CA2265923A1 - Human proteins having secretory signal sequences and dnas encoding these proteins - Google Patents

Abstract

[Problems to be solved] To provide human proteins having secretory signal sequences and cDNAs encoding said proteins. [Means to solve the problems]
Proteins containing any of the amino acid sequences represented by Sequence No. 1 to Sequence No. 9 and DNAs encoding said proteins exemplified by cDNAs containing any of the base sequences represented by Sequence No. 10 to Sequence No. 18. Said proteins can be provided by expressing cDNAs encoding human proteins having secretory signal sequences with verified secretory functions and recombinants of these human cDNAs.

Description

W0 98/11217CA 02265923 l999-03- l2PCT/JP97/032391DESCRIPTIONHuman Proteins Having SecretorySignal Sequences and DNAs Encoding These ProteinsTECHNICAL FIELDThe present invention relates to human proteins havingsecretory signal sequences and DNAs encoding these proteins.The proteins of the present invention can be used aspharmaceuticals or as antigens for preparing antibodiesagainst said proteins. The cDNAs of the present invention canbe used as probes for the gene diagnosis and gene sources forthe gene therapy. Furthermore, the cDNAs can be used as genesources for large—scale production of the proteins encoded bysaid cDNAs.BACKGROUND ARTCells secrete .many’ proteins outside the cells. Thesesecretory proteins play important roles for the proliferationcontrol, the differentiation induction, the materialtransportation, the biological protection, etc. in the cells.Different from intracellular proteins, the secretory proteinsexert their actions outside the cells, whereby they can beadministered in the intracorporeal manner such as theinjection or the drip to anticipate the potentialities asmedicines. In fact, a number of human secretory proteinsinterferons, erythropoietin,such as interleukins,thrombolytic agents, etc. have been currently utilized asM. M..i.......,u...4.»...............~ .. . .A............,.CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/032392medicines. In addition, secretory proteins other than thosedescribed above have been undergoing clinical trials todevelop as pharmaceuticals. Since it has been conceived thatthe human cells still produce many unknown secretoryproteins, availability of these secretory proteins as well asgenes encoding them is expected to lead to the development ofnovel pharmaceuticals using these proteins.Heretofore, such a secretory protein has been obtained bya method comprising the isolation and purification of thetarget protein from a large amount of the blood or a cellculture supernatant by using the biological activity as anindicator, determination of its primary structure followed bycloning of the corresponding CDNA on the basis of theinformation on the thus-obtained amino acid sequence, andproduction of the recombinant protein using said CDNA.However, the contents of the secretory proteins aregenerally so low that the isolation and purification aredifficult in many cases. On the other hand, secretoryproteins and type—I membrane proteins possess hydrophobicsequences, defined as the secretory signal sequences,consisting of about 20 amino acid residues at the amino acidtermini (the N-termini). Therefore, the cloning of genesencoding the secretory proteins or type—I membrane proteinsis expected to be performed by using the presence or theabsence of these secretory signal sequences as indicators.DISCLOSURE OF INVENTIONThe object of the present invention is to provide novelhuman proteins having secretory signal sequences and DNAsW0 98ll1217CA 02265923 l999-03- l2PCTIJP97/03239encoding said proteins.As the result of intensive studies, the present inventorswere successful in cloning of cDNAs having secretory signalsequences from a human full—length cDNA bank, therebycompleting the present invention. That is to say, the presentinvention provides proteins containing any of the amino acidsequences represented by Sequence No. 1 to Sequence No. 9that are human proteins having secretory signal sequences.The present invention, also, provides DNAS encoding saidproteins exemplified as cDNAs containing any of the basesequences represented by Sequence No. 10 to sequence No. 18.Each of the proteins of the present invention can beobtained, for example, by a method for isolation from humanorgans, cell lines, etc, a method for preparation of thepeptide by the chemical synthesis on the basis of the aminoacid sequence of the present invention, or a nmthod forproduction with the recombinant DNA technology using the DNAencoding the human secretory protein of the presentinvention, wherein the method for obtainment by therecombinant DNA technology is employed preferably. Forexample, an in vitro expression can be achieved bypreparation of an RNA by the in vitro transcription from avector having a CDNA of the present invention, followed bythe in vitro translation using this RNA as a template. Also,the recombination of the translation domain to a suitableexpression vector by the method known in the art leads to theexpression of a large amount of the encoded protein by usingEscherichia coli, Bacillus subtilis, yeasts, animal cells,and so on.. . .. ._~.....4 .....4..._.m . .. ....‘.................—.....—..—.-. ...... .,CA 02265923 l999-03- 12W0 93/ 1 1217 PCT/JP97/032394In the case in which a protein of the present inventionis expressed by’a microorganism such as Escherichia coli, thetranslation region of a cDNA of the present invention isconstructed. in an expression. vector’ having an origin, apromoter, ribosome-binding site(s), cDNA—cloning site(s), aterminator, etc. that can be replicated in the microorganismand, after transformation of the host cells with saidexpression vector, the thus—obtained transformant isincubated, whereby the protein encoded by said cDNA can beproduced on a large scale in the microorganism. In that case,a maturation protein can be obtained by performing theexpression with inserting an initiation codon in thetranslation region where the secretary signal sequence isremoved. Alternatively, a fusion protein with another proteincan be expressed. Only a protein portion encoding said cDNAcan be obtained by cleavage of said fusion protein with anappropriate protease.In the case in which a protein of the present inventionis secretory—expressed in animal cells, the protein of thepresent invention can be secretory-produced as a maturationprotein outside the cells, when the translation region ofsaid cDNA is subjected to recombination to an expressionvector for animal cells that has a promoter for the animalcells, a splicing domain, a poly(A) addition site, etc.,followed by transfection into the animal cells.The proteins of the present invention include peptidefragments (more than 5 amino acid residues) containing anypartial amino acid sequence of the amino acid sequencesrepresented by Sequence No. 1 to Sequence No. 9. TheseWO 98/11217CA 02265923 l999-03- l2PCT/JP97/032395fragments can be used as antigens for preparation of theantibodies. Also, the proteins of the present invention aresecreted in the forum of maturation. proteins outside thecells, after the signal sequences are removed. Therefore,these maturation proteins shall come within the scope of thepresent invention. The N-terminal amino acid sequences of thematuration proteins can be easily identified by using themethod for the cleavage—site determination in a signalsequence [Japanese Patent Kokai Publication No. 1996—187l0O].Furthermore, many secretory proteins are subjected to theprocessing after the secretion to be converted to the activeforms. These activated proteins or peptides shall come withinthe scope of the present invention. When glycosylation sitesexpression inare present in the amino acid sequences,cells affords glycosylated proteins.appropriate animalTherefore, these glycosylated proteins or peptides also shallcome within the scope of the present invention.include all DNASinventionThe DNAs of the presentencoding the above—mentioned proteins. Said DNAs can beobtained using the method by chemical synthesis, the methodby CDNA cloning, and so on.Each of the cDNAs of the present invention can be clonedfrom, for example, a CDNA library of the human cell origin.The CDNA is synthesized using as a template a poly(A)+ RNAextracted from human cells. The human cells may be cellsdelivered from the human body, for example, by the operationor may be the culture cells. The CDNA can be synthesized byusing any method selected from the Okayama—Berg method[Okayama, H. and Berg, P., Mol. Cell. Biol. 2: 161-170CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/032396(1982)], the Gubler—Hoffman method [Gubler, U. and Hoffman,J. Gene 25: 263-269 (l983)], and so on, but it is preferredto use the capping method [Kato, S. et al., Gene 150: 243-250(l994)] as illustrated in Examples in order to obtain a full-length clone in an effective manner.The primary selection of a CDNA encoding a human proteinhaving a secretory signal sequence is performed by thesequencing of a gmrtial base sequence of the CDNA cloneselected at random from the CDNA library, sequencing of theamino acid sequence encoded by the base sequence, andrecognition of the presence or absence of hydrophobic site(s)in the resulting N—terminal amino acid sequence region. Next,the secondary selection is carried out by determination ofthe whole base sequence by the sequencing and the proteinexpression by the in vitro translation. The ascertainment ofthe CDNA of the present invention for encoding the proteinhaving the secretory signal sequence is performed by usingthe signal sequence detection method [Yokoyama—Kobayashi, M.et al., Gene 163: 193-196 (l995)]. In other words, theascertainment for the coding portion of the inserted CDNAfragment to function as a signal sequence is provided byfusing a cDNA fragment encoding the N-terminus of the targetprotein with a CDNA encoding the protease domain of urokinaseand then expressing the resulting CDNA in COS7 cells todetect the urokinase activity in the cell culture medium.The cDNAs of the present invention are characterized bycontaining any of the base sequences represented by SequenceNo. 10 to Sequence No. 18 (n: any of the base sequencesrepresented by Sequence No. 19 to Sequence No. 27. Table 1W0 98/11217CA 02265923 l999-03- l2PCT/JP97/032397summarizes the clone number (HP number), the cells affordingthe CDNA, the total base number of the CDNA, and the numberof the amino acid residues of the encoded protein, for eachof the cDNAs.Table 1Sequence HP Cells Number Number ofNumber Number of Bases Amino AcidResidues1, 10. 19 HP00658 HT—1080 1296 1542, 11. 20 m>0o714 KB 3311 ' 3153. 12. 21 HP00876 Stomach cancer 1152 1584. 13. 22 HP01134 Liver 1749 3765. 14. 23 HP10029 KB 988 1736, 15. 24 HP10189 KB 390 937, 16. 25 HP10269 U937 4667 11728, 17. 26 HP10298 Stomach cancer 1086 1229. 18, 27 HP10368 Stomach cancer 866 175Hereupon, the same clone as any of the cDNAs of thepresent invention can be easily obtained by screening of theCDNA library constructed from the cell line or the humantissue employed in the present invention, by the use of anoligonucleotide probe synthesized on the basis of thecorresponding CDNA base sequence depicted in Sequence No. 19to Sequence No. 27.In general, the polymorphism due to the individualdifference is frequently observed in human genes. Therefore,any cDNA that is subjected to insertion or deletion of one orCA 02265923 l999-03- 12W0 98/11217 PCT/JP97/032398plural nucleotides and/or substitution with other nucleotidesin Sequence No. 10 to Sequence No. 27 shall come within thescope of the present invention.In a similar manner, any protein that is produced bythese modifications comprising insertion or deletion of oneor plural nucleotides and/or substitution with othernucleotides shall come within the scope of the presentinvention, as far as said protein possesses the activity ofthe corresponding protein having the amino acid sequencerepresented by Sequence No. 1 to Sequence No. 9.The cDNAs of the present invention include CDNA fragments(more than 10 bp) containing any partial base sequence of thebase sequence represented by Sequence No. 10 to No. 18 or ofthe base sequence represented by Sequence No. 19 to No. 27.For example, as illustrated in Examples, the portion encodingthe secretory signal sequence can be employed as means tosecrete an optionally selected protein outside the cells byfusing with a CDNA encoding another protein. Also, DNAfragments consisting of a sense chain and an anti—sense chainshall come within this scope. These DNA fragments can be usedas the probes for the gene diagnosis.BRIEF DESCRIPTION OF DRAWINGSFigure 1: A figure depicting the structure of thesecretory signal sequence detection vector pSSD3.Figure 2: A figure depicting the construction of thesecretory signal sequence — the urokinase fusion gene.Figure 3: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/03239by clone HP00685.Figure 4: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HPOO7l4.Figure 5: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HPOO876.Figure 6: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HP01l34.Figure 7: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HPlO029.Figure 8: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HP10l89.Figure 9: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HP10269.Figure 10: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HPl0298.Figure 11: A figure depicting thehydrophobicity/hydrophilicity profile of the protein encodedby clone HP10368.BEST MODE FOR CARRING OUT INVENTIONEXAMPLEThe present invention is embodied in more detail by theCA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323910following examples, but this embodiment is not intended torestrict the present invention. The basic operations and theenzyme reactions with regard to the DNA recombination arecarried out according to the literature ["Molecular Cloning.A Laboratory Manual", Cold Spring Harbor Laboratory, 1989].Unless otherwise stated, restrictive enzymes and a variety ofmodification enzymes to be used were those available fromTakara Shuzo Co., Ltd. The manufacturer's instructions wereused for the buffer compositions as well as for the reactionconditions, in each of the enzyme reactions. The cDNAsynthesis was carried out according to the literature [Kato,S. et al., Gene 150: 243-250 (1994)].