immunol. 137:3494-3500, 1986; Takai et al . , J. Immunol.140:508-512, 1988; Bertagnolli et al . , J. Immunol. 149:3778-3783, 1992. Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Gueryetal., J. Immunol. 134:536-544, 1995; Inaba et al . , Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al . , Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al . , Science 264:961-965, 1994; Macatonia et al . , Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al . , Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990. Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al . , Cytometry 13: 795-808, 1992; Gorczyca et al . , Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53: 1945-1951, 1993; Itoh et al. , Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145: 4037-4045, 1990; Zamai et al . , Cytometry 14:891-897, 1993; Gorczyca et al . , International Journal of Oncology 1:639-648, 1992. Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al. , Blood 84 : 111-117, 1994; Fine et al. , Cellular Immunology 155:111-122, 1994; Galy et al . , Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991. Hematopoi sis Regulating Activity A protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokmes, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; m supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, m conjunction with chemotherapy to prevent or treat consequent myelo-suppression; supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use m place of or complimentary to platelet transfusions; and/or m supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility m various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobmuria) , as well as in repopulatmg the stem cell compartment post irradiation/chemotherapy, either m-vivo or ex-vivo (i.e., m conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous) ) as normal cells or genetically manipulated for gene therapy. The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above. Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described m: Johansson et al . Cellular Biology 15:141- 151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993. Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho- hematopoiesis) include, without limitation, those described m: Methylcellulose colony forming assays, Freshney, M.G. In Culture of Hematopoietic Cells . R.I. Freshney, et al . eds .Vol pp .265-268, Wiley-Liss, Inc., New York, NY. 1994; Hirayama et al . , Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A. In Culture of Hematopoietic Cells. R.I. Freshney, et al . eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, NY. 1994; Neben et al., Experimental Hematology 22 : 353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R.E. In Culture of Hematopoietic Cells. R.I. Freshney, et al . eds. Vol pp. 1-21, Wiley-Liss, Inc., New York, NY. 1994; Long term bone marrow cultures m the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells . R.I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, NY. 1994; Long term culture initiating cell assay, Sutherland, H.J. In Culture of Hematopoietic Cells. R.I. Freshney, et al . eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, NY. 1994. Tissue Growth Activity A protein of the present invention also may have utility m compositions used for bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions and ulcers. A protein of the present invention, which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application m the healing of bone fractures and cartilage damage or defects m humans and other animals. Such a preparation employing a protein of the invention may have prophylactic use m closed as well as open fracture reduction and also m the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful m cosmetic plastic surgery. A protein of this invention may also be used in the treatment of peπodontal disease, and m other tooth repair processes . Such agents may provide an environment to attract bone-formmg cells, stimulate growth of bone-formmg cells or induce differentiation of progenitors of bone-formmg cells. A protein of the invention may also be useful m the treatment of osteoporosis or osteoarthπtis, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes. Another category of tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation. A protein of the present invention, which induces tendon/ligament-like tissue or other tissue formation m circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects m humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use m preventing damage to tendon or ligament tissue, as well as use m the improved fixation of tendon or ligament to bone or other tissues, and m repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful m cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide an environment to attract tendon or ligament-formmg cells, stimulate growth of tendon- or ligament-formmg cells, induce differentiation of progenitors of tendon- or ligament-formmg cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful m the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art . The protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson' s disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the invention. Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like. It is expected that a protein of the present invention may also exhibit activity for generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium) , muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues . Part of the desired effects may be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate . A protein of the invention may also exhibit angiogenic activity. A protein of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage. A protein of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above. The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium ) . Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978). Activin/Inhibin Activity A protein of the present invention may also exhibit activin- or inhibin-related activities. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH) , while activms and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH) . Thus, a protein of the present invention, alone or m heterodimers with a member of the mhibm α family, may be useful as a contraceptive based on the ability of mhibms to decrease fertility m female mammals and decrease spermatogenesis m male mammals. Administration of sufficient amounts of other mhibms can induce infertility m these mammals. Alternatively, the protein of the invention, as a homodimer or as a heterodimer with other protein subunits of the mhibm-β group, may be useful as a fertility inducing therapeutic, based upon the ability of activm molecules m stimulating FSH release from cells of the anterior pituitary. See, for example, United States Patent 4,798,885. A protein of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs. The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for activm/mhiDm activity include, without limitation, those described m: Vale et al . , Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al . , Nature 318:659-663, 1985; Forage et al . , Proc. Natl. Acad. Sci. USA 83 : 3091-3095, 1986. Chemotaπti c/Chemokmeti c Activity A protein of the present invention may have chemotactic or chemokmetic activity (e.g., act as a chemokme) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosmophils, epithelial and/or endothelial cells. Chemotactic and chemokmetic proteins can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokmetic proteins provide particular advantages in treatment of wounds and other trauma to tissues, as well as treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result m improved immune responses against the tumor or infecting agent. A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide m any known assay for cell chemotaxis. The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols m Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley- Interscience (Chapter 6.12, Measurement of alpha and beta Chemokmes 6.12.1-6.12.28; Taub et al. J. Clm. Invest. 95:1370-1376, 1995; Lmd et al . APMIS 103:140-146, 1995; Muller et al Eur. J. Immunol. 25: 1744-1748; Gruber et al . J. of Immunol. 152:5860-5867, 1994; Johnston et al . J. of Immunol.153: 1762-1768, 1994. Hemostatic and Thrombolytic Activity A protein of the invention may also exhibit hemostatic or thrombolytic activity. As a result, such a protein is expected to be useful in treatment of various coagulation disorders (mcludmghereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events m treating wounds resulting from trauma, surgery or other causes. A protein of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke). The activity of a protein of the invention may, among other means, be measured by the following methods: Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al . , J. Clm. Pharmacol. 26:131-140, 1986; Burdick et al . , Thrombosis Res. 45:413-419, 1987; Humphrey et al . , Fibrmolysis 5:71-79 (1991); Schaub, Prostaglandms 35:467-474, 1988. Receptor/Ligand Activity A protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectms, mtegrms and their ligands) and receptor/ligand pairs involved m antigen presentation, antigen recognition and development of cellular and humoral immune responses) . Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions. The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for receptor-ligand activity include without limitation those described m: Current Protocols m Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al . , Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med.168: 1145-1156, 1988; Rosenstem etal., J.Exp.Med. 169:149-160 1989; Stoltenborg et al . , J. Immunol. Methods 175:59-68, 1994; Stitt et al . , Cell 80:661-670, 1995. Anti-Inflammatory Activity Proteins of the present invention may also exhibit anti-mflammatory activity. The anti- flammatory activity may be achieved by providing a stimulus to cells involved the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors whicn more directly inhibit or promote an inflammatory response. Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions) , including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS) ) , lschemia-reperfusion injury, endotox lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokme-mduced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of ytokmes such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material. Tumor Inhibition Activity In addition to the activities described above for immunological treatment or prevention of tumors, a protein of the invention may exhibit other anti-tumor activities. A protein may inhibit tumor growth directly or indirectly (such as, for example, via ADCC) . A protein may exhibit its tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue, by inhibiting formation of tissues necessary to support tumor growth (such as, for example, by inhibiting angiogenesis) , by causing production of other factors, agents or cell types which inhibit tumor growth, or by suppressing, eliminating or inhibiting factors, agents or cell types which promote tumor growth Other Activities A protein of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change m bone form or shape) ; effecting biorhythms or caricadic cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional factors or component (s) ; effecting behavioral characteristics, including, without limitation, appetite, libiαo, stress, cognition (including cognitive disorders) , depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells m lineages other than hematopoietic lineages; hormonal or endocrine activity; m the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); lmmunoglobulm-like activity (such as, for example, the ability to bind antigens or complement) ; and the ability to act as an antigen m a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein. Examples The present invention is embodied m more detail by the following examples, but this embodiment is not intended to restrict the present invention. The basic operations and the enzyme reactions with regard to the DNA recombination are carried out according to the literature ["Molecular Cloning. A Laooratory Manual", Cold Spring Harbor Laboratory, 1989] . Unless otherwise stated, restrictive enzymes and a variety of modification enzymes to be used were those available from TAKARA SHUZO. The manufacturer' s instructions were used for the buffer compositions as well as for the reaction conditions, m each of the enzyme reactions. The cDNA synthesis was carried out according to the literature [Kato, S. et al . , Gene 150: 243-250 (1994)]. (1) Preparation of Poly (A) τ RNA The histiocyte lympnoma cell line U937 (ATCC CRL 1593) stimulated by phorbol ester, tissues of stomach cancer delivered by the operation, and the liver were used for human cells to extract mRNAs . The cell line was incubated by a conventional procedure. After about 1 g of the human cells was homogenized in 20 ml of a 5.5 M guanidinium thiocyanate solution, a total mRNA was prepared according to the literature [Okayama, H. et al., "Method in Enzymology", Vol. 164, Academic Press, 1987]. This was subjected to chromatography on oligo (dT) -cellulose column washed with a 20 mM Tris-hydrochloride buffer solution (pH 7.6), 0.5 M NaCl, and 1 mM EDTA to obtain a poly (A) τ RNA according to the above-described literature. (2) Construction of cDNA Library Ten micrograms of the above-mentioned poly (A) + RNA were dissolved in a 100 mM Tris-hydrochloride buffer solution (pH 8) , one unit of an RNase-free, bacterial alkaline phosphatase was added, and the reaction was run at 37°C for one hour. After the reaction solution was subjected to phenol extraction, followed by ethanol precipitation, the resulting pellet was dissolved