(1) Preparation of Poly(A)+ RNAThe fibrosarcoma cell line HT—l080 (ATCC CCL 121), theepidermoid carcinoma cell line KB (ATCC CRL 17), thehistiocyte lymphoma cell line U937 (ATCC CRL 1593) stimulatedby phorbol esters, tissues of stomach cancer delivered by theoperation, and liver were used for human cells to extractmRNAs. Each of the cell lines was cultured by a conventionalprocedure.After about 1 g of human tissues was homogenized in 20 mlof a 5.5 M guanidinium thiocyanate solution, total mRNAs wereprepared in accordance with the literature [Okayama, H. etal., "Methods in Enzymology" Vol. 164, Academic Press, 1987].These mRNAs were subjected to chromatography using anoligo(dT)~cellu1ose column washed with 20 mM Tris-hydrochloric acid buffer solution (pH 7.6), 0.5 M NaCl, and1 mM EDTA to obtain a poly(A)+ RNA in accordance with theabove—mentioned literature.W0 98/11217CA 02265923 l999-03- l2PCT/JP97/0323911(2) Construction of CDNA LibraryTo a solution of 10 ug of the above—mentioned poly(A)+ RNAin 100 mM Tris—hydrochloric acid buffer solution (pH 8) wasadded one unit of an RNase—free, bacterium—origin alkalinephosphatase and the resulting solution was allowed to reactat 37°C for one hour. After the reaction solution underwentthe phenol extraction followed by the ethanol precipitation,the obtained pellets were dissolved in a mixed solution of 50mM sodium acetate (pH 6), 1 mM EDTA, 0.1% 2—mercaptoethanol,and 0.01% Triton X-100. Thereto was added one unit of atobacco—origin pyrophosphatase (Epicenter Technologies) andthe resulting solution at a total volume of 100 pl wasallowed to react at 37°C for one hour. After the reactionsolution underwent the phenol extraction followed by theethanol precipitation, the thus-obtained pellets weredissolved in water to obtain a decapped poly(A)+ RNAsolution.To a solution of the decapped poly(A)+ RNA and 3 nmol ofa DNA-RNA chimeric oligonucleotide (5’-dG—dG-dG—dG-dA-dA—dT-dT—dC—dG-dA—G—G-A-3’) in a mixed aqueous solution of 50 mMTris-hydrochloric acid buffer solution (pH 7.5), 0.5 mM ATP,5 mM MgCl2, 10 mM 2-mercaptoethanol, and 25% polyethyleneglycol were added 50 units of T4 RNA ligase and the resultingsolution at a total volume of 30 ul was allowed to react at20°C for 12 hours. After the reaction solution underwent thephenol extraction followed by the ethanol precipitation, thethus-obtained pellets were dissolved in water to obtain a)+chimeric oligo—capped poly(A RNA.CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323912After the vector pKAl developed by the present inventors(Japanese Patent Kokai Publication No. l992—1l7292) wasdigested with KpnI, an about 60-dT tail was inserted by aterminal transferase. This product was digested with EcoRV toremove the dT tail at one side and the resulting molecule wasused as a vectorial primer.After 6 pg of the previously-prepared chimeric oligo—capped poly(A)+ RNA was annealed with 1.2 pg of the vectorialprimer, the product was dissolved in a mixed solution of 50mM Tris—hydrochloric acid buffer solution (pH 8.3), 75 mMKCl, 3 mM MgCl2, 10 mM dithiothreitol, and 1.25 mM dNTP (dATP+ dCTP + dGTP + dTTP), mixed with 200 units of a reversetransferase (GIBCO—BRL), and the resulting solution at atotal volume of 20 pl was allowed to react at 42°C for onehour. After the reaction solution underwent the phenolextraction followed by the ethanol precipitation, the thus-obtained pellets were dissolved in a mixed solution of 50 mMTris—hydrochloric acid buffer solution (pH 7.5), 100 mM NaCl,10 mM MgCl2, and 1 mM dithiothreitol. Thereto were added 100units of EcoRI and the resulting solution at a total volumeof 20 pl was allowed to react at 37°C for one hour. After thereaction solution underwent the phenol extraction followed bythe ethanol precipitation, the obtained pellets weredissolved in a mixed solution of 20 mM Tris-hydrochloric acidbuffer solution (pH 7.5), 100 mM KCl, 4 mM MgCl2, 10 mM(NH4)2SO4, and 50 pg/ml bovine serum albumin. Thereto wereadded 60 units of Escherichia coli DNA ligase and theresulting solution was allowed to react at 16°C for 16 hours.W0 98/11217CA 02265923 l999-03- 12PCT/JP97/0323913To the reaction solution were added 2 ul of 2 mM dNTP, 4units of Escherichia coli DNA polymerase I, and 0.1 unit ofEscherichia coli DNase H and the resulting solution. wasallowed to react at 12°C for one hour and then at 22°C forone hour.Next, the cDNA—synthesis reaction solution was used totransform Escherichia coli DH12S (GIBCO—BRL). Thetransformation was carried out by the electroporation method.A portion of the transformant was inoculated on a 2xYT agarculture medium containing 100 ug/ml ampicillin, which wasincubated at 37°C overnight. A colony grown on the culturemedium was randomly picked up and inoculated on 2 ml of the2xYT culture medium containing 100 pg/ml ampicillin, whichwas incubated at 37°C overnight. The culture medium: wascentrifuged to separate the cells, from which a plasmid DNAwas prepared by the alkaline lysis method. After the plasmidDNA was double-digested with EcoRI and NotI, the product wassubjected to 0.8% agarose gel electrophoresis to determinethe size of the CDNA insert. In addition, by the use of theobtained plasmid as a template, the sequence reaction usingM13 universal primer labeled with a fluorescent dye and Taqpolymerase (a kit of Applied Biosystems Inc.) was carried outand the product was analyzed by a fluorescent DNA-sequencer(Applied Biosystems Inc.) to determine the base sequence ofthe CDNA 5’—terminal of about 400 bp. The sequence data werefiled as a homo—protein cDNA bank data base.(3) Selection of cDNAs Encoding Proteins Having SecretorySignal SequenceThe base sequence registered in the homo—protein cDNA.......... ..............-..............,... .CA 02265923 l999-03- 12W0 98/11217 PCT/JP97/0323914bank was converted to three frames of amino acid sequencesand the presence or absence of an open reading frame (ORF)beginning from the initiation codon. Then, the selection wasmade for the presence of a signal sequence that ischaracteristic to a secretory protein at the N-terminal ofthe portion encoded by ORF. These clones were sequenced fromthe both 5’ and 3’ directions by using the deletion method todetermine the whole base sequence. Thehydrophobicity/hydrophilicity profiles were obtained forproteins encoded by ORF by the Kyte—Doolittle method [Kyte,J. & Doolittle, R. F., J. Mol. Bio. 157: 105-132 (l982)] toexamine the presence or absence of a hydrophobic region. Inthe case in which there is not. a hydrophobic region ofputative transmembrane domain(s) in the amino acid sequenceof an encoded protein, this protein was considered as amembrane protein that did not possess a secretory protein ortransmembrane domain(s).(4) Construction of Secretory Signal Detection VectorpSSD3One microgram of pSSD1 carrying the SV40 promoter and aCDNA encoding the protease domain of urokinase [Yokoyama—Kobayashi, M. et al., Gene 163: 193-196 (1995)] was digestedwith 5 units of Bg1II and 5 units of EcoRV. Then, afterdephosphorylation at the 5’ terminal by the CIP treatment, aDNA fragment of about 4.2 kbp was purified by cutting offfrom the gel of agarose gel electrophoresis.Two oligo DNA linkers, Ll (5’-GATCCCGGGTCACGTGGGAT—3')and L2 (5’—ATCCCACGTGACCCGG-3’), were synthesized andphosphorylated by T4 polynucleotide kinase. After annealingCA 02265923 l999-03- 12W0 98/1 12 17 PCT/JP97/0323915of the both linkers, followed by ligation with thepreviously-prepared pSSDl fragment by T4 DNA ligase,Escherichia coli JMl09 was transformed. A plasmid pSSD3 wasprepared from the transformant and the objective recombinantwas confirmed by the determination of the base sequence ofthe linker—inserted fragment. Figure 1 illustrates thestructure of the thus—obtained plasmid. The present plasmidvector carries three types of blunt-end formation restrictionenzyme sites, Smal, PmaCI, and EcoRV. Since these cleavagesites are positioned in succession at an interval of 7 bp,selection of an appropriate site in combination of threetypes of frames for the inserting cDNA allows to construct avector expressing a fusion protein.(5) Functional Verification of Secretory Signal SequenceWhether the N-terminal hydrophobic region in thesecretory protein clone candidate obtained in the above-mentioned steps functions as the secretory signal sequencewas verified by the method described in the literature[Yokoyama-Kobayashi, M. et al., Gene 163: 193-196 (1995)].First, the plasmid containing the target CDNA was cleaved atan appropriate restriction enzyme site that existed at thedownstream from the portion expected for encoding thesecretory signal sequence. In the case in which thisrestriction enzyme site was a protruding 5'—terminus, thesite was blunt-ended by the Klenow treatment. Digestion withHindIII was further carried out and a DNA fragment containingthe SV40 promoter and a CDNA encoding the secretory sequenceat the downstream from the promoter was separated by agarosegel electrophoresis. This fragment was inserted between theCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323916pSSD3 HindIII site and a restriction enzyme site selected soas to match with the urokinase-coding frame, therebyconstructing a vector expressing a fusion protein of thesecretory signal portion of the target cDNA and the urokinaseprotease domain (refer to Figure 2).After Escherichia coli (host: JM109) bearing the fusion-protein expression vector was incubated at 37°C for 2 hoursin 2 nu. of the 2xYT culture medium containing 100 pg/mlampicillin, the helper phage Ml3KO7 (50 ul) was added and theincubation was continued at 37°C overnight. A supernatantseparated by centrifugation underwent precipitation withpolyethylene glycol to obtain single—stranded phageparticles. These particles were suspended in 100 pl of 1 mMTris—O.1 mM EDTA, pH 8 (TE). Also, there was used as acontrol a suspension of single—stranded particles prepared inthe same manner from the vector pKAl—UPA containing pSSD3and a full—length CDNA of urokinase [Yokoyama—Kobayashi, M.et al., Gene 163: 193-196 (1995)].The simian-kidney—origin culture cells, COS7, wereincubated at 37°C in the presence of 5% CO2 in the Dulbecco'smodified Eagle's culture medium (DMEM) containing 10% fetalcalf albumin. Into a 6-well plate (Nunc Inc., 3 cm in the5well diameter) were inoculated 1 x 10 COS7 cells andincubation was carried out at 37°C for 22 hours in thepresence of 5% CO2. After the culture medium was removed, thecell surface was washed with a phosphate buffer solution andthen washed again with DMEM containing 50 mM Tris-hydrochloric acid (pH 7.5) (TDMEM). To the cells were added1 ul of the single—stranded phage suspension, 0.6 ml of theCA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323917DMEM culture medium, and 3 pl of TRANSFECTAMTM (IBF Inc.) andthe resulting mixture was incubated at 37°C for 3 hours inthe presence of 5% CO2. .After the sample solution wasremoved, the cell surface was washed with TDMEM, 2 ml perwell of DMEM containing 10% fetal calf albumin was added, andthe incubation was carried out at 37°C for 2 days in thepresence of 5% CO2.To 10 ml of 50 mM phosphate buffer solution (pH 7.4)containing 2% bovine fibrinogen (Miles Inc.), 0.5% agarose,and 1 mM potassium chloride were added 10 units of humanthrombin (Mochida Pharmaceutical Co., Ltd.) and the resultingmixture was solidified in a plate of 9 cm in diameter toprepare a fibrin plate. Ten microliters of the culturesupernatant of the transfected COS7 cells were spotted on thefibrin plate, which was incubated at 37°C for 15 hours. Thediameter of the thus-obtained clear circle was taken as anindex for the urokinase activity. Table 2 shows therestriction enzyme site used for cutting off the CDNAfragment from each clone, the restriction enzyme site usedfor cleavage of pSSD3, and the presence or absence of a clearcircle. Except for pSSD3 used as the control, each of thesamples formed a clear circle to identify that urokinase wassecreted in the culture medium. That is to say, it isindicated that each of the CDNA fragments codes for the aminoacid sequence that functions as the secretory signalsequence.CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323918Table 2HP Number Restriction Enzyme Site Clear CirclecDNA* VectorHPOO658 HindIII (K) SmaI +HP00714 PvuII PmaCI +HP00876 NcoI (K) PmaCI +HP01134 PmaCI PmaCI +HP10029 ApaI (K) SmaI +HP10189 BglI (K) PmaCI +_HP10269 PvuII PmaCI +HP10298 HindIII (K) PmaCI +HP10368 EcoRV PmaCI +pKA1—UPA +pSSD3 —* (K) means that cleavage with the restriction enzyme isfollowed by the Klenow treatment.(6) Protein Synthesis by In Vitro TranslationThe plasmid vector carrying the CDNA. of the presentinvention was utilized for the in vitrotranscription/translation by the TNT rabbit reticulocytelysate kit (Promega Biotec). In this case, [35S]methioninewas added and the expression product was labeled with theradioisotope. All reactions were carried out by following theprotocols attached to the kit. Two micrograms of the plasmidwas allowed to react at 30°C for 90 minutes in total 25 ml ofa reaction solution containing 12.5 pl of the TNT rabbitreticulocyte lysate, 0.5 pl of the buffer solution (attachedto the kit), 2lpl of an amino acid mixture (methionine-free),CA 02265923 l999-03- 12W0 93/11217 PCT/JP97/03239192 pl (0.37 MBq/pl) of [35S]methionine (Amersham Corporation),0.5 ul of T7 RNA polymerase, and 20 U of RNasin. Also, theexperiment in the presence of the membrane system was carriedout by adding 2.5 ul of the dog pancreatic microsome fraction(Promega Biotec) into this reaction system. To 3 ul of thereaction solution was added 2 ul of an SDS sampling buffer(125 mM Tris-hydrochloric acid buffer solution, pH 6.8, 120mM 2-mercaptoethanol, 2% SDS solution, 0.025% bromophenolblue, and 20% glycerol) and the resulting solution was heatedat 95°C for 3 minutes and then subjected to SDS-polyacrylamide gel electrophoresis. The molecular weight ofthe translation product was determined by carrying out theautoradiography. Table 3 shows the molecular weight of the invitro translation product obtained from each of the clones inthe presence/absence of the membrane microsome together withthe calculated value of the molecular weight of the proteinencoded by ORF of the cDNA....,..w.4.......................__..~.,.m. \ . ‘....,...«.............-..........,.,.,........,CA 02265923 l999-03- 12WO 98/11217 PCT/JP97/0323920Table 3Se— HP Calcu— In Vitro Translation Productquence Number lated (KDa)No_ (pa) Without Membrane With MembraneSystem Added System Added*1 HP00658 17,037 18 162 HPO0714 37,106 47 —3 HPO0876 18,230 18 —4 HP01134 42,947 42 495 HP10029 18,894 21 186 HP10189 9,113 12 —7 HPlO269 129,572 130 -8 HP10298 13,161 16 -9 HP10368 19,979 19 18* - means "Not examined".(7) Clone Examples<HP00658> (Sequence Number 1, 10, 19)Determination of the whole base sequence for the CDNAinsert of clone HP00658 obtained from the human fibrosarcomacell line HT—1080 CDNA libraries revealed the structureconsisting of a 5’-non-translation region of 55 bp, an ORF of465 bp, and a 3'-non-translation region of 776 bp. The ORFcodes for a protein consisting of 154 amino acid residueswith a hydrophobic region of a putative secretory signalsequence at the N—terminal. Figure 3 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte-Doolittle method. Search of the proteindata base using the amino acid sequence encoded by the ORFCA 02265923 l999-03- 12W0 98/11217 PCT/JP97/0323921revealed that the N—terminal 63 amino acid residues thereofwere completely identical with those in the RANTES protein(EMBL Accession No. 21121) except for one amino acid residueat position 7 (arginine in RANTES and alanine in the presentprotein), but the sequences in both proteins were completelydifferent after position 64. Hereupon, RANTES consisted of 91amino acid residues, whereas the present protein consisted oflonger 154 amino acid residues. The in vitro translationresulted in the formation of a translation product of 18 kDathat was almost consistent with the molecular weight of17,037 predicted from the ORF. In this case, the addition ofthe microsome resulted in the formation of a 16-kDa productin which the secretory signal sequence portion was putativelyremoved by cleavage. This result together with the result onpSSD3 verifies that the present protein possesses thesecretory signal sequence. Application of the (—3,—1) rule,a method for predicting the signal sequence cleavage site[von Heijne, G., Nucl. Acid Res. 14: 4683-4690 (1986)],allows to expect that the maturation protein starts fromserine at position 24.Comparison of the base sequences for the both proteinsrevealed that the base sequence from position 2 to position325 in the present CDNA was deficient in the RANTES cDNA. Itis considered that this deficiency resulted in induction ofa frame shift to fornl an ORF‘ of a «different size. Somemutations were observed in other regions, wherein thehomology was 97.7% up to position 241 and was 98.0% afterposition 325. RANTES has been obtained as a T cell—specificprotein [Schall, T. J. et al., J. Immunol. 141: 1018-1025/1 )\ . M.............u.........2.........,.... ,.-._...............—m..-...-...................,......,...CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323922(1988)], whereas the present CDNA was obtained from thefibrosarcoma cells. Accordingly, the present protein isconsidered to possess a different function fronx that ofRANTES.Furthermore, the search of GenBank using the basesequence of the present CDNA revealed that any EST possessingthe homology of 90% or more was not found.<HP007l4> (Sequence Number 2, 11, 20)Determination of the whole base sequence for the CDNAinsert of clone HP00714 obtained from the human epidermoidcarcinoma cell line KB CDNA libraries revealed the structureconsisting of a 5’-non—translation region of 56 bp, an ORF of948 bp, and a 3’-non—translation region of 2310 bp. The ORFcodes for a protein consisting of 315 amino acid residueswith a hydrophobic region of a putative secretory signalsequence at the N-terminal. Figure 4 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte-Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 47 kDa that was somewhat larger than the molecularweight of 37,106 predicted from the ORF. Since the molecularweight of the human reticulocalbin analogous to the presentprotein is also larger by about 10 kDa than the molecularweight expected from the translation—product band on SDS—PAGE[Ozawa, M., J. Biochem. 117: 1113-1119 (1995)), the molecularweight difference in the present protein is considered to bearisen from its physicochemical properties. Application ofthe (—3,—l) rule, a method for predicting the signal sequencecleavage site; allows to expect that the maturation proteinCA 02265923 l999-03- 12W0 93/11217 PCT/JP97/0323923starts from lysine at position 20. There is a possibilitythat the present protein exists in the endoplasmic reticulumbecause this protein possesses the C—terminal sequence HDEFanalogous to KDEL, the signal motif sequence localized in theendoplasmic reticulum.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasanalogous to the human reticulocalbin (GenBank Accession No.D42073). Table 4 indicates the comparison of the amino acidsequences between the human protein of the present invention(HP) and the human reticulocalbin (RC). - represents a gap,* represents an amino acid residue identical to that in theprotein of the present invention, and . represents an aminoacid residue analogous to that in the protein of the presentinvention. The both proteins possessed a homology of 60.5%.Table 4HP ’ MDLRQFLMCLSLCTAFALSKPTEKKDR-VHHEPQLSDKVHNDAQSFDYDH,&**, ,mL&*x“”&“_x}mmmRC MARGGRGRRLGLALGLLLALVLAPRVLRAKPTVRKERVVRPDSELGBRPPBDNHSFOYDHHP DAFLGAEBAKTFDQLTFEESKERLGKIVSKIDGDKDGFVTVDELKDWIKFAQKRWIYBDV_**** x,.********_**x***x***__**_* *****,,***,xx* _***,*_,,*RC BAPLGKBDSKTFDQLTPDESKERLGKIVDRIDNDGDGFVTTEELKTWIKRVQKRYIFDNVHP BRQWKGHDLNEDGLVSWEEYKNATYGYVLDDP———-DPDDGFNYKQMMVRDBRRFKMADK_ **_,* ,,*_ ,x*****_x**x* *__* '*,,x ,_x_*_ *x**;** xxRC AKVWKDYDRDKDDKISWBBYKQATYGYYLGNPAEFHDSSDHHTFKKMLPRDERRFKAADLHP DGDLIATKEEFTAFLHPEEYDYMKDIVVQETMEDIDKNADGFIDLEBYIGDMYSHDGNTDW.....‘,,...m........n-»....-.......u.—..............,..._..,.. . ,‘ ...,_.u...u......................4y....._. ............. VIWO 98111217CA 02265923 l999-03- l2PCT/JP97/0323924_x**_**,***********_,,**_*** **,***x**_***_* _***,*x_**,,*_RC NGDLTATREBFTAFLHPEBFBHMKEIVVLBTLBDIDKNGDGFVDODEYIADMFSHBENGPHP BPBWVKTBREQFVEFRDKNRDGKMDKEBTKDWILPSDYDHAEAEARHLVYBSDHNKDGKLxx xx .***** xxxx *_*** xx x__,**** *****_**x***xx***_x**_**RC EPDWVLSEREDFNEFRDLNKDGKLDKDEIRHWILPQDYDHAQAEARHLVYESDKNKDEKLHP TKEEIVDKYDLFVGSQATDFGEALVR—HDBFxxxxx , , _ _ __*x*****_,**_*,_ xxx.RC TKEBILENWNMFVGSQATNYGEDLTKNHDELFurthermore, the search of GenBank using the basesequence of the present cDNA revealed that there existed someESTs possessing the homology of 90% or more and containingthe initiation codon (for example, Accession No. F3872), butany of the sequences thereof did not allow to predict thepresent protein.Reticulocalbin is a protein localized on the membranesurface of the endoplasmic reticulum and has been consideredto participate in the protein folding. Accordingly, theprotein of the present invention is considered to beapplicable to the folding process of recombinant proteins.<HP00876> (Sequence Number 3, 12, 21)Determination of the whole base sequence for the CDNAinsert of clone HPO876 obtained from the human stomach cancerCDNA libraries revealed the structure consisting of a 5’-non-translation region of 146 bp, an ORF of 477 bp, and a 3'—non-translation region of 529 bp. The ORF codes for a proteinconsisting of 158 amino acid residues with a hydrophobicregion of a putative secretory signal sequence at the N-terminal. Figure 5 depicts the hydrophobicity/hydrophilicityCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323925profile of the present protein obtained by the Kyte-Doolittlemethod. The in vitro translation resulted in the formation ofa translation product of 18 kDa that was almost consistentwith the molecular weight of 18,230 predicted from the ORF.In this case, the addition of the microsome resulted in theformation of a 16-kDa product in which the secretory signalsequence portion was putatively removed by cleavage. Thisresult together with the result on pSSD3 verifies that thepresent protein possesses the secretory signal. Applicationof the (—3,—l) rule, a method for predicting the signalsequence cleavage site, allows to expect that the maturationprotein starts from glycine at position 18 or aspartic acidat position 23.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasanalogous to several type—C lectins. As an example, Table 5indicates the comparison of the amino acid sequences betweenthe human protein of the present invention (HP) and therattlesnake lectin (CL) (Swiss—PROT Accession No. P21963). —represents a gap, * represents an amino acid residueidentical to that in the protein of the present invention,and . represents an amino acid residue analogous to that inthe protein of the present invention. The both proteinspossessed a homology of 35.3%.CA 02265923 l999-03- 12W0 98/1 1217 PCTIJP97/0323926Table 5HP MASRSMRLLLLLSCLAKTGVLGDIIMRPSCAPGWFYHKSNCYGYFRKLRNWSDAELBCQS.*. .*. .. ** *..*..*.***. *..CL NNCPLDWLPMNGLCYKIFNQLKTWBDABMFCRKHF YGNGAHLASILSLKBASTIABYISGYQRSfl—PIWIGLHDPQKRQQWQWIDGAMYLYRSWS* * ****_ , *, _******,*,_,* .****,* ,* *_*_* , x _x_CL YKPGCHLASPHRYGESLBIAEYISDYHKGQENVWIGLRDKKKDFSWEWTDRSCTDYLTWDHP GKSMGG——NKH—CAEMSSNNNFLTWSSNBCNKRQHFLCKYRPCL KNQPDHYQNKBFCVELVSLTGYRLWNDQVCESKDAFLCQCKFFurthermore, the search of GenBank using the basesequence of the present cDNA revealed that any EST possessingthe homology of 90% or more was not found.After 1 ug of the plasmid pHP00876 was digested with 20units of PvuII, the product was subjected to 1% agarose gelelectrophoresis and an about 700-bp DNA fragment was cut offfrom the gel. Next, 1 pg of pET—21a (Novagen) was digestedwith 20 units of NheI, the product was subjected to theKlenow treatment followed by 1% agarose gel electrophoresisand an about 5.4-kbp DNA fragment was cut off from the gel.After ligation of the vector fragment and the cDNA fragmentusing a ligation kit, Escherichia coli BL21 (DE3) (Novagen)was transformed. A pdasmid pET876 was prepared from thetransformant and the objective recombinant was confirmed fromthe restriction enzyme cleavage map. The present expressionvector expresses a protein in which methionine-alanine wasW0 98/11217CA 02265923 l999-03- l2PCT/JP97/0323927inserted before a protein starting from serine at position 29in the protein encoded by the clone HPO0876.A. suspension. of pET876/BL2l (DE3) in 5 nu. of the LBculture medium containing 100 ug/ml ampicillin was incubatedin a shaker at 37°C and isopropylthiogalactoside was added toreached to about 0.5. After themake 1 mM when A600incubation was continued at 37°C for 6 hours, cells werecollected tar centrifugation and. suspended jJ1 25 nu. of acolumn buffer solution for the amylose column (10 mM Tris-hydrochloric acid, pH 7.4, 200 mM Nacl, and 1 mM EDTA). Theresulting suspension was sonicated and then the insolublefraction was subjected to SDS-polyacrylamide electrophoresisto identify a band originating from the expression of thepresent vector at a position of about 14 kDa.Since lectins recognize and then bind to sugar chains,lectins are useful as sugar—chain detection reagents and asInaffinity carriers for purification of glycoproteins.addition, extracellular secretory lectins play importantroles also in intercellular signal transduction and therebyare useful as medicines.<HPOl134> (Sequence Number 4, 13, 22)Determination of the whole base sequence for the CDNAinsert of clone HP0l134 obtained from the human liver cDNAlibraries revealed the structure consisting of a 5’—non—translation region of 116 bp, an ORF of 1131 bp, and a 3’-non—translation region of 502 bp. The ORF codes for a proteinconsisting of 376 amino acid residues with a hydrophobicregion of a putative secretory signal sequence at the N-terminal. Figure 6 depicts the hydrophobicity/hydrophilicityCA 02265923 l999-03- 12W0 98/1 1217 PCTIJP97/0323928profile of the present protein obtained by the Kyte—Doolittlemethod. The in vitro translation resulted in the formation ofa translation product of 42 kDa that was almost consistentwith the molecular weight of 42,947 predicted from the ORF.In this case, the addition of the microsome resulted in theformation of a 49-kDa product in which a sugar chain wasputatively‘ added by’ N—glycosylation after the secretion.Hereupon, there exist in the amino acid sequence of thisprotein four possible N—glycosylation sites (Asn—Gly-Thr atposition 91, Asn-Glu—Thr en; position 167, .Asn—Thr—Ser atposition 263, and Asn-Lys-Thr at position 272). The aboveresult together with the result on pSSD3 verifies that thepresent protein possesses the secretory signal. Applicationof the (-3,—1) rule, a method for predicting the signalsequence cleavage site, allows to expect that the maturationprotein starts from alanine at position 17 or valine atposition 18.