in a solution containing 50 mM sodium acetate (pH 6) , 1 mM EDTA, 0.1% 2-mercaptoethanol, and 0.01% Triton X-100. Thereto was added one unit of a tobacco-origin acid pyrophosphatase (Epicentre Technologies) and a total 100 μl volume of the resulting mixture was reacted at 37°C for one hour. After the reaction solution was subj ected to phenol extraction, followed by ethanol precipitation, the resulting pellet was dissolved in water to obtain a solution of a decapped poly (A) " RNA. The decapped poly (A) τ RNA and 3 nmol of a chimeric DNA- RNA oligonucleotide (5' -dG-dG-dG-dG-dA-dA-dT-dT-dC-dG-dA-G-G- A-3' ) were dissolved m a solution containing 50 mM Tπs- hydrochloride buffer solution (pH 7.5), 0.5 mM ATP, 5 mM MgCl,, 10 mM 2-mercaptoethanol, and 25% polyethylene glycol, whereto was added 50 units of T4RNA ligase and a total 30 μl volume of the resulting mixture was reacted at 20°C for 12 hours. After the reaction solution was subjected to phenol extraction, followed by ethanol precipitation, the resulting pellet was dissolved in water to obtain a chimeric-oligo-capped poly (A) + RNA. After digestion of vector pKAl (Japanese Patent Kokai Publication No. 1992-117292) developed by the present inventors with Kpnl, about 60 dT tails were added using a terminal trans ferase . A vector primer to be used below was prepared by digestion of this product with EcoRV to remove a dT tail at one side. After 6 μg of the previously-prepared chimeric-oligo- capped poly (A) + RNA was annealed with 1.2 μg of the vector primer, the resulting product was dissolved in a solution containing 50 mM Tris-hydrochloride buffer solution (pH 8.3), 75 mM KCl, 3 mM MgCl,, 10 mM dithiothreitol, and 1.25 mM dNTP (dATP + dCTP + dGTP + dTTP) , 200 units of a reverse transcπptase (GIBCO-BRL) were added, and the reaction in a total 20 μl volume was run at 42°C for one hour. After the reaction solution was subjected to phenol extraction, followed by ethanol precipitation, the resulting pellet was dissolved m a solution containing 50 mM Tris- hydrochloride buffer solution (pH7.5), 100 mM NaCl, 10 mM MgCl,, and 1 mM dithiothreitol. Thereto were added 100 units of EcoRI and a total 20 μl volume of the resulting mixture was reacted at 37°C for one hour. After the reaction solution was subjected to phenol extraction, followed by ethanol precipitation, the resulting pellet was dissolved in a solution containing 20 mM Tris-hydrochloride buffer solution (pH7.5), 100 mM KCl, 4mMMgCl 2 , 10 mM (NH 4 ) 2 S0 4 , and 50 μg/ml of the bovine serum albumin. Thereto were added 60 units of an Escheri chia coli DNA ligase and the resulting mixture was reacted at 16°C for 16 hours. To the reaction solution were added 2 μl of 2 mM dNTP, 4 units of Escherichia coli DNA polymerase I, and 0.1 unit of Escheri chia coli RNase H and the resulting mixture was reacted at 12°C for one hour and then at 22 " C for one hour. Next, the cDNA-synthesis reaction solution was used for transformation of Escheri chia coli DH12S (GIBCO-BRL) . The transformation was carried out by the electroporation method. A portion of the transformant was sprayed on the 2xYT agar culture medium containing 100 μg/ml ampicillin and the mixture was incubated at 37°C overnight. A colony formed on the agar medium was picked up at random and inoculated on 2 ml of the 2xYT culture medium containing 100 μg/ml ampicillin. After incubation at 37°C overnight, the culture mixture was centrifuged to separate the mycelia, from which a plasmid DNA was prepared by the alkaline lysis method. The plasmid DNA was subjected to double digestion with EcoRI and NotI, followed by 0.8% agarose gel electrophoresis, to determine the size of the cDNA insert. Furthermore, using the thus-obtained plasmid as a template, the sequence reaction was carried out by using an M13 universal primer labeled with a fluorescent dye and a Taq polymerase (a kit of Applied Biosyste s) and then the product was examined with a fluorescent DNA sequencer (Applied Biosystems) to determine an about 400-bp base sequence at the 5' -terminus of the cDNA. The sequence data were filed as the homo/protein cDNA bank database. (3) Selection of cDNAs Encoding Proteins Having Transmembrane Domains A base sequence registered m the homo/protein cDNA bank was converted to three frames of ammo acid sequences and the presence or absence of an open reading frame (ORF) beginning from the initiation codon was examined. Then, the selection was made for the presence of a signal sequence that is characteristic to a secretory protein at the N-termmus of the portion encoded by the ORF. These clones were sequenced from the both 5' and 3' directions by the use of the deletion method using exonuclease III to determine the whole base sequence. The hydrophobicity/hydrophilicity profiles were obtained for proteins encoded by the ORF by the Kyte-Doolittle method [Kyte, J. & Doolittle, R. F. , J. Mol. Biol.157: 105-132 (1982) ] to examine the presence or absence of a hydrophobic region. In the case m which there is a hydrophobic region of a putative transmembrane domain in the ammo acid sequence of an encoded protein, this protein was judged as a membrane protein. (4) Functional Verification of Secretory Signal Sequence or Transmembrane Domains It was verified by the method described m the literature [Yokoyama-Kobayashi, M. et al., Gene 163: 193-196 (1995)] that the N-termmal hydrophobic region m the secretory protein clone candidate obtained in the above-mentioned steps functions as a secretory signal sequence. First, the plasmid containing the target cDNA was cleaved at an appropriate restriction enzyme site existing at the downstream of the portion expected for encoding the secretory signal sequence. In the case in which this restriction site was a protruding terminus, the site was blunt-ended by the Klenow treatment or treatment with the mung-bean nuclease. Digestion with Hindlll was further carried out and a DNA fragment containing the SV40 promoter and a cDNA encoding the secretory signal sequence at the downstream of the promoter was separated by agarose gel electrophoresis . The resulting fragment was inserted between Hindlll in pSSD3 (DDBJ/EMBL/GenBank Registration No. AB007632) and a restriction enzyme site selected so as to match with the urokinase-coding frame, thereby constructing a vector expressing a fusion protein of the secretory signal sequence of the target cDNA and the urokinase protease domain. After Escheri chi a coli (host: JM109) bearing the fusion-protein expression vector was incubated at 37°C for 2 hours in 2 ml of the 2xYT culture medium containing 100 μg/ml of ampicillin, the helper phage M13K07 (50 μl) was added and the incubation was continued at 37 °C overnight. A supernatant separated by centrifugation underwent precipitation with polyethylene glycol to obtain single-stranded phage particles. These particles were suspended in 100 μl of 1 mM Tris-0.1 mM EDTA, pH 