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasanalogous to several cysteine proteinases. As an example,Table 6 indicates the comparison of the amino acid sequencesbetween the human protein of the present invention (HP) andthe tangerine cysteine proteinase (CP) (GenBank.Accession No.Z47793). — represents a gap, * represents an amino acidresidue identical to that in the protein of the presentinvention, and . represents an amino acid residue analogousto that in the protein of the present invention. The bothproteins possessed a homology of 49% among the N-terminalregion of 286 amino acid residues.CA 02265923 l999-03- l2wo 98/11217 PCT/JP97/0323929Table 6HP MVWKVAVFLSVALGIGAVPIDDFBDGGKHx xx xx _, x,,CP MTRLASGVLITLLVALAGIADGSRDIAGDILKLPSEAYRFFHNGGGGAKVNDDDDSVGTRHP WVVIVAGSNGWYNYRHDAUACHAYQIIHRNGIPDEQIVVMMYDDIAYSEDNPTPGIVINRx_x__xxxxx,,xxxxxxx xxxxx _,_ x_ xx_x_x xxxxxx_ x xx xx__xx_CP WAVLLAGSNGFWNYRHQADICHAYQLLRKGGLKDENIIVFMYDDIAFNEENPRPGVIINHHP PNGTDVYQGVPKUYTGBDVTPONFLAVLRGDAEAVKGIGSGKVLKSGPQDHVFIYFTDHGx_x_xxx_xxxxxxxxxxxx __x_xx; x, ,x_,x xxxxx,_xxx xx xx___xxxCP FHGDDVYKGVPKDYTGBDVTVBKFFAVVLGNKTALTG—GSGKVVDSGPNDHIFIFYSDHGHP STGILVFPNED-LHVKDLNETIHYMYKHKMYRKMVFYIBACESGSMMN—HLPDNINVYAT..*.* .*.. .....* . . . . .. *...***.*******... * ...*.***CF GPGVLGMPTSRYIYADBLIDVLKKKHASGNYKSLVFYLBACBSGSIFEGLLLEGLNIYATHP TAANPRESSYACYY---¥DEKRSTY---LGDWYSVNWMBDSDVEDLTKETLHKOYHLVKSxx,x, xxx,, x, _ ,,,x xxx xx._xxxxxx_,_x ,xxxx,xx,xxx,CF TASNABESSWGTYCPGEIPGPPPEYSTCLGDLYSIAWMEDSDIHNLRTETLHQQYBLVKTHP HT--———NTSHVMflYGNKTISTMKVMQFQGMKRKASSPVFLPPVTHLDLTPSFDVPLTIM,x ,xxxxxxx; _,x_ ,,, , xCF RTASYNSYGSHVMQYGDIGLSKNNLFTYLGTNPANDNYTFVDENSLRPASKAVNQRDADLFurthermore, the search of GenBank using the basesequence of the present cDNA revealed that there existed someESTs possessing the homology of 90% or more (for example,Accession No. F0l300), but they were shorter than the presentCDNA and any molecule containing the initiation codon was notidentified.CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323930Extracellular secretory proteases possess a variety ofphysiological functions and thereby are useful as medicines.In addition, the proteases have been utilized as researchreagents for the structure analysis of proteins by restricteddegradation and so on.<HPl0029> (Sequence Number 5, 14, 23)Determination of the whole base sequence for the CDNAinsert of clone HP10029 obtained from the human epidermoidcarcinoma cell line KB CDNA libraries revealed the structureconsisting of a 5’—non—translation region of 8 bp, an ORF of522 bp, and a 3’—non—translation region of 458 bp. The ORFcodes for a protein consisting of 173 amino acid residueswith a hydrophobic region of a putative secretory signalsequence at the N-terminal. Figure 7 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte—Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 21 kDa that was almost consistent with themolecular weight of 18,894 predicted from the ORF. In thiscase, the addition of the microsome resulted in the formationof a 18-kDa product in which the secretory signal sequenceportion was putatively’ removed by cleavage. This resulttogether with the result on pSSD3 verifies that the presentprotein possesses the secretory signal sequence. Applicationof the (-3,-1) rule, a method for predicting the signalsequence cleavage site, allows to expect that the maturationprotein starts from valine at position 32. There is apossibility that the present protein exists in theendoplasmic reticulum because this protein possesses the C-CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323931terminal sequence RTEL analogous to KDEL, the signal motifsequence localized in the endoplasmic reticulum.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasnot homologous with any of known proteins. Hereupon, thesearch of GenBank using the base sequence revealed that thereexisted some ESTS possessing the homology of 90% or more (forexample, Accession No. H87021), but they were shorter thanthe present CDNA and any molecule containing the initiationcodon was not identified.<HPl0l89> (Sequence Number 6, 15, 24)Determination of the whole base sequence for the cDNAinsert of clone HP10189 obtained from the human epidermoidcarcinoma cell line KB cDNA libraries revealed the structureconsisting of a 5’-non—translation region of 101 bp, an ORFof 222 bp, and a 3’—non—translation region of 67 bp. The ORFcodes for a protein consisting of 73 amino acid residues witha hydrophobic region of a putative secretory signal sequenceat the N—termina1. Figure 8 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte-Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 10 kDa that was almost consistent with themolecular weight of 9,113 predicted from the ORF. Applicationof the (-3,—1) rule, a method for predicting the signalsequence cleavage site, allows to expect that the maturationprotein starts from alanine at position 27.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasCA 02265923 l999-03- 12W0 93/1 1217 PCT/JP97/0323932not homologous with any of known proteins. Hereupon, thesearch of GenBank using the base sequence revealed that thereexisted some ESTS possessing the homology of 90% or more andcontaining the initiation codon (for example, Accession No.N56270), but a frame shift had occurred and the same ORF asthat in the present cDNA was not identified.<HP10269> (Sequence Number 7, 16, 25)Determination of the whole base sequence for the cDNAinsert of clone HPl0269 obtained from the human lymphoma cellline U937 CDNA libraries revealed the structure consisting ofa 5’—non—translation region of 753 bp, an ORF of 351 bp, anda 3’—non-translation region of 395 bp. The ORF codes for aprotein consisting of 1172 amino acid residues with ahydrophobic region of a putative secretory signal sequence atthe N—terminal. Figure 9 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte-Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 130 kDa that was almost consistent with themolecular weight of 129,571 predicted from the ORF.Application of the (—3,—1) rule, a method for predicting thesignal sequence cleavage site, allows to expect that thematuration protein starts from glutamine at position 18..The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasanalogous to the B3 chain of laminin S. Table 7 indicates thecomparison of the amino acid sequences between the humanprotein of the present invention (HP) and the B3 chain ofhuman laminin S (B3) (GenBank Accession No. L25541)CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323933Table 7Amino Acid Residue Number HP B3124 Gln Arg269 Pro Deficient388 Pro Ala426 Gln Arg4 2 7 Gly Arg439 Arg Deficient441 Asp Glu603 Arg Pro8 15 Gly AlaComparison of the base sequence of the present cDNA andthe base sequence described in the data base reveals that the5’—terminus in the present cDNA is longer by 600 or more bpand the 81—bp 5'-terminus in the base sequence described inthe data base is not consistent at all with the base sequenceof the present CDNA. Accordingly, the both proteins originatefrom different mRNAs.As an extracellular matrix, laminin deeply participatesin the proliferation and differentiation of cells.Accordingly, laminin has been employed as an additive for thecell culture and so on.<HP10298> (Sequence Number 8, 17, 26)Determination of the whole base sequence for the cDNA-insert of clone HPl0298 obtained from the human stomachcancer cDNA libraries revealed the structure consisting of a5’-non—translation region of 137 bp, an ORF of 369 hp, and aCA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97l03239343'—non—translation region of 580 bp. The ORF codes for aprotein consisting of 122 amino acid residues with ahydrophobic region of a putative secretory signal sequence atthe N—terminal. Figure 10 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte—Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 16 kDa that was almost consistent with themolecular weight of 13,161 predicted from the ORF.Application of the (—3,—l) rule, a method for predicting thesignal sequence cleavage site, allows to expect that thematuration protein starts from leucine at position 18. Thereis also a possibility that the present protein possessing thehydrophobic C-terminal sequence of about 20 amino acidresidues binds to the membrane via this portion.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasnot homologous with any of known proteins. Hereupon, thesearch of GenBank using the base sequence revealed that thereexisted some ESTS possessing the homology of 90% or more andcontaining the initiation codon (for example, Accession No.D78655), but many sequences were not distinct and the sameORF as that in the present CDNA was not identified.<HPl0368> (Sequence Number 9, 18, 27)Determination of the whole base sequence for the cDNAinsert of clone HP10368 obtained from the human stomachcancer CDNA libraries revealed the structure consisting of a5'-non-translation region of 72 bp, an ORF of 528 bp, and a3'—non—translation region of 266 bp. The ORF codes for aCA 02265923 l999-03- 12W0 98/11217 PCT/JP97/0323935protein consisting of 175 amino acid residues with ahydrophobic region of a putative secretory signal sequence atthe N—terminal. Figure 11 depicts thehydrophobicity/hydrophilicity profile of the present proteinobtained by the Kyte-Doolittle method. The in vitrotranslation resulted in the formation of a translationproduct of 20 kDa that was almost consistent with themolecular weight of 19,979 predicted from the ORF. In thiscase, the addition of the microsome resulted in the formationof a 19-kDa product in which the secretory signal sequenceportion was putatively removed by cleavage. This resulttogether with the result on pSSD3 verifies that the presentprotein possesses the secretory signal. Application of the (-3,—1) rule, a method for predicting the signal sequencecleavage site, allows to expect that the maturation proteinstarts from leucine at position 19 or arginine at position21. There is a possibility that the present protein exists inthe endoplasmic reticulum because this protein possesses theC—terminal sequence KTEL analogous to KDEL, the signal motifsequence localized in the endoplasmic reticulum.The search of the protein data base using the amino acidsequence of the present protein revealed that the protein wasnot homologous with any of known proteins. Hereupon, thesearch of GenBank using the base sequence revealed that thereexisted some ESTS possessing the homology of 90% or more andcontaining the initiation codon (for example, Accession No.T86663), but many sequences were not distinct and the sameORF as that in the present CDNA was not identified. ._. N/-V’ . w».wm.m.m..~.....‘ u CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323936INDUSTRIAL APPLICATIONThe present invention provides human proteins havingsecretory signal sequences and cDNAs encoding said proteins.All of the proteins of the present invention are putativeproteins controlling the proliferation and differentiation ofthe cells, because said proteins are secreted outside thecells and exist in the extracellular liquid or on the cellmembrane surface. Therefore, the proteins of the presentinvention can be used as pharmaceuticals or as antigens forpreparing antibodies against said proteins. Furthermore, saidDNAS can be used for the expression of large amounts of saidproteins.In addition to the activities and uses described above,the polynucleotides and proteins of the present invention mayexhibit one or more of the uses or biological activities(including those associated with assays cited herein)identified below. Uses or activities described for proteinsof the present invention may be provided by administration oruse of such proteins or by administration or use ofpolynucleotides encoding such proteins (such as, for example,in gene therapies or vectors suitable for introduction ofDNA).Research Uses and UtilitiesThe polynucleotides provided by the present invention canbe used by the research community for various purposes. Thepolynucleotides can be used to express recombinant proteinfor analysis, characterization or therapeutic use; as markersfor tissues in which the corresponding protein ispreferentially expressed (either constitutively or at aCA 02265923 l999-03- 12W0 98/1 1217 PCTIJP97/0323937particular stage of tissue differentiation or development orin disease states); as molecular weight markers on Southerngels; as chromosome markers or tags (when labeled) toidentify chromosomes or to map related gene positions; tocompare with endogenous DNA sequences in patients to identifypotential genetic disorders; as probes to hybridize and thusdiscover novel, related DNA sequences; as a source ofinformation to derive PCR primers for genetic fingerprinting;as a probe to "subtract—out" known sequences in the processof discovering other novel polynucleotides; for selecting andmaking oligomers for attachment to a "gene chip" or othersupport, including for examination of expression patterns; toraise anti—protein antibodiesusing DNA immunizationtechniques; and as an antigen to raise anti—DNA antibodies orelicit another immune response. Where the polynucleotideencodes a protein which binds or potentially