8 (TE) . Also, there were used as controls suspensions of single-stranded phage particles prepared in the same manner from pSSD3 and from the vector pKAl-UPA containing a full-length cDNA of urokinase [Yokoyama-Kobayashi, M. et al., Gene 163: 193-196 (1995) ] . The culture cells originating from the simian kidney, COS7, were incubated at 37°C in the presence of 5% C0 2 in the Dulbecco's modified Eagle's culture medium (DMEM) containing 10% fetal calf albumin. Into a 6-well plate (Nunc Inc., 3 cm in the well diameter) were inoculated 1 X 10 D COS7 cells and incubation was carried out at 37°C for 22 hours in the presence of 5% CO, . After the culture medium was removed, the cell surface was washed with a phosphate buffer solution and then washed again with DMEM containing 50 mM Tris-hydrochloric acid (pH 7.5) (TDMEM) . To the resulting cells was added a suspension of 1 μl of the single-stranded phage suspension, 0.6 ml of the DMEM culture medium, and 3 μl of TRANSFECTAM™ (IBF Inc.) and the resulting mixture was incubated at 37°C for 3 hours in the presence of 5% CO,. After the sample solution was removed, the cell surface was washed with TDMEM, 2 ml per well of DMEM containing 10% fetal calf albumin was added, and the incubation was carried out at 37 " C for 2 days in the presence of 5% C0 2 . To 10 ml of 50 mM phosphate buffer solution (pH 7.4) containing 2% bovine fibrinogen (Miles Inc.), 0.5% agarose, and 1 mM calcium chloride were added 10 units of human thrombin (Mochida Pharmaceutical Co . , Ltd.) and the resulting mixture was solidified in a plate of 9 cm in diameter to prepare a fibrin plate. Ten microliters of the culture supernatant of the tansfected C0S7 cells were spotted on the fibrin plate, which was incubated at 37°C for 15 hours. In the case in which a clear circle appears on the fibrin plate, it is judged that the cDNA fragment codes for the ammo acid sequence functioning as a secretory signal sequence. On the other hand, m case m which a clear circle is not formed, the cells were washed well, then the fibrin sheet was placed on the cells, and incubation was carried out at 37°C for 15 hours. In case m which a clear portion is formed on the fibrin sheet, it indicates that the urokinase activity was expressed on the cell surface. In other words, the cDNA fragment is judged to code for the transmembrane domains. (5) Protein Synthesis by In Vitro Translation The plasmid vector bearing the cDNA of the present invention was used for m vitro transcription/translation with a T N T rabbit reticulocyte lysate kit (Promega). In this case, [ 35 S] methionme was added to label the expression product with a radioisotope . Each of the reactions was carried out according to the protocols attached to the kit. Two micrograms of the plasmid was reacted at 30 " C for 90 minutes in a total 25 μl volume of the reaction solution containing 12.5 μl of T N T rabbit reticulocyte lysate, 0.5 μl of a buffer solution (attached to kit) , 2 μl of an ammo acid mixture (methionme-free) , 2 μl of [ D S ] methionme (Amersham) (0.37 MBq/μl), 0.5 μl of T7RNA polymerase, and 20 U of RNasm. To 3 μl of the resulting reaction solution was added 2 μl of the SDS sampling buffer ( 125 mM Tπs-hydrochloric acid buffer, pH6.8, 120 mM 2-mercaptoethanol, 2% SDS solution, 0.025% bromophenol blue, and 20% glycerol) and the resulting mixture was heated at 95°C for 3 minutes and then subjected to SDS-polyacrylamide gel electrophoresis . The molecular weight of the translation product was determined by carrying out the autoradiograph. (6) Expression by C0S7 Escheri cnia coli bearing the expression vector of the protein of the present invention was infected with helper phage M13K07 and smgle-stranded phage particles were obtained by the above-mentioned procedure. The thus-obtained phage was used for introducing each expression vector m the culture cells originating from the simian kidney, COS7. After incubation at 37°C for 2 days m the presence of 5% CO,, the incubation was continued for one hour m the culture medium containing [ 15 S]cystme or [ J S]methιonme . Collection and dissolution of the cells, followed by subjecting to SDS-PAGE, allowed to observe the presence of a band corresponding to the expression product of each protein, on the membrane fraction which did not exist m the COS7 cells. For instance, the molecular weights of HP01498, HP01565, HP01737, HP010435 and HP010495 were respectively 20 kDa, 13 kDa, 52 kDa, 33 kDa and 20 kDa. (7) Clone Examples <HP01244> (Sequence Nos. 1, 11, and 21) Determination of the whole base sequence of the cDNA insert of clone HP01244 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 15-bp 5'- nontranslation region, a 372-bp ORF, and a 592-bp 3'- nontranslation region. The ORF codes for a protein consisting of 123 ammo acid residues and there existed a signal-like sequence at the N-termmus and one transmembrane domain at the C-termmal. Figure 1 depicts the hydrophobicity/hydrophilicity profile , obtained by the Kyte-Doolittle method, of the present protein . In vitro translation resulted in formation of a translation product of 14 kDa that was almost consistent with the molecular weight of 12 , 911 predicted from the ORF . The search of the protein data base by using the amino acid sequence of the present protein revealed that the protein was analogous to the chicken stem cell antigen 2 ( GenBank Accession No . L34554 ) . Table 2 shows the comparison of the amino acid sequence between the human protein o f the present invention (HP ) and the chicken stem cell antigen 2 ( GG ) . Therein, the marks of - , * , and . represent a gap , an amino acid residue identical with the protein of the present invention, and an amino acid residue analogous to the protein of the present invention, respectively . The both proteins possessed a homology of 33 . 9% in the entire region . Table 2 HS MKAVLLALLMAGLALQPGTΛLLCYSCKΛQVSNEDCLQVKNCTQLGEQCWTA— RIRAVGL GG MKAFLFAVLAAVLCVERAHTLICFSCSDASSNWACLTPVKCAENEEHCVTTYVGVGIGGK HS LT-V I SKGCSLNCVDDSQDYYVGKKN I TCCDTDLCXASGAHALQPAAA I LAL— LPALGL GG SGQS I SKGCSPVCPSAG I NLG I AAASVYCCDSFLCNI SGSSSVKASYAVLALG I LVSFVY HS LLWGPGQL . *. . GG VLRARE Furthermore , the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more (for example, Accession No. AA476643) m EST, but many sequences were not distinct and the same ORF as that m the present cDNA was not found. <HP01498> (Sequence Nos. 2, 12, and 23) Determination of the whole base sequence of the cDNA insert of clone HP01498 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 227-bp 5'- nontranslation region, a 663-bp ORF, and a 389-bp 3'- nontranslation region. The ORF codes for a protein consisting of 220 ammo acid residues and there existed four transmembrane domains. Figure 2 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted m formation of a translation product of 22 kDa that was almost consistent with the molecular weight of 23,318 predicted from the ORF. The search of the protein data base by using the ammo acid sequence of the present protein revealed that the protein was analogous to the rat protein RVP1 (NBRF Accession No. A39484) . Table 3 shows the comparison of the ammo acid sequence between the human protein of the present invention (HP) and the rat protein RVP1 (RN) . Therein, the marks of -, *, and . represent a gap, an ammo acid residue identical with the protein of the present invention, and an am o acid residue analogous to the protein of the present invention, respectively. The both proteins possessed a homology of 81.8% m the entire region. Hereupon, the rat protein had a sequence longer by 60 ammo acid residues at the C-termmal side . Table 3 HS MS GLEITGTALAVLGWLGTIVCCALPMWRVSAFIGSNI ITSQNIWEGLWMNCVVQSTGQ RN MSMSLEITGTSLAVLGWLCTIVCCALPMWRVSAFIGSSI ITAQITWEGLWMNC-VQSTGQ HS MQCK V YDSLLALPQDLQAARAL I VVA I LLAAFGLLVALVGAQCTNCVQDDTAKAK I T I VA RN MQCKMYDSLLALPQDLQAARAL I VVS I LLAAFGLLVALVGAQCTNCVQDETAKAK I T I VA HS G VLFLLAALLTLVPVSWSANT I I RDFYNP WPE AQKREMGAGLYVGWAAAALQLLGGALL RN GVLFLLAAVLTLVPVSWSANT I I RDFYNPLVPEAQKREMGTGLYVGWAAAALQLLGGALL HS CCSCPPREKKYTATKVVYSAPRSTGPGASLGTGYDRKDYV RN CCSCPPRE-KYAPTK I LYSAPRSTGPGTGTGTAYDRKTTSERPGARTPHHHHYQPSMYPT Furthermore , the search of the GenBank using the base sequences of the present cDNA has revealed the presence o f sequences that possessed a homology of 90 % or more ( for example , Accession No . H72008 ) in EST , but many sequences were not distinct and the same ORF as that in the present cDNA was not found . The rat protein RVP1 is one of membrane proteins which are induced by androgen withdrawal and apoptosis in the rat ventral prostate [Briehl , M . M . et al . , Mol . Endocrinol . 5 : 1381-1388 ( 1991 ) ] . Accordingly, the present protein is considered to play an important role in the signal transduction that is associated with apoptosis . <HP01565> ( Sequence Nos . 3 , 13 , and 25 ) Determination of the whole base sequence of the cDNA insert of clone HP01565 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 62-bp 5'- nontranslation region, a 246-bp ORF, and a 527-bp 3'- nontranslation region. The ORF codes for a protein consisting of 81 ammo acid residues and there existed two transmembrane domains . Figure 3 depicts the hydrophoDicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted m formation of a translation product of 10 kDa that was almost consistent with the molecular weight of 9,374 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has revealed the presence of sequences that were analogous to the nematode putative protein F49C12.13 (GenBank Accession No. Z68227). Table 4 shows the comparison of the ammo acid sequence between the human protein of the present invention (HP) and the nematode putative protein F49C12.13 (CE) . Therein, the marks of -, *, and . represent a gap, an ammo acid residue identical with the protein of the present invention, and an ammo acid residue analogous to the protein of the present invention, respectively. The both proteins possessed a homology of 47.4 o m the entire region. Table 4 HS MAYHGLTVPLIVMSVFWGFVGFLVPWFIPKGPNRGVIITMLVTCSVCCYLFWL CE MCNFSYFQLQMGILIPLVSVSAFWAI IGFGGPWIVPKGPNRGIIQLMII TAVCCWWFWI HS IAILAQLNPLFGPQLKNETIWYLKYHWP CE MVFLHQLNPLIGPQIWKTIRWISEKWGDAPNVIW Furthermore, the search of the GenBank using the base sequences of the present cDNA nas revealed the presence of sequences that possessed a homology of 90% or more (for example, Accession No . N57319) EST, but, since they are partial sequences, it can not be judged whether or not any of these sequences codes for the same protein as the protein of the present invention. <HP01606> (Sequence Nos. 4, 14, and 27) Determination of the whole base sequence of the cDNA insert of clone HP01606 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 124-bp 5'- nontranslation region, a 906-bp ORF, and a 226-bp 3'- nontranslation region. The ORF codes for a protein consisting of 301 ammo acid residues and there existed seven transmembrane domains. Figure 4 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted m formation of a translation product of 31 kDa that was almost consistent with tne molecular weight of 32,594 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has revealed the presence of sequences that were analogous to the nematode putative protein F13H11.9 (GenBank Accession No. AF003389) . Table 5 shows the comparison of the amino acid sequence between the human protein of the present invention (HP) and the nematode putative protein F13H11.9 (CE) . Therein, the marks of -, *, and . represent a gap, an amino acid residue identical with the protein of the present invention, and an amino acid residue analogous to the protein of the present invention, respectively. The both proteins possessed a homology of 45.1% in the region of 195 amino acid residues at the C-terminal side. Table δ HS MLALRVARGSWGALRGAAWAPGTRPSKRRACWALLPPVPCCLGCLAERWRLRPAALGLRL CE MIVTSMFR HS PGIGQRNHCSGAGKAAPRPAAGAGAAAEAPGGQWGPASTPSLYENPWTIPNMLS TRIGL CE GIACRCELQLLLTPRRMLRNFSSLEQKQSPKIESLPPEERGKYKVA-TIPNAICTARIAA HS APVLGYLIIEEDFNIALGVFALAGLTDLLDGFIARNWANQRSALGSALDPLADKILISIL CE TPLIGYLVVQHNFTPAFVLFTVAGATDLLDGFIARNVPGQKSLLGSVLDPVADKLLISTM HS YVSLTYADLIPVPLTYMIISRDVMLIAAVFYVRYRTLPTPRTLAKYFNPCYATARLKPTF CE FITMTYAGLIPLPLTSVVILRDICLIGGGFYKRYQVMSPPYSLSRFFNPQVSSMQVVPTM HS ISKVNTAVQLILVAASLAAPVFNYADSIY—LQILWCFTAFTTAASAYSYYHYGRKTVQV CE MSKINTVLQITLVALSLSSPVFDFSTGAOVIVGLGCITGFTTIYSGLQYASGKAIKKI Furthermore, the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more (for example, Accession No. C16798) EST, but many sequences were not distinct and the same ORF as that m the present cDNA was not found. <HP01737> (Sequence Nos. 5, 15, and 29) Determination of the whole base sequence of the cDNA insert of clone HP01737 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 21-bp 5'- nontranslation region, a 1152-bp ORF, and a 132-bp 3'- nontranslation region. The ORF codes for a protein consisting of 383 ammo acid residues and there existed two transmembrane domains. Figure 5 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted m formation of a translation product of 45 kDa that was almost consistent with the molecular weight of 43,222 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has revealed the presence of sequences that were analogous to the nematode putative protein K09E9.2 (GenBank Accession No. Z79602) . Table 6 shows the comparison of the ammo acid sequence between the human protein of the present invention (HP) and the nematode putative protein K09E9.2 (CE) . Therein, the marks of -, * , and . represent a gap, an ammo acid residue identical with the protein of the present invention, and an ammo acid residue analogous to the protein of the present invention, respectively. The both proteins possessed a homology of 42.2% m the region of 195 ammo acid residues at the C-terminal side . Table 6 HS MEALGKLKQFDAYPKTLEDFRVKTCGGATVTIVSGLLMLLLFLSELQYYLTTEVHPELYV CE MSLLWSLKHFDAYRKPMDDFRVKTLSGGLVTLIATIAIVLLIVLETKQFLSTEVLEHLFV HS D-KSRGDKLK I NI DVLFPHMPCA YLS I DAMDVAGEQQLDVEHNLFKQRLDKDG I P VSSEA CE DSTTSDERVHIEFDITFTKLPCNFITVDVMDVSSEAQENINDDIYRLRLDPEGRNISESA HS ERHELGKVEVTVFDPDSLDPDRCESCYGAEAEDIKCCNTCEDVREAYRRRGWAFKNPDTI CE QKIEI NQNKTSVETTDV I QEVKCGSCYGAAADG I-CCNTCDDVKSAYAVKGWQV-N I EEV HS EQCRREGFSQKMQEQKNEGCQVYGFLEVNKVAGNFHFAPGKSFQQSHVHVHDLQSFGLDN CE EQCKNDKWVKEFNEHKNEGCRVYGT VKVAKV AGNFHLAPGDPHQA RSHVHDLHXLDP VK HS I NMTHY I QHLSFGEDYPG I VNPLDHTNVTAPQASM FQYFVKVVPT V YMKVDGE VLRTNQ CE FDASHTVNHVSFGKSFPGKNYPLDGKVNTDNRGG I MYQYYVKVVPTRYDYLDGRVDQSHQ HS FSVTRHEKVANGLLGDQGLPGVFVLYELSPMMVKLTEKHRSFTHFLTGVCAI IGGMFTVA CE FSVTTHKK— DLGFRQSGLPGFFLQYEFSPLMVQYEEFRQSFASFLVSLCA I VGGVFAMA HS GLIDSLIYHSARAIQKKIDLGKTT CE QLVDITIYHSSRYMKSRIAGGKLT Furthermore , the search o f the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more ( for example , Accession No . H42261 ) in EST, but , since they are partial sequences , it can not be j udged whether or not any of these sequences codes for the same protein as the protein of the present invention . <HP01962> (Sequence Nos. 6, 16, and 31) Determination of the whole base sequence of the cDNA insert of clone HP01962 obtained from cDNA libraries of human liver revealed the structure consisting of a 73-bp 5' -nontranslation region, a 600-bp ORF, and a 226-bp 3' -nontranslation region. The ORF codes for a protein consisting of 199 ammo acid residues and there existed at least three transmembrane domains. Figure 6 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted formation of a translation product of 21 kDa that was almost consistent with the molecular weight of 22, 134 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has revealed the presence of sequences that were analogous to a rat phosphatidylethanolamme N-methyltransferase (SWISS-PROT Accession No. Q08388) . Table 7 shows the comparison of the ammo acid sequence between the human protein of the present invention (HP) and the rat phosphatidylethanolamme N-methyltransferase (RN) . Therein, the marks of -, *, and . represent a gap, an ammo acid residue identical with the protein of the present invention, and an ammo acid residue analogous to the protein of the present invention, respectively. The both proteins possessed a homology of 80.8% in the entire region. Table 7 HS MTRLLGYVDPLDPSFVAAV I T I TFNPLYWNVVARWEHKTRKLSRAFGSPYLACYSLSVT I RN SWLLGYVDPTEPSFVAAVLTI VFNPLFWWVARWEQRTRKLSRAFGSPYLACYSLGSI I HS LLLNFLRSHCFTQAMLSQPRMESLDTPAAYSLGLALLGLGVVLVLSSFFALGFAGTFLGD RN LLLNILRSHCFTQAiMMSQPKMEGLDSHTIYFLGLALLGWGLVFVLSSFYALGFTGTFLGD HS YFGILKEARVTVFPFNILDNPMYWGSTANYLGWAIMHASPTGLLLTVLVALTYIVALLYE RN YFG I LKESRVTTFPFSVLDNPMYWGSTANYLGWALMHASPTGLLLTVLVALVYVVALLFE HS EPFTAEIYRQKASGSHKRS RN EPFTAEIYRRKATRLHKRS Furthermore, the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more and contained an initiation codon (for example, Accession No. H83024) in EST, but many sequences were not distinct and the same ORF as that in the present cDNA was not found. The rat phosphatidylethanolamme N-methyltransferase is a membrane protein which is associated with the biosynthesis of phosphatidylethanolamme [Cui, Z. et al., J. Biol. Chem. 268: 16655-16663 (1993)]. The present protein is considered to be a human homologue of the phosphatidylethanolamme N- methyltransf erase and is utilized for the diagnosis and treatment of diseases that are associated with abnormalities of this enzyme. <HP10435> (Sequence Nos. 7, 17, and 23) Determination of the whole base sequence of the cDNA insert of clone HP10435 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of an 8-bp 5'- nontranslation region, a 690-bp ORF, and a 207-bp 3'- nontranslation region. The ORF codes for a protein consisting of 229 amino acid residues and there existed one transmembrane domain each at the N-terminus and at the C-terminus. Figure 7 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. Introduction of an expression vector, wherein the Hindlll-Ball fragment containing a cDNA portion coding for the N-terminal 109 amino acid residues of the present protein was inserted into the Hindlll-EcoRV site of pSSD3, into the COS7 cells revealed the urokinase activity on the cell surface to indicate that the present protein remains in the membrane. In vitro translation resulted in formation of a translation product of 24 kDa that was almost consistent with the molecular weight of 24, 688 predicted from the ORF. The search of the protein data base using the amino acid sequence of the present protein has not revealed the presence of any known protein having an analogy. Also, the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more and contained an initiation codon (for example, Accession No. H87685) in EST, but many sequences were not distinct and the same ORF as that in the present cDNA was not found. <HP10479> (Sequence Nos. 8, 18, and 35) Determination of the whole base sequence of the cDNA insert of clone HP10479 obtained from cDNA libraries of the human lymphoma U937 revealed the structure consisting of a 38-bp 5'- nontranslation region, a 537-bp ORF, and a 266-bp 3'- nontranslation region. The ORF codes for a protein consisting of 178 amino acid residues and there existed a signal-like sequence at the N-terminus and one transmembrane domain at the C-terminus. Figure 8 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. Introduction of an expression vector, wherein the Hindlll-Banll (blunt-ended by treatment with T4DNA polymerase) fragment containing a cDNA portion coding for the N-terminal 45 amino acid residues of the present protein was inserted into the Hindlll-Smal site of pSSD3, into the C0S7 cells revealed the urokinase activity in the culture medium to indicate that the present protein is the type-I membrane protein. In vitro translation resulted in formation of a translation product of 33 kDa that was larger than the molecular weight of 19, 453 predicted from the ORF. Application of the (-3,-1) rule, a method for predicting the cleavage site in the secretory signal sequence, allows to expect that the maturation protein starts from glutamine at position 22. The search of the protein data base using the amino acid sequence of the present protein has revealed the presence of sequences that were analogous to the mouse ion channel homologue RIC (GenBank Accession No. U72680) . Table 8 shows the comparison of the amino acid sequence between the human protein of the present invention (HP) and the mouse ion channel homologue RIC (MM) . Therein, the marks of -, * , and . represent a gap, an amino acid residue identical with the protein of the present invention, and an amino acid residue analogous to the protein of the present invention, respectively . The both proteins possessed a homology of 48 .1% in the entire region . Table 8 HS MSPSGRLCLLT I VGL I LPTRGQTLKDTTSSSSADST