binds to anotherprotein (such as, for example, in a receptor—ligandinteraction), the polynucleotide can also be used ininteraction trap assays (such as, for example, that describedin Gyuris et al., Cell 75:79l-803 (1993)) to identifypolynucleotides encoding the other protein.with which bindingoccurs or to identify inhibitors of the binding interaction.The proteins provided by the present invention cansimilarly be used in assay to determine biological activity,including in a panel of multiple proteins for high-throughputscreening; to raise antibodies or to elicit another immuneresponse; as a reagent (including the labeled reagent) inassays designed to quantitatively determine levels of theprotein (or its receptor) in biological fluids; as markersCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323938for tissues in which the corresponding protein ispreferentially expressed (either constitutively or at aparticular stage of tissue differentiation or development orin a disease state); and, of course, to isolate correlativereceptors or ligands. Where the protein binds or potentiallybinds to another protein (such as, for example, in areceptor—ligand interaction), the protein can be used toidentify the other protein with which binding occurs or toidentify inhibitors of the binding interaction. Proteinsinvolved in these binding interactions can also be used toscreen for peptide or small molecule inhibitors or agonistsof the binding interaction.Any or all of these research utilities are capable ofbeing developed into reagent grade or kit format forcommercialization as research products.Methods for performing the uses listed above are wellknown to those skilled in the art. References disclosingsuch methods include without limitation "Molecular Cloning:A Laboratory Manual", 2d ed., Cold Spring Harbor LaboratoryPress, Sambrook, J., E.F. Fritsch and T. Maniatis eds., 1989,and "Methods in Enzymology: Guide to Molecular CloningTechniques", Academic Press, Berger, S.L. and A.R. Kimmeleds., 1987.Nutritional UsesPolynucleotides and proteins of the present invention canalso be used as nutritional sources or supplements. Suchuses include without limitation use as a protein or aminoacid supplement, use as a carbon source, use as a nitrogensource and use as a source of carbohydrate. In such casesCA 02265923 l999-03- 12WO 98/11217 PCT/JP97/0323939the protein or polynucleotide of the invention can be addedto the feed of a particular organism or can be administeredas a separate solid or liquid preparation, such as in theform of powder, pills, solutions, suspensions or capsules.In the case of microorganisms, the protein or polynucleotideof the invention can be added to the medium in or on whichthe microorganism is cultured.Cvtokine and Cell Proliferation/DifferentiationActivityA protein of the present invention may exhibit cytokine,cell proliferation (either inducing or inhibiting) or celldifferentiation (either inducing or inhibiting) activity ormay induce production of other cytokines in certain cellpopulations. Many protein factors discovered to date,including all known cytokines, have exhibited activity in oneor more factor dependent cell proliferation assays, and hencethe assays serve as a convenient confirmation of cytokineactivity. The activity of a protein of the present inventionis evidenced by any" one of a number of routine factordependent cell proliferation assays for cell lines including,without limitation, 32D, DA2, DAlG, T10, B9, B9/11, BaF3,MC9/G, M+ (preB M+), 2E8, RB5, DAl, 123, T1165, HT2, CTLL2,TF—l, Mo7e and CMK.The activity of a protein of the invention may, amongother means, be measured by the following methods:Assays for T—cell or thymocyte proliferation includewithout limitation those described in: Current Protocols inImmunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H.Margulies, E.M. Shevach, W Strober, Pub. Greene PublishingAssociates and Wiley—Interscience (Chapter 3, In Vitro assays“M...i...a..u......u».iw1.».M,.".,,. , . r........‘....“ ., ...W...4._...._..4.........M...,..._......‘CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323940for Mouse Lymphocyte Function 3.1—3.19; Chapter 7,Immunologic studies in Humans); Takai et al., J. Immunol.137:3494-3500, 1986; Bertagnolli et al., J. Immunol.145:1706—1712, 1990; Bertagnolli et al., Cellular Immunology133:327-341, 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 ofspleen cells, lymph node cells or thymocytes include, withoutlimitation, those described in: P0 lyclonal T cellstimulation, Kruisbeek, A.M. and Shevach, E.M. In CurrentProtocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp.3.12.1—3.12.14, John Wiley" and Sons, Toronto. 1994; andMeasurement of mouse and human Interferon y, Schreiber, R.D.In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol1 pp. 6.8.1—6.8.8, John Wiley and Sons, Toronto. 1994.Assays for proliferation and differentiation ofhematopoietic and lymphopoietic cells include, withoutlimitation, those described in: Measurement of Human andMurine Interleukin 2 and Interleukin 4, Bottomly, 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 andSons, 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 humaninterleukin 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 andSons, Toronto. 1991; Smith et al., Proc. Natl. Acad. Sci.W0 98/11217CA 02265923 l999-03- l2PCT/JP97/0323941U.S.A. 83:l857—186l, 1986; Measurement of human Interleukin11 — Bennett, F., Giannotti, J., Clark, S.C. and Turner, K.J. In Current Protocols in Immunology. J.E.e.a. Coligan eds.Vol 1 6.15.1 John Wiley and Sons, Toronto. 1991;PP-Measurement of mouse and human Interleukin 9 — Ciarletta, A.,Giannotti, J., Clark,S.C. and Turner, K.J. In CurrentProtocols iJ1 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 willamong others, that affect APC—T cellidentify, proteinsinteractions as well as direct T—cell effects by measuringproliferation and cytokine production) include, withoutlimitation, those described in: Current Protocols inImmunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H.Margulies, E.M. Shevach, W Strober, Pub. Greene PublishingAssociates and Wiley—Interscience (Chapter 3, In Vitro assaysfor Mouse Lymphocyte Function; Chapter 6, Cytokines and theircellular receptors; Chapter 7, Immunologic studies inHumans); Weinberger et al., Proc. Natl. Acad. Sci. USA7726091-6095, 1980; Weinberger et al., Eur. J. Immun.ll:405-411, 1981; Takai et al., J. Immunol. l37:3494-3500,1986; Takai et al., J. Immunol. l40:508-512, 1988.Immune Stimulating or Suppressinq ActivityA protein of the present invention may also exhibitimmune stimulating or immune suppressing activity, includingwithout limitation the activitiesfor which assays aredescribed herein. A protein may be useful in the treatmentof various immune deficiencies and disorders (includingsevere combined immunodeficiency (SCID)), e.g., in regulating,.....-..........,...,......lW ,.. . , ,.,......._...................._....._.r...r..,.... .CA 02265923 l999-03- 12W0 98/11217 PCT/JP97/0323942(up or down) growth and proliferation of T and/or Blymphocytes, as well as effecting the cytolytic activity ofNK cells and other cell populations. These immunedeficiencies may be genetic or be caused by viral (e.g., HIV)as well as bacterial orfungal infections, or may result fromautoimmune disorders. .More specifically, infectious diseasescauses by viral, bacterial, fungal or other infection may betreatable using a protein of the present invention,including infections by HIV, hepatitis viruses,herpesviruses, mycobacteria, Leishmania spp., malaria spp.and various fungal infections such as candidiasis. Ofcourse, in this regard, a protein of the present inventionmay’ also be useful where a .boost to the immune systemgenerally may be desirable, i.e., in the treatment of cancer.Autoimmune disorders which may be treated using a proteinof the present invention include, for example, connectivetissue disease, multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis, autoimmune pulmonaryinflammation, Guillain—Barre syndrome, autoimmunethyroiditis, insulin dependent diabetes mellitis, myastheniagravis, graft—versus—host disease and.autoimmune inflammatoryeye disease. Such a protein of the present invention mayalso to be useful in the treatment of allergic reactions andconditions, such as asthma (particularly allergic asthma) orother respiratory’ problems. Other conditions, in whichimmune suppression is desired (including, for example, organtransplantation), may also be treatable using a protein ofthe present invention.Using the ‘proteins of the invention it may also beCA 02265923 l999-03- 12W0 98/1 1217 PCTIJP97/0323943possible to immune responses, in a number of ways. Downregulation may be in the form of inhibiting or blocking animmune response already in progress or may involve preventingthe induction of an immune response. The functions ofactivated T cells may be inhibited by suppressing T cellresponses or by inducing specific tolerance in T cells, orboth. Immunosuppression of T cell responses is generally anactive, non-antigen-specific, process which requirescontinuous exposure of the T cells to the suppressive agent.Tolerance, which involves inducing non—responsiveness oranergy in T cells, is distinguishable from immunosuppressionin that it is generally antigen-specific and persists afterexposure to the tolerizing agent has ceased. Operationally,tolerance can be demonstrated by the lack of a T cellresponse upon reexposure to specific antigen in the absenceof the tolerizing agent.Down regulating or preventing one or more antigenfunctions (including without limitation B lymphocyte antigenfunctions (such as , for example, B7)), e.g., preventing highlevel lymphokine synthesis by activated T cells, will beuseful in situations of tissue, skin and organtransplantation and in graft-versus—host disease (GVHD). Forexample, blockage of T cell function should result in reducedtissue destruction in tissue transplantation. Typically, intissue transplants, rejection of the transplant is initiatedthrough its recognition as foreign by T cells, followed by animmune reaction that destroys the transplant. Theadministration of a molecule which inhibits or blocksinteraction of a B7 lymphocyte antigen with its naturalCA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323944ligand(s) on immune cells (such as a soluble, monomeric formof a peptide having B7—2 activity alone or in conjunctionwith a monomeric form of a peptide having an activity ofanother B lymphocyte antigen (e.g., B7—l, B7-3) or blockingantibody), prior to transplantation can lead to the bindingof the molecule to the natural ligand(s) on the immune cellswithout transmitting the corresponding costimulatory signal.Blocking B lymphocyte antigen function in this matterprevents cytokine synthesis by immune cells, such as T cells,and thus acts as an immunosuppressant. Moreover, the lack ofcostimulation may also be sufficient to anergize the T cells,thereby inducing tolerance in a subject. Induction oflong-term tolerance by B lymphocyte antigen—blocking reagentsmay avoid the necessity of repeated administration of theseblocking reagents. To achieve sufficient immunosuppressionor tolerance in a subject, it may also be necessary to blockthe function of a combination of B lymphocyte antigens.The efficacy of particular blocking reagents inpreventing organ transplant rejection or GVHD can be assessedusing animal models that are predictive of efficacy inhumans. Examples of appropriate systems which can be usedinclude allogeneic cardiac grafts in rats and xenogeneicpancreatic islet cell grafts in mice, both of which have beenused to examine the immunosuppressive effects of CTLA4Igfusion proteins in vivo as described in Lenschow et al.,Science 257:789—792 (1992) and Turka et al., Proc. Natl.Acad. Sci USA, 89:l1l02-11105 (1992). In addition, murinemodels of GVHD (see Paul ed., Fundamental Immunology, RavenPress, New York, 1989, pp. 846-847) can be used to determineCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323945the effect of blocking B lymphocyte antigen function in vivoon the development of that disease.Blocking antigen function may also be therapeuticallyuseful for treating autoimmune diseases. Many autoimmunedisorders are the result of inappropriate activation of Tcells that are reactive against self tissue and which promotethe production of cytokines and autoantibodies involved inthe pathology of the diseases. Preventing the activation ofautoreactive T cells may reduce or eliminate diseasesymptoms. Administration of reagents which blockcostimulation of T cells by disrupting receptor:ligandinteractions of B lymphocyte antigens can be used to inhibitT cell activation and prevent production of autoantibodies orT cell-derived cytokines which may be involved in the diseaseprocess. Additionally, blocking reagents may induceantigen-specific tolerance of autoreactive T cells whichcould lead to long-term relief from the disease. Theefficacy of blocking reagents in preventing or alleviatingautoimmune disorders can be determined using a number ofwell—characterized animal models of human autoimmunediseases. Examples include murine experimental autoimmuneencephalitis, systemic lupus erythmatosis in MRL/lpr/lpr miceor NZB hybrid mice, murine autoimmune collagen arthritis,diabetes mellitus in NOD mice and BB rats, and murineexperimental myasthenia gravis (see Paul ed., FundamentalImmunology, Raven Press, New York, 1989, pp. 840-856).Upregulation of an antigen function (preferably a Blymphocyte antigen function), as a means of up regulatingimmune responses, may also be useful in therapy.CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323946Upregulation of immune responses may be in the form ofenhancing an existing immune response or eliciting an initialimmune response. For example, enhancing an immune responsethrough stimulating B lymphocyte antigen function may beuseful in cases of viral infection. In addition, systemicviral diseases such as influenza, the commoncold, andencephalitis might be alleviated by the administration ofstimulatory forms of B lymphocyteantigens systemically.Alternatively, anti—viral immune responses may beenhanced in an infected patient by removing T cells from thepatient, costimulating the T cells in vitro with viralantigen—pulsed APCs either expressing a peptide of thepresent invention or together with a stimulatory form of asoluble peptide of the present invention and reintroducingthe in vitro activated T cells into the patient. Anothermethod of enhancing anti-viral immune responses would be toisolate infected cells from a patient, transfect them with anucleic acid encoding a protein of the present invention asdescribed herein such that the cells express all or a portionof the protein on their surface, and reintroduce thetransfected cells into the patient. The infected cells wouldnow be capable of delivering a costimulatory signal to, andthereby activate, T cells in vivo.In another application, up regulation or enhancement ofantigen function (preferably B lymphocyte antigen function)may be useful in the induction of tumor immunity. Tumorcells (e.g., sarcoma, melanoma, lymphoma, leukemia,neuroblastoma, carcinoma) transfected with a nucleic acidW0 98/11217CA 02265923 l999-03- l2PCT/JP97/0323947encoding at least one peptide of the present invention can beadministered to a subject to overcome tumor—specifictolerance in the subject. If desired, the tumor cell can betransfected to express a combination of peptides. Forexample, tumor cells obtained from a patient can betransfected ex vivo with an expression vector directing theexpression of a peptide having B7—2-like activity alone, orin conjunction with a peptide having B7—1—like activityand/or B7-3-like activity. The transfected tumor cells arereturned to the patient to result in expression of thepeptides on the surface of the transfected cell.Alternatively, gene therapy techniques can be used to targeta tumor cell for transfection in vivo.The presence of the peptide of the present inventionhaving the activity of £1 B lymphocyte antigen(s) on thesurface of the tumor cell provides thenecessarycostimulation signal to T cells to induce a T cell mediatedimmune response against the transfected tumor cells. Inaddition, tumor cells which lack MHC class I or MHC class IImolecules, or which fail to reexpress sufficient amounts ofMHC class I or MHC class II molecules, can be transfectedwith nucleic acid encoding all or a portion of (e.g., acytoplasmic-domain truncated portion) of an MHC class I achain protein and B2 microglobulin protein or an MHC classIIa chain protein and an MHC class IIB chain protein tothereby express MHC class I or MHC class II proteins on thecell surface. Expression of the appropriate class I or classII MHC in conjunction with a peptide having the activity ofa B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T_. -.. .......................,. 1‘\JVII .... , CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97/0323948cell mediated immune response against the transfected tumorcell. Optionally, a gene encoding an antisense constructwhich blocks expression of an MHC class II associatedprotein, such as the invariant chain, can also becotransfected with a DNA encoding a peptide having theactivity of a B lymphocyte antigen to promote presentation oftumor associated antigens and induce tumor specific immunity.Thus, the induction of a T cell mediated immune response ina human subject may be sufficient to overcome tumor-specifictolerance in the subject.The activity of a protein of the invention may, amongother means, be measured by the following methods:Suitable assays for thymocyte or splenocyte cytotoxicityinclude, without limitation, those described in: CurrentProtocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek,D.H. Margulies, E.M. Shevach, W Strober, Pub. GreenePublishing Associates and Wiley-Interscience (Chapter 3, InVitro assays for Mouse Lymphocyte Function 3.l—3.l9; Chapter7, Immunologic studies in Humans); Herrmann et al., Proc.Natl. Acad. Sci. USA 78:2488—2492, 1981; Herrmann et al., J.Immunol. 128:l968-1974, 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—5l2, 1988; Herrmannet al., Proc. Natl. Acad. Sci. USA 78:2488—2492, 1981;Herrmann et al., J. Immunol. 128:1968—1974, 1982; Handa etal., J. Immunol. 135:1564-1572, 1985; Takai et al., J.Immunol. 137:3494—3500, 1986; Bowmanet al., J. Virology61:1992—1998; Takai et al., J. Immunol. 140:508—512, 1988;Bertagnolli et al., Cellular Immunology 133:327-341, 1991;CA 02265923 l999-03- 12W0 98/11217 PCT/JP97/0323949Brown et al., J. Immunol. 153:3079—3092, 1994.Assays for T-cell-dependent immunoglobulin responses andisotype switching (which will identify, among others,proteins that modulate T—cell dependent antibody responsesand that affect Thl/Th2 profiles) include, withoutlimitation, those described in: Maliszewski, J. Immunol.l44:3028—3033, 1990; and Assays for B cell function: In Vitroantibody production, Mond, J.J. and Brunswick, M. In CurrentProtocols 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 willidentify, among others, proteins that generate predominantlyTh1 and CTL responses) include, without limitation, thosedescribed 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 andWiley—Interscience (Chapter 3, In Vitro assays for MouseLymphocyte Function 3.1—3.l9; Chapter 7, Immunologic studiesin Humans); Takai et al., J. Immunol. 137:3494—3500, 1986;Takai et al., J. Immunol. l40:508-512, 1988; Bertagnolli etal., J. Immunol. 149:3778-3783, 1992.Dendritic cell-dependent assays (which. will identify,among others, proteins expressed by dendritic cells thatactivate naive T—cells) include, without limitation, thosedescribed in: Guery et al., J. Immunol. l34:536—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 Medicinel82:255-260, 1995; Nair et al., Journal of VirologyCA 02265923 l999-03- 12W0 93/11217 PCT/JP97/032395067:4062-4069, 1993; Huang et al., Science 264:96l-965, 1994;Macatonia et al., Journal of Experimental Medicine169:1255~l264, 1989; Bhardwaj et al., Journal of ClinicalInvestigation 94:797—807, 1994; and Inaba et al., Journal ofExperimental Medicine l72:631-640, 1990.Assays for lymphocyte survival/apoptosis (which willidentify, among others, proteins that prevent apoptosis aftersuperantigen induction and proteins that regulate lymphocytehomeostasis) include, without limitation, those described in:Darzynkiewicz et al., Cytometry 13:795—808, 1992; Gorczyca etal., Leukemia 7:659—670, 1993; Gorczyca et al., CancerResearch 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—cellcommitment and development include,without limitation, thosedescribed in: Antica et al., Blood 84:1ll—117, 1994; Fine etal., Cellular Immunology 155:111—122, 1994; Galy et al.,Blood 85:2770—2778, 1995; Toki et al., Proc. Nat. Acad Sci.USA 88:7548—755l, 1991.Hematopoiesis Regulating ActivityA. protein of the present invention. may’ be useful inregulation of hematopoiesis and, consequently, in thetreatment of myeloid or lymphoid cell deficiencies. Evenmarginal biological activity in support of colony formingcells or of factor—dependent cell lines indicates involvementin regulating hematopoiesis, e.g. in supporting the growthand proliferation of erythroid progenitor cells alone or inCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323951combination with other cytokines, thereby indicating utility,for example, in treating various anemias or for use inconjunction with irradiation/chemotherapy to stimulate theproduction of erythroid precursors and/or erythroid cells; insupporting the growth and proliferation of myeloid cells suchas granulocytes and monocytes/macrophages (i.e., traditionalCSF activity) useful, for example, in conjunction withchemotherapy to prevent or treat consequentmyelo-suppression; in supporting the growth and proliferationof megakaryocytes and consequently of platelets therebyallowing prevention or treatment of various platelet‘disorders such as thrombocytopenia, and generally for use inplace of or complimentary to platelet transfusions; and/or insupporting the growth and proliferation of hematopoietic stemcells which are capable of maturing to any and all of theabove-mentioned hematopoietic cells and therefore findtherapeutic utility in various stem cell disorders (such asthose usually treated with transplantation, including,without limitation, aplastic anemia and paroxysmal nocturnalhemoglobinuria), as well as in repopulating the stem cellcompartment post irradiation/chemotherapy, either in—vivo orex-vivo (i.e., in conjunction with bone marrowtransplantation or with peripheral progenitor celltransplantation (homologous or heterologous)) as normal cellsor genetically manipulated for gene therapy.The activity of a protein of the invention may, amongother means, be measured by the following methods:Suitable assays for proliferation and differentiation ofvarious hematopoietic lines are cited above.CA 02265923 l999-03- 12W0 98/ 1 1217 PCT/JP97l0323952Assays for embryonic stem cell differentiation (whichwill identify, among others, proteins that influenceembryonic differentiation hematopoiesis) include, withoutlimitation, those described in: Johansson et al. CellularBiology l5:l41—151, 1995; Keller et al., Molecular andCellular Biology 13:473—486, 1993; Mcclanahan et al., Blood8l:2903-2915, 1993.Assays for stem cell survival and differentiation (whichwill identify, among others, proteins that regulatelympho-hematopoiesis) include, without limitation, thosedescribed in: 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., NewYork, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA89:5907—5911, 1992; Primitive hematopoietic colony formingcells with high proliferative potential, McNiece, I.K. andBriddell, R.A. In Culture of Hematopoietic Cells. R.I.Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., NewYork, NY. 1994; Neben et al., Experimental Hematology22:353—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.., NewYork, NY. 1994; Long term bone marrow cultures in thepresence of stromal cells, Spooncer, E., Dexter, M. andAllen, 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.WO 98/11217CA 02265923 l999-03- l2PCT/JP97/0323953Tissue Growth ActivityA protein of the present invention also may have utilitycartilage, tendon,in compositions used for bone, ligamentand/or nerve tissue growth or regeneration, as well as forwound healing and tissue repair and replacement, and in thetreatment of burns, incisions and ulcers.A protein of the present invention, which inducescartilage and/or bone growth in circumstances where bone isnot normally formed, has application in the healing of bonefractures and cartilage damage or defects in humans and otheranimals. Such a preparation employing a protein of theinvention may have prophylactic use in closed as well as openfracture reduction and also in the improved fixation ofartificial joints. De novo bone formation induced by anosteogenic agent contributes to the repair of congenital,trauma induced, or oncologic resection induced craniofacialdefects, and also is useful in cosmetic plastic surgery.A protein of this invention may also be used in thetreatment of periodontal disease, and in other tooth repairprocesses. Such agents may provide an environment to attractbone-forming cells, stimulate growth of bone-forming cells orinduce differentiation of progenitors of bone-forming cells.A protein of the invention may also be useful in thetreatment of osteoporosis or osteoarthritis, such as throughstimulation of bone and/or cartilage repair or by blockinginflammation or processes of tissue destruction (collagenaseactivity, osteoclast activity, etc.) mediated by inflammatoryprocesses.Another category of tissue regeneration activity that mayCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323954be attributable to the protein of the present invention istendon/ligament formation. A protein of the presentinvention, which induces tendon/ligament—like tissue or othertissue formation in circumstances where such tissue is notnormally formed, has application in the healing of tendon orligament tears, deformities and other tendon or ligamentdefects in humans and other animals. Such a preparationemploying a tendon/ligament—like tissue inducing protein mayhave prophylactic use in preventing damage to tendon orligament tissue, as well as use in the improved fixation oftendon or ligament to bone or other tissues, and in repairingdefects to tendon or ligament tissue. De novotendon/ligament-like tissue formation induced by acomposition of the present invention contributes to therepair of congenital, trauma induced, or other tendon orligament defects of other origin, and is also useful incosmetic plastic surgery for attachment or repair of tendonsor ligaments. The compositions of the present invention mayprovide an environment to attract tendon~ or ligament—formingcells, stimulate growth of tendon— or ligament—forming cells,induce differentiation of progenitors of tendon— orligament-forming cells, or induce growth of tendon/ligamentcells or progenitors ex vivo for return in vivo to effecttissue repair. The compositions of the invention may also beuseful in the treatment of tendinitis, carpal tunnel syndromeand other tendon or ligament defects. The compositions mayalso include an appropriate matrix and/or