I MD I QVPTRAPDAVYTELQPTSPT MM MSLSSRLCLLTIVALI LPSRGQTPKKPTSIFTADQTSATTRDNVPDPDQTSPGVQTTPLI HS PT PADETPQ— PQTQTQQLEG-TDGPLVTDPETHKSTKAAHPTDDTTTLSERPSPSTDV MM WTREEATGSQTAAQTETQQLTKMATSNPVSDPGPHTSSKKGTP AVSRIEPLSPSKNF HS QTDPQTLKPSGFHEDDPFFYDEHTLRKRGLLVAAVLFITGI I I LTSGKCRQLSRLCRNHC MM MPPSYIEHPLDSNENNPFYYDDTTLRKRGLLVAAVLFITGI I ILTSGKCRQLSQFCLNRH HS R * MM R Furthermore , the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90 % or more ( for example , Access ion No . AA296696 ) in EST , but , since they are partial sequences , it can not be j udged whether or not any of these sequences codes for the same protein as the protein of the present invention . The mouse ion channel homologue RIC is one of proteins which are induced on introduction of E2a-Pbxl oncoprotein into the NIH3T3 fibroblast cells and has been considered to play an important role m the cell cycle and proliferation [Fu, X. et al., Mol. Cell. Biol. 17: 1503-1512 (1997)]. <HP10481> (Sequence Nos. 9, 19, and 37) Determination of the whole base sequence of the cDNA insert of clone HP10481 obtained from cDNA libraries of the human lymphoma U937 revealed the structure consisting of a 104-bp 5'- nontranslation region, a 1332-bp ORF, and a 15-bp 3'- nontranslation region. The ORF codes for a protein consisting of 443 ammo acid residues and there existed one transmembrane domain at the N-termmus. Figure 9 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte- Doolittle method, of the present protein. Introduction of an expression vector, wherein the Hmdlll-PvuII fragment containing a cDNA portion coding for the N-termmal 148 ammo acid residues of the present protein was inserted into the Hmdlll-EcoRV site of pSSD3, into the COS7 cells revealed the urokinase activity on the cell surface to indicate that the present protein is the type-II membrane protein. In vitro translation resulted formation of a translation product of 51 kDa that was almost consistent with the molecular weight of 51,145 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has not revealed the presence of any known protein having an analogy. Also, the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90% or more (for example, Accession No. AA354554) m EST, but any of the sequences was shorter than the present cDNAs and was not found to contain the initiation codon. <HP10495> (Sequence Nos. 10, 20, and 39) Determination of the wnole base sequence of the cDNA insert of clone HP10495 obtained from cDNA libraries of human stomach cancer revealed the structure consisting of a 62-bp 5'- nontranslation region, a 393-bp ORF, and a 431-bp 3'- nontranslation region. The ORF codes for a protein consisting of 130 ammo acid residues and there existed two transmembrane domains. Figure 10 depicts the hydrophobicity/hydrophilicity profile, obtained by the Kyte-Doolittle method, of the present protein. In vitro translation resulted m formation of a translation product of 25 kDa that was larger than the molecular weight of 14,964 predicted from the ORF. The search of the protein data base using the ammo acid sequence of the present protein has not revealed the presence of any known protein having an analogy. Also, the search of the GenBank using the base sequences of the present cDNA has revealed the presence of sequences that possessed a homology of 90* or more (for example, Accession No. AA431001) in EST, but each of them was shorter than the present cDNA and was not found to contain the initiation codon. INDUSTRIAL APPLICABILITY The present invention provides human proteins having transmembrane domains and cDNAs coding for these proteins as well as eucaryotic cells expressing said cDNAs . All of the proteins of the present invention exist in the cell membrane, so that they are considered to be proteins controlling the proliferation and the differentiation of the cells. Accordingly, the proteins of the present invention can be employed as pharmaceuticals such as carcinostatic agents relating to the control of the proliferation and the differentiation of the cells or as antigens for preparing antibodies against said proteins. The cDNAs of the present invention can be utilized as probes for the gene diagnosis and gene sources for the gene therapy. Furthermore, the cDNAs can be utilized for large-scale expression of said proteins. Cells, wherein these membrane protein genes are introduced and membrane proteins are expressed in large amounts, can be utilized for detection of the corresponding ligands, screening of novel low-molecular pharmaceuticals, and so on. The present invention also provides genes corresponding to the polynucleotide sequences disclosed herein. "Corresponding genes" are the regions of the genome that are transcribed to produce the mRNAs from which cDNA polynucleotide sequences are derived and may include contiguous regions of the genome necessary for the regulated expression of such genes. Corresponding genes may therefore include but are not limited to coding sequences, 5' and 3' untranslated regions, alternatively spliced exons, introns, promoters, enhancers, and silencer or suppressor elements. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes m appropriate genomic libraries or other sources of genomic materials. An "isolated gene" is a gene that has been separated from the adjacent coding sequences, if any, present the genome of the organism from which the gene was isolated. Organisms that have enhanced, reduced, or modified expression of the gene(s) corresponding to the polynucleotide sequences disclosed herein are provided. The desired change m gene expression can be achieved through the use of antisense polynucleotides or ribozymes that bind and/or cleave the mRNA transcribed from the gene (Albert and Morris, 1994, Trends Pharmacol. Sci. 15(7): 250-254; Lavarosky et al . , 1997, Biochem. Mol. Med. 62(1): 11-22; and Hampel, 1998, Prog. Nucleic Acid Res . Mol. Biol. 58: 1-39; all of which are incorporated by reference herein) . Transgenic animals that have multiple copies of the gene(s) corresponding to the polynucleotide sequences disclosed herein, preferably produced by transformation of cells with genetic constructs that are stably maintained withm the transformed cells and their progeny, are provided. Transgenic animals that have modified genetic control regions that increase or reduce gene expression levels, or that change temporal or spatial patterns of gene expression, are also provided (see European Patent No . 0649464 Bl, incorporated by reference herein) . In addition, organisms are provided m which the gene(s) corresponding to the polynucleotide sequences disclosed herein have been partially or completely inactivated, through insertion of extraneous sequences into the corresponding gene(s) or through deletion of all or part of the corresponding gene(s). Partial or complete gene mactivation can be accomplished through insertion, preferably followed by imprecise excision, of transposable elements (Plasterk, 1992, Bioessays 14(9): 629-633 Zwaal et al . , 1993, Proc. Natl. Acad. Sci. USA 90(16) : 7431-7435 Clark et al . , 1994, Proc. Natl. Acad. Sci. USA 91(2): 719-722 all of which are incorporated by reference herein) , or through homologous recombination, preferably detected by positive/negative genetic selection strategies (Mansour et al . , 1988, Nature 336: 348-352; U.S. Patent Nos. 5, 464, 764; 5, 487, 992; 5,627,059; 5,631,153; 5,614, 396; 5,616,491; and 5, 679, 523; all of which are incorporated by reference herein) . These organisms with altered gene expression are preferably eukaryotes and more preferably are mammals. Such organisms are useful for the development of non-human models for the study of disorders involving the corresponding gene's), and for the development of assay systems for the identification of molecules that interact with the protein product (s) of the corresponding gene(s) . Where the protein of the present invention is membrane-bound (e.g., is a receptor), the present invention also provides for soluble forms of such protein. In such forms part or all of the mtracellular and transmembrane domains of the protein are deleted such that the protein is fully secreted from the cell which it is expressed. The mtracellular and transmembrane domains of proteins of the invention can oe identified m accordance with known techniques for determination of such domains from sequence information. Proteins and protein fragments of the present invention include proteins with ammo acid sequence lengths that are at least 25% (more preferably at least 50%, and most preferably at least 75%) of the length of a disclosed protein and have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with that disclosed protein, where sequence identity is determined by comparing the ammo acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps. Also included m the present invention are proteins and protein fragments that contain a segment preferably comprising 8 or more (more preferably 20 or more, most preferably 30 or more) contiguous ammo acids that shares at least 75% sequence identity (more preferably, at least 85% identity; most preferably at least 95% identity) with any such segment of any of the disclosed proteins. Species homologs of the disclosed polynucleotides and proteins are also provided by the present invention. As used herein, a "species homologue" is a protein or polynucleotide with a different species of origin from that of a given protein or polynucleotide, but with significant sequence similarity to the given protein or polynucleotide, as determined by those of skill m the art. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species. The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally- occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous, or related to that encoded by the polynucleotides. The invention also includes polynucleotides with sequences complementary to those of the polynucleotides disclosed herein. The present invention also includes polynucleotides capable of hybridizing under reduced stringency conditions, more preferably stringent conditions, and most preferably highly stringent conditions, to polynucleotides described herein. Examples of stringency conditions are shown in the table below: highly stringent conditions are those that are at least as stringent as, for example, conditions A-F; stringent conditions are at least as stringent as, for example, conditions G-L; and reduced stringency conditions are at least as stringent as, for example, conditions M-R. Table 9 t : The hybrid length is that anticipated for the hybridized regιon(s) of the hybridizing polynucleotides When hybridizing a polynucleotide to a target polynucleotide of unknown sequence, the hybrid length is assumed to be that of the hybridizing polynucleotide. When polynucleotides of known sequence are hybridized, the hybrid length can be determined by aligning the sequences of the polynucleotides and identifying the region or regions of optimal sequence complementarity. t : SSPE (lxSSPE is 0.15M NaCl, lOmM NaH 2 P0 4 , and 1.25mM EDTA, pH7.4) can be substituted for SSC (lxSSC is 0.15M NaCl and 15mM sodium citrate) in the hybridization and wash buffers: washes are performed for 15 minutes after hybridization is complete. *T B - T R : The hybridization temperature for hybrids anticipated to be less than 50 base pairs in length should be 5-10°C less than the melting temperature (T m ) of the hybrid, where T m is determined according to the following equations For hybrids less than 18 base pairs in length, T m (°C)=2(#of A + T bases) + 4(# of G + C bases). For hybrids between 18 and 49 base pairs in length, T m (°C)=81.5 + 16.6(logι 0 [Na + ]) + 0.41 (%G+C) - (600/N), where N is the number of bases m the hybrid, and [Na + ] is the concentration of sodium ions in the hybridization buffer ([Na + ] for lxSSC=0.165M). Additional examples of stringency conditions for polynucleotide hybridization are provided m Sambrook, J., E.F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, chapters 9 and 11, and Current Protocols m Molecular Biology, 1995, F.M. Ausubel et al . , eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4, incorporated herein by reference. Preferably, each such hybridizing polynucleotide has a length that is at least 25% (more preferably at least 50%, and most preferably at least 75%) of the length of the polynucleotide of the present invention to which it hybridizes, and has at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with the polynucleotide of the present invention to which it hybridizes, where sequence identity is determined by comparing the sequences of the hybridizing polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.

Claims: CLAIMS 1. A protein comprising any of the amino acid sequences represented by Sequence Nos. 1 to 10. 2. A DNA coding for the protein according to Claim 1. 3. A cDNA comprising any of the base sequences represented by Sequence Nos. 11 to 20. 4. The cDNA according to Claim 3 comprising any of the base sequences represented by Sequence Nos. 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39. 5. A vector capable of expressing the DNA or cDNA according to any of Claims 2 to 4 in in vitro translation or an eucaryotic cell. 6. A transformation eucaryotic cell capable of expressing the DNA or cDNA according to any of Claim 2 to 4 to produce the protein according to Claim 1.

Inventors: KATO SEISHI, KOBAYASHI MIDORI, SEKINE SHINGO, YAMAGUCHI TOMOKO, KATO, SEISHI, KOBAYASHI, MIDORI, SEKINE, SHINGO, YAMAGUCHI, TOMOKO
Applicants: KATO SEISHI, KOBAYASHI MIDORI, PROTEGENE INC, SAGAMI CHEM RES, SEKINE SHINGO, YAMAGUCHI TOMOKO, KATO, SEISHI, KOBAYASHI, MIDORI, PROTEGENE INC., SAGAMI CHEMICAL RESEARCH CENTER, SEKINE, SHINGO, YAMAGUCHI, TOMOKO
Application year: 1998
Main classification: C12N15
IPC codes: C07K14, C12N15