sequestering agentas a carrier as is well known in the art.The protein of the present invention may also be usefulCA 02265923 l999-03- 12W0 98/1 1217 PCTIJP97/0323955for proliferation of neural cells and for regeneration ofnerve and brain tissue, i.e. for the treatment of central andperipheral nervous system diseases and neuropathies, as wellas mechanical and traumatic disorders, which involvedegeneration, death or trauma to neural cells or nervetissue. More specifically, a protein may be used in thetreatment of diseases of the peripheral nervous system, suchas peripheral nerve injuries, peripheral neuropathy andlocalized neuropathies, and central nervous system diseases,such as Alzheimer's, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, and Shy-Dragersyndrome. Further conditions which may be treated inaccordance with the present invention include mechanical andtraumatic disorders, such as spinal cord disorders, headtrauma and cerebrovascular diseases such as stroke.Peripheral neuropathies resulting from chemotherapy or othermedical therapies may also be treatable using a protein ofthe invention.Proteins of the invention may also be useful to promotebetter or faster closure of non-healing wounds, includingwithout limitation pressure ulcers, ulcers associated withvascular insufficiency, surgical and traumatic wounds, andthe like.It is expected that a protein of the present inventionmay also exhibit activity for generation or regeneration ofother tissues, such as organs (including, for example,pancreas, liver, intestine, kidney, skin, endothelium),muscle (smooth, skeletal or cardiac) and vascular (includingvascular endothelium) tissue, or for promoting the growth ofCA 02265923 l999-03- 12W0 98/ l 1217 PCT/JP97l0323956cells comprising such tissues. Part of the desired effectsmay be by inhibition or modulation of fibrotic scarring toallow normal tissue to regenerate. A protein of theinvention may also exhibit angiogenic activity.A protein of the present invention may also be useful forgut protection or regeneration and treatment of lung or liverfibrosis, reperfusion injury in various tissues, andconditions resulting from systemic cytokine damage.A protein of the present invention may also be useful forpromoting or inhibiting differentiation of tissues describedabove from precursor tissues or cells; or for inhibiting thegrowth of tissues described above.The activity of a protein of the invention may, amongother means, be measured by the following methods:Assays for tissue generation activity include, withoutlimitation, those described in: International PatentPublication No. W095/16035 (bone, cartilage, tendon);International Patent Publication No. W095/05846 (nerve,neuronal); International Patent Publication No. W091/07491(skin, endothelium ).Assays for wound healing activity include, withoutlimitation, those described in: Winter, Epidermal WoundHealing, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), YearBook Medical Publishers, Inc., Chicago, as modified byEaglstein and Mertz, J. Invest. Dermatol 7l:382-84 (1978).Activin/Inhibin ActivityA protein. of the present invention. may also exhibitactivin— or inhibin-related activities. Inhibins arecharacterized by their ability to inhibit the release ofW0 98/11217CA 02265923 l999-03- l2PCT/JP97l0323957follicle stimulating hormone (FSH), while activins and arecharacterized by their ability to stimulate the release offollicle stimulating hormone (FSH). Thus, a protein of thepresent invention, alone or in heterodimers with a member ofthe inhibin a family, may be useful as a contraceptive basedon the ability of inhibins to decrease fertility in femalemammals and decrease spermatogenesis in male mammals.Administration of sufficient amounts of other inhibins caninduce infertility in these mammals. Alternatively, theprotein of the invention, as a homodimer or as a heterodimerwith other protein subunits of the inhibin—B group, may beuseful as a fertility inducing therapeutic, based upon theability of activin molecules in stimulating FSH release fromcells of the anterior pituitary. See, for example, UnitedStates Patent 4,798,885. A protein of the invention may alsobe useful for advancement of the onset of fertility insexually immature mammals, so as to increase the lifetimereproductive performance of domestic animals such as cows,sheep and pigs.The activity of a protein of the invention may, amongother means, be measured by the following methods:withoutAssays for activin/inhibin activity include,limitation, those described in: Vale et al., Endocrinology9l:562-572, 1972; Ling et al., Nature 32l:779~782, 1986; ValeNature 32l:776-779, 1986; Natureet al., Mason et al.,318:659-663, 1985; Forage et al., Proc. Natl. Acad. Sci. USA83:309l—3095, 1986.Chemotactic/Chemokinetic ActivityA protein of the present invention may have chemotacticCA 02265923 l999-03- 12W0 98/ 11217 PCT/JP97/0323958or chemokinetic activity (e.g., act as a chemokine) formammalian cells, including, for example, monocytes,fibroblasts, neutrophils, T—cells, mast cells, eosinophils,epithelial and/or endothelial cells. Chemotactic andchemokinetic proteins can be used to mobilize or attract adesired cell population to a desired site of action.Chemotactic or chemokinetic proteins provide particularadvantages in treatment of wounds and other trauma totissues, as well as in treatment of localized infections.For example, attraction of lymphocytes, monocytes orneutrophils to tumors or sites of infection may result inimproved immune responses against the tumor or infectingagent.A. protein or peptide has chemotactic activity for aparticular cell population if it can stimulate, directly orindirectly, the directed orientation or movement of such cellpopulation. Preferably, the protein or’ peptide has theability to directly stimulate directed movement of cells.Whether a particular protein has chemotactic activity for apopulation of cells can be readily determined by employingsuch protein or peptide in any known assay for cellchemotaxis.The activity of a protein of the invention may, amongother means, be measured by the following methods:Assays for chemotactic activity (which will identifyproteins that induce or prevent chemotaxis)consist of assaysthat measure the ability of a protein to induce the migrationof cells across a membrane as well as the ability of aprotein to induce the adhesion of one cell population toW0 98Ill217CA 02265923 l999-03- l2PCT/JP97l0323959another cell population. Suitable assays for movement andadhesion 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 (Chapter6.12, Measurement of alpha and beta Chemokines6.l2.l—6.12.28; Taub et al. J. Clin. Invest. 95:l370-1376,1995; Lind et al. APMIS lO3:l40—l46, 1995; Muller et al Eur.1744-1748; of Immunol.J. Immunol. 25: Gruber et al. J.152:5860-5867, 1994; Johnston et al. J. of Immunol. 153:1762-1768, 1994.Hemostatic and Thrombolvtic ActivityA protein of the invention may also exhibit hemostatic orthrombolytic activity. As a result,such a protein isexpected to be useful in treatment of various coagulationdisorders (includinghereditary disorders, such ashemophilias) or to enhance coagulation and other hemostaticevents in treating wounds resulting from trauma, surgery orother causes. A protein of the invention may also be usefulfor dissolving or inhibiting formation of thromboses and fortreatment and prevention of conditions resulting therefrominfarction of cardiac and central(such as, for example,nervous system vessels (e.g., stroke).The activity of a protein of the invention may, amongother means, be measured by the following methods:Assay for hemostatic and thrombolytic activity include,without limitation, those described in: Linet et al., J.Clin. Pharmacol. 26:131—140, 1986; Burdick et al., ThrombosisRes. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71—79CA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323960(1991); Schaub, Prostaglandins 35:467—474, 1988.Receptor/Ligand ActivitvA protein of the present invention may also demonstrateactivity as receptors, receptor ligands or inhibitors oragonists of receptor/ligand interactions. Examples of suchreceptors and ligands include, without limitation, cytokinereceptors and their ligands, receptor kinases and theirligands, receptor phosphatases and their ligands, receptorsinvolved in cell—cell interactions and their ligands(including without limitation, cellular adhesion molecules(such as selectins, integrins and their ligands) andreceptor/ligand pairs involved in antigen presentation,antigen recognition and development of cellular and humoralimmune responses). Receptors and ligands are also useful forscreening of potential peptide or small molecule inhibitorsof the relevant receptor/ligand interaction. A protein ofthe present invention (including, without limitation,fragments of receptors and ligands) may themselves be usefulas inhibitors of receptor/ligand interactions.The activity of a protein of the invention may, amongother means, be measured by the following methods:Suitable assays for receptor—ligand activity includewithout limitation those described inzcurrent Protocols inImmunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H.Margulies, E.M. Shevach, W.Strober, Pub. Greene PublishingAssociates and Wiley—Interscience (Chapter 7.28, Measurementof 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:l145-1156, 1988; RosensteinCA 02265923 l999-03- 12W0 98/1 1217 PCT/JP97/0323961et al., J. Exp. Med. l69:l49—l6O 1989; Stoltenborg etal., J. Immunol. Methods l75:59—68, 1994; Stitt et al., Cell80:66l-670, 1995.Anti—Inflammatorv ActivityProteins of the present invention may also exhibitanti—inflammatory activity. The anti—inflammatory activitymay be achieved by providing a stimulus to cells involved inthe inflammatory response, by inhibiting or promotingcell—cell interactions (such as, for example, cell adhesion),by inhibiting or promoting chemotaxis of cells involved inthe inflammatory process, inhibiting or promoting cellextravasation, or by stimulating or suppressing production ofother factors which more directly inhibit or promote aninflammatory response. Proteins exhibiting such activitiescan be used to treat inflammatory conditions includingchronic or acute conditions), including without limitationinflammation associated with infection (such as septic shock,sepsis or systemic inflammatory response syndrome (SIRS)),ischemia—reperfusion injury, endotoxin lethality, arthritis,complement-mediatedhyperacuterejection,nephritis,cytokineor chemokine—induced lung injury, inflammatory’bowel disease,Crohn's disease or resulting from over production of ytokinessuch as TNF or IL-1. Proteins of the invention may also beuseful to treat anaphylaxis and hypersensitivity to anantigenic substance or material.Tumor Inhibition ActivityIn addition to the activities described above forimmunological treatment or prevention of tumors, a protein ofthe invention may exhibit other anti-tumor activities. A-..l............................................‘ ., 4 1. ‘..-.................u..»...»................i...,,\ . ...‘..,..4....._......m...~........, .,... . ..CA 02265923 l999-03- 12W0 98/1 1217 PCTlJP97l0323962protein may inhibit tumor growth directly or indirectly (suchas, for example, via ADCC). A protein may exhibit its tumorinhibitory activity by acting on tumor tissue or tumorprecursor tissue, by inhibiting formation of tissuesnecessary to support tumor growth (such as, for example, byinhibiting angiogenesis), by causing production of otherfactors, agents or cell types which inhibit tumor growth, orby suppressing, eliminating or inhibiting factors, agents orcell types which promote tumor growthOther ActivitiesA protein of the invention may also exhibit one or moreof the following additional activities or effects: inhibitingthe growth, infection or function of, or killing, infectiousagents, including, without limitation, bacteria, viruses,fungi and other parasites; effecting (suppressing orenhancing) bodily characteristics, including, withoutlimitation, height, weight, hair color, eye color, skin, fatto lean ratio or other tissue pigmentation, or organ or bodypart size or shape (such as, for example, breast augmentationor‘ diminution, change in bone fornx or shape); effectingbiorhythms or caricadic cycles or rhythms; effecting thefertility of male or female subjects; effecting themetabolism, catabolism, anabolism, processing, utilization,storage or elimination of dietary fat, lipid, protein,carbohydrate, vitamins, minerals, cofactors or othernutritional factors or component(s); effecting behavioralcharacteristics, including, without limitation, appetite,libido, stress, cognition (including cognitive disorders),depression (including depressive disorders) and violentW0 98/11217CA 02265923 l999-03- l2PCT/JP97/0323963behaviors; providing analgesic effects or other pain reducingeffects; promoting differentiation and growth of embryonicstem cells in lineages other than hematopoietic lineages;hormonal or endocrine activity; in the case of enzymes,correcting deficiencies of the enzyme and treatingdeficiency—related diseases; treatment of hyperproliferativedisorders (such as, for example, psoriasis);immunoglobulin-like activity (such as, for example, theability to bind antigens or complement); and the ability toact as an antigen in a vaccine composition to raise an immuneresponse against such protein or another material or entitywhich is cross—reactive with such protein.CA 02265923 1999-03-l2W0 98/1 1217 PCTIJP97/0323964SEQUENCE LISTINGSequence No.: 1Sequence length: 154Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: FibrosarcomaCell line: HT—1080Clone name: HP00658Sequence descriptionMet Lys Val Ser Ala Ala Ala Leu Ala Val Ile Leu Ile Ala Thr Ala1 5 10 15Leu Cys Ala Pro Ala Ser Ala Ser Pro Tyr Ser Ser Asp Thr Thr Pro20 25 30Cys Cys Phe Ala Tyr Ile Ala Arg Pro Leu Pro Arg Ala His Ile Lys35 40 45Glu Tyr Phe Tyr Thr Ser Gly Lys Cys Ser Asn Pro Ala Val Val His50 S5 60Arg Ser Arg Met Pro Lys Arg Glu Gly Gln Gln Val Trp Gln Asp Phe65 70 75 80Leu Tyr Asp Ser Arg Leu Asn Lys Gly Lys Leu Cys His Pro Lys Glu85 90 95Pro Pro Ser Val Cys Gln Pro Arg Glu Glu Met Gly Ser Gly Val His100 105 110Gln Leu Phe Gly Asp Glu Leu Gly Trp Arg Val Leu Glu Pro Glu Leu .‘.<..n........._........«..-._.a.....-...au.—¢.»«.........~.-CA 02265923 1999-03-l2W0 98/ 11217 PCT/JP97/0323965115 120 125Thr Gln Ile Cys Leu Phe Leu Leu Ala Leu Val Leu Ala Trp Glu Ala130 135 140Ser Pro His Tyr Pro Thr Pro Pro Ala Pro145 150Sequence No.: 2Sequence length: 315Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KBClone name: HP00714Sequence descriptionMet Asp Leu Arg Gln Phe Leu Met Cys Leu Ser Leu Cys Thr Ala Phe1 5 10 15Ala Leu Ser Lys Pro Thr Glu Lys Lys Asp Arg Val His His Glu Pro20 25 30Gln Leu Ser Asp Lys Val His Asn Asp Ala Gln Ser Phe Asp Tyr Asp35 40 45His Asp Ala Phe Leu Gly Ala Glu Glu Ala Lys Thr Phe Asp Gln Leu50 55 60Thr Pro Glu Glu Ser Lys Glu Arg Leu Gly Lys Ile Val Ser Lys Ile65 70 75 80Asp Gly Asp Lys Asp Gly Phe Val Thr Val Asp Glu Leu Lys Asp TrpCA 02265923 1999-03-l2W0 98111217 PCT/JP97/032396685 90 95Ile Lys Phe Ala Gln Lys Arg Trp Ile Tyr Glu Asp Val Glu Arg Gln100 105 110Trp Lys Gly His Asp Leu Asn Glu Asp Gly Leu Val Ser Trp Glu Glu115 120 125Tyr Lys Asn Ala Thr Tyr Gly Tyr Val Leu Asp Asp Pro Asp Pro Asp130 135 140Asp Gly Phe Asn Tyr Lys Gln Met Met Val Arg Asp Glu Arg Arg Phe145 150 155 160Lys Met Ala Asp Lys Asp Gly Asp Leu Ile Ala Thr Lys Glu Glu Phe165 170 175Thr Ala Phe Leu His Pro Glu Glu Tyr Asp Tyr Met Lys Asp Ile Val180 185 190Val Gln Glu Thr Met Glu Asp Ile Asp Lys Asn Ala Asp Gly Phe Ile195 200 205Asp Leu Glu Glu Tyr Ile Gly Asp Met Tyr Ser His Asp Gly Asn Thr210 215 220Asp Glu Pro Glu Trp Val Lys Thr Glu Arg Glu Gln Phe Val Glu Phe225 230 235 240Arg Asp Lys Asn Arg Asp Gly Lys Met Asp Lys Glu Glu Thr Lys Asp245 250 255Trp Ile Leu Pro Ser Asp Tyr Asp His Ala Glu Ala Glu Ala Arg His260 265 270Leu Val Tyr Glu Ser Asp Gln Asn Lys Asp Gly Lys Leu Thr Lys Glu275 280 285Glu Ile Val Asp Lys Tyr Asp Leu Phe Val Gly Ser Gln Ala Thr Asp290 295 300Phe Gly Glu Ala Leu Val Arg His Asp Glu Phe305 310 315CA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97I0323967Sequence No.: 3Sequence length: 158Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name: HP00876Sequence descriptionMet Ala Ser Arg Ser Met Arg Leu Leu Leu Leu Leu Ser Cys Leu Ala1 5 10 15Lys Thr Gly Val Leu Gly Asp Ile Ile Met Arg Pro Ser Cys Ala Pro20 25 30Gly Trp Phe Tyr His Lys Ser Asn Cys Tyr Gly Tyr Phe Arg Lys Leu35 40 45Arg Asn Trp Ser Asp Ala Glu Leu Glu Cys Gln Ser Tyr Gly Asn Gly50 55 60Ala His Leu Ala Ser Ile Leu Ser Leu Lys Glu Ala Ser Thr Ile Ala65 70 75 80Glu Tyr Ile Ser Gly Tyr Gln Arg Ser Gln Pro Ile Trp Ile Gly Leu85 90 95His Asp Pro Gln Lys Arg Gln Gln Trp Gln Trp Ile Asp Gly Ala Met100 105 110Tyr Leu Tyr Arg Ser Trp Ser Gly Lys Ser Met Gly Gly Asn Lys His115 120 125Cys Ala Glu Met Ser Ser Asn Asn Asn Phe Leu Thr Trp Ser Ser Asn, ._..,.................»........«.....m«...n... mm _ ...‘ 4~ . . 4 .,... ., 4V4—A):v4I1‘Auvo0 ..W0 98/11217130CA13502265923 1999-03-1268140PCT/JP97l03239Glu Cys Asn Lys Arg Gln His Phe Leu Cys Lys Tyr Arg Pro145Sequence No.: 4150Sequence length: 376Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:155Organism species: Homo sapiensCell kind:Clone name:LiverHP01134Sequence descriptionMet Val Trp1Ala Val ProIle Val Ala35Ala Cys His50Gln Ile Val65Pro Thr ProGln Gly ValLys V315Ile Asp20Gly SerAla TyrVal MetGly Ile85Pro Lys100AlaAspAsnGlnMet70ValAspValProGlyIle55TyrIleTyrPheGluTrp40IleAspAsnThrLeu Ser Val Ala10Asp Gly Gly Lys25Tyr Asn Tyr ArgHis Arg Asn Gly60Asp Ile Ala Tyr75ProArg Asn Gly90Gly Glu Asp Val105LeuHisHis45IleSerThrThrIle15Trp Val30Gln AlaPro AspGlu AspAsp Val95Pro Gln110GlyValAspGluAsn80TyrAsnCA 02265923 1999-03-l2W0 98/ 1 1217 PCT/JP97/0323969Phe Leu Ala Val Leu Arg Gly Asp Ala Glu Ala Val Lys Gly Ile Gly115 120 125Ser Gly Lys Val Leu Lys Ser Gly Pro Gln Asp His Val Phe Ile Tyr130 135 140Phe Thr Asp His Gly Ser Thr Gly Ile Leu Val Phe Pro Asn Glu Asp145 150 155 160Leu His Val Lys Asp Leu Asn Glu Thr Ile His Tyr Met Tyr Lys His165 170 175Lys Met Tyr Arg Lys Met Val Phe Tyr Ile Glu Ala Cys Glu Ser Gly180 185 190Ser Met Met Asn His Leu Pro Asp Asn Ile Asn Val Tyr Ala Thr Thr195 200 205Ala Ala Asn Pro Arg Glu Ser Ser Tyr Ala Cys Tyr Tyr Asp Glu Lys210 215 220Arg Ser Thr Tyr Leu Gly Asp Trp Tyr Ser Val Asn Trp Met Glu Asp225 230 235 240Ser Asp Val Glu Asp Leu Thr Lys Glu Thr Leu His Lys Gln Tyr His245 250 255Leu Val Lys Ser His Thr Asn Thr Ser His Val Met Gln Tyr Gly Asn260 265 270Lys Thr Ile Ser Thr Met Lys Val Met Gln Phe Gln Gly Met Lys Arg275 280 285Lys Ala Ser Ser Pro Val Pro Leu Pro Pro Val Thr His Leu Asp Leu290 295 300Thr Pro Ser Pro Asp Val Pro Leu Thr Ile Met Lys Arg Lys Leu Met305 310 315 320Asn Thr Asn Asp Leu Glu Glu Ser Arg Gln Leu Thr Glu Glu Ile Gln325 330 335Arg His Leu Asp Tyr Glu Tyr Ala Leu Arg His Leu Tyr Val Leu ValCAW0 98l1l2l7340 302265923 1999-03-l2PCT/JP97/032397045 350Asn Leu Cys Glu Lys Pro Tyr Pro Leu His Arg Ile Lys Leu Ser Met355 360Asp His Val Cys Leu Gly His Tyr370 375Sequence No.2 5Sequence length: 173Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KBClone name: HP10029Sequence descriptionMet Ala Ala Pro Ser Gly Gly Trp1 5Ala Ala Leu Leu Leu Gly Ala Val20Ser Glu Pro Thr Thr Val Ala Phe_35 40His Ser Phe Ser His Asn Val Gly P50 55Phe Thr Tyr Ala Ser Gln Gly65 70Leu Gly Thr Ser Glu Asp His GlnAsn GlyAla LeuAsp ValHis Phe365Val Arg Ala Ser Leu Trp10 15Arg Pro Ala Glu Ala Val25 30Arg Pro Gly Gly Val Val45ro Gly Asp Lys Tyr Thr Cys Met60Gly Thr Asn Glu Gln Trp Gln Met Ser75 80Thr Cys Thr Ile Trp ArgCA 02265923 1999-03-l2W0 98/1 1217 PCTIJP97/032397185 90 95Pro Gln Gly Lys Ser Tyr Leu Tyr Phe Thr Gln Phe Lys Ala Glu Val100 105 110Arg Gly Ala Glu Ile Glu Tyr Ala Met Ala Tyr Ser Lys Ala Ala Phe115 120 125Glu Arg Glu Ser Asp Val Pro Leu Lys Thr Glu Glu Phe Glu Val Thr130 135 140Lys Thr Ala Val Ala His Arg Pro Gly Ala Phe Lys Ala Glu Leu Ser145 150 155 160Lys Leu Val Ile Val Ala Lys Ala Ser Arg Thr Glu Leu165 170Sequence No.: 6Sequence length: 73Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KBClone name: HPl0189Sequence descriptionMet Gly Val Lys Leu Glu Ile Phe Arg Met Ile Ile Tyr Leu Thr Phe1 5 10 15Pro Val Ala Met Phe Trp Val Ser Asn Gln Ala Glu Trp Phe Glu Asp20 25 30Asp Val Ile Gln Arg Lys Arg Glu Leu Trp Pro Pro Glu Lys Leu Gln.,.,¢ mWm4“_,m.,,,W‘w . l V ...‘...........-........."..._‘..l._ . . . , .. ,...-..-...............a.-.........................._........,.,CA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97/032397235 40 45Glu Ile Glu Glu Phe Lys Glu Arg Leu Arg Lys Arg Arg Glu Glu Lys50 55 60Leu Leu Arg Asp Ala Gln Gln Asn Ser65 70Sequence No.: 7Sequence length: 1172Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiensCell kind: Histiocyte lymphomaCell line: U937Clone name: HP10269Sequence descriptionMet Arg Pro Phe Phe Leu Leu Cys Phe Ala Leu Pro Gly Leu Leu His1 5 10 15Ala Gln Gln Ala Cys Ser Arg Gly Ala Cys Tyr Pro Pro Val Gly Asp20 25 30Leu Leu Val Gly Arg Thr Arg Phe Leu Arg Ala Ser Ser Thr Cys Gly35 40 45Leu Thr Lys Pro Glu Thr Tyr Cys Thr Gln Tyr Gly Glu Trp Gln Met50 55 60Lys Cys Cys Lys Cys Asp Ser Arg Gln Pro His Asn Tyr Tyr Ser His65 70 75 80Arg Val Glu Asn Val Ala Ser Ser Ser Gly Pro Met Arg Trp Trp GlnCA 02265923 1999-03-l2W0 98/11217 PCT/JP97/032397385 90 95Ser Gln Asn Asp Val Asn Pro Val Ser Leu Gln Leu Asp Leu Asp Arg100 105 110Arg Phe Gln Leu Gln Glu Val Met Met Glu Phe Gln Gly Pro Met Pro115 120 125Ala Gly Met Leu Ile Glu Arg Ser Ser Asp Phe Gly Lys Thr Trp Arg130 135 140Val Tyr Gln Tyr Leu Ala Ala Asp Cys Thr Ser Thr Phe Pro Arg Val145 150 155 160Arg Gln Gly Arg Pro Gln Ser Trp Gln Asp Val Arg Cys Gln Ser Leu165 170 175Pro Gln Arg Pro Asn Ala Arg Leu Asn Gly Gly Lys Val Gln Leu Asn180 185 190Leu Met Asp Leu Val Ser Gly Ile Pro Ala Thr Gln Ser Gln Lys Ile195 200 205Gln Glu Val Gly Glu Ile Thr Asn Leu Arg Val Asn Phe Thr Arg Leu210 215 220Ala Pro Val Pro Gln Arg Gly Tyr His Pro Pro Ser Ala Tyr Tyr Ala225 230 235 240Val Ser Gln Leu Arg Leu Gln Gly Ser Cys Phe Cys His Gly His Ala245 250 255Asp Arg Cys Ala Pro Lys Pro Gly Ala Ser Ala Gly Pro Ser Thr Ala260 265 270Val Gln Val His Asp Val Cys Val Cys Gln His Asn Thr Ala Gly Pro275 280 285Asn Cys Glu Arg Cys Ala Pro Phe Tyr Asn Asn Arg Pro Trp Arg Pro290 295 300Ala Glu Gly Gln Asp Ala His Glu Cys Gln Arg Cys Asp Cys Asn Gly305 310 315 320 CA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97/0323974His Ser Glu Thr Cys His Phe Asp Pro Ala Val Phe Ala Ala Ser Gln325 330 335Gly Ala Tyr Gly Gly Val Cys Asp Asn Cys Arg Asp His Thr Glu Gly340 345 350Lys Asn Cys Glu Arg Cys Gln Leu His Tyr Phe Arg Asn Arg Arg Pro355 360 365Gly Ala Ser Ile Gln Glu Thr Cys Ile Ser Cys Glu Cys Asp Pro Asp370 375 380Gly Ala Val Pro Gly Ala Pro Cys Asp Pro Val Thr Gly Gln Cys Val385 390 395 400Cys Lys Glu His Val Gln Gly Glu Arg Cys Asp Leu Cys Lys Pro Gly405 410 415Phe Thr Gly Leu Thr Tyr Ala Asn Pro Gln Gly Cys His Arg Cys Asp420 425 430Cys Asn Ile Leu Gly Ser Arg Arg Asp Met Pro Cys Asp Glu Glu Ser435 440 445Gly Arg Cys Leu Cys Leu Pro Asn Val Val Gly Pro Lys Cys Asp Gln450 455 460Cys Ala Pro Tyr His Trp Lys Leu Ala Ser Gly Gln Gly Cys Glu Pro#65 470 475 480Cys Ala Cys Asp Pro His Asn Ser Leu Ser Pro Gln Cys Asn Gln Phe485 490 495Thr Gly Gln Cys Pro Cys Arg Glu Gly Phe Gly Gly Leu Met Cys Ser500 505 510Ala Ala Ala Ile Arg Gln Cys Pro Asp Arg Thr Tyr Gly Asp Val Ala515 520 525Thr Gly Cys Arg Ala Cys Asp Cys Asp Phe Arg Gly Thr Glu Gly Pro530 535 540Gly Cys Asp Lys Ala Ser Gly Arg Cys Leu Cys Arg Pro Gly Leu ThrCA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97l0323975545 550 555 560Gly Pro Arg Cys Asp Gln Cys Gln Arg Gly Tyr Cys Asn Arg Tyr Pro565 570 575Val Cys Val Ala Cys His Pro Cys Phe Gln Thr Tyr Asp Ala Asp Leu580 585 590Arg Glu Gln Ala Leu Arg Phe Gly Arg Leu Arg Asn Ala Thr Ala Ser595 600 605Leu Trp Ser Gly Pro Gly Leu Glu Asp Arg Gly Leu Ala Ser Arg Ile610 615 620Leu Asp Ala Lys Ser Lys Ile Glu Gln Ile Arg Ala Val Leu Ser Ser625 630 635 640Pro Ala Val Thr Glu Gln Glu Val Ala Gln Val Ala Ser Ala Ile Leu645 650 655Ser Leu Arg Arg Thr Leu Gln Gly Leu Gln Leu Asp Leu Pro Leu Glu.660 665 670Glu Glu Thr Leu Ser Leu Pro Arg Asp Leu Glu Ser Leu Asp Arg Ser675 680 685Phe Asn Gly Leu Leu Thr Met Tyr Gln Arg Lys Arg Glu Gln Phe Glu690 695 700Lys Ile Ser Ser Ala Asp Pro Ser Gly Ala Phe Arg Met Leu Ser Thr705 710 715 720Ala Tyr Glu Gln Ser Ala Gln Ala Ala Gln Gln Val Ser Asp Ser Ser725 730 735Arg Leu Leu Asp Gln Leu Arg Asp Ser Arg Arg Glu Ala Glu Arg Leu740 745 750Val Arg Gln Ala Gly Gly Gly Gly Gly Thr Gly Ser Pro Lys Leu Val755 760 765Ala Leu Arg Leu Glu Met Ser Ser Leu Pro Asp Leu Thr Pro Thr Phe770 775 780CA 02265923 1999-03-l2W0 98/11217 PCT/JP97l0323976Asn Lys Leu Cys Gly Asn Ser Arg Gln Met Ala Cys Thr Pro Ile Ser785 790 795 800Cys Pro Gly Glu Leu Cys Pro Gln Asp Asn Gly Thr Ala Cys Gly Ser805 810 815Arg Cys Arg Gly Val Leu Pro Arg Ala Gly Gly Ala Phe Leu Met Ala820 825 830Gly Gln Val Ala Glu Gln Leu Arg Gly Phe Asn Ala Gln Leu Gln Arg835 840 845Thr Arg Gln Met Ile Arg Ala Ala Glu Glu Ser Ala Ser Gln Ile Gln850 855 860Ser Ser Ala Gln Arg Leu Glu Thr Gln Val Ser Ala Ser Arg Ser Gln865 870 875 880Met Glu Glu Asp Val Arg Arg Thr Arg Leu Leu Ile Gln Gln Val Arg885 890 895Asp Phe Leu Thr Asp Pro Asp Thr Asp Ala Ala Thr Ile Gln Glu Val900 905 910Ser Glu Ala Val Leu Ala Leu Trp Leu Pro Thr Asp Ser Ala Thr Val915 920 925Leu Gln Lys Met Asn Glu Ile Gln Ala Ile Ala Ala Arg Leu Pro Asn930 935 940Val Asp Leu Val Leu Ser Gln Thr Lys Gln Asp Ile Ala Arg Ala Arg945 950 955 960Arg Leu Gln Ala Glu Ala Glu Glu Ala Arg Ser Arg Ala His Ala Val965 970 975Glu Gly Gln Val Glu Asp Val Val Gly Asn Leu Arg Gln Gly Thr Val980 985 990Ala Leu Gln Glu Ala Gln Asp Thr Met Gln Gly Thr Ser Arg Ser Leu995 1000 1005Arg Leu Ile Gln Asp Arg Val Ala Glu Val Gln Gln Val Leu Arg ProCA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97/03239771010 1015 1020Ala Glu Lys Leu Val Thr Ser Met Thr Lys Gln Leu Gly Asp Phe Trp1025 1030 1035 1040Thr Arg Met Glu Glu Leu Arg His Gln Ala Arg Gln Gln Gly Ala Glu1045 1050 1055Ala Val Gln Ala Gln Gln Leu Ala Glu Gly Ala Ser Glu Gln Ala Leu1060 1065 1070Ser Ala Gln Glu Gly Phe Glu Arg Ile Lys Gln Lys Tyr Ala Glu Leu1075 1080 1085Lys Asp Arg Leu Gly Gln Ser Ser Met Leu Gly Glu Gln Gly Ala Arg1090 1095 1100Ile Gln Ser Val Lys Thr Glu Ala Glu Glu Leu Phe Gly Glu Thr Met1105 1110 1115 1120Glu Met Met Asp Arg Met Lys Asp Met Glu Leu Glu Leu Leu Arg Gly1125 1130 1135Ser Gln Ala Ile Met Leu Arg Ser Ala Asp Leu Thr Gly Leu Glu Lys1140 1145 1150Arg Val Glu Gln Ile Arg Asp His Ile Asn Gly Arg Val Leu Tyr Tyr1155 1160 1165Ala Thr Cys Lys1170Sequence No.: 8Sequence length: 122Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:.. “....V..........:......,.........m...‘....: . ,.CA 02265923 1999-03-l2W0 98/1121778Organism species: Homo sapiensCell kind: Stomach cancerClone name: HP10298Sequence descriptionPCT/JP97/03239Met Gly Leu Leu Leu Leu Val Pro Leu Leu Leu Leu Pro Gly Ser Tyr1 5 10Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Ser Asn Ser Ala20 25 30Gln Asn Leu Gly Asn Gly His Gly Lys Asp Leu Leu Asn Gly35 40 45Leu Val Val Glu Thr Pro Glu Glu Thr Leu Phe Thr Arg Ile50 SS 60Val Gly Pro Gln Ser Leu Gly Ser Glu Ala Leu Ala Ser Pro65 70 75Arg Ala Ala Cys Thr Val Phe Thr Ala Thr Ala Ser Thr Arg85 90Gly Pro Pro Leu Pro His Ser Leu Thr Gly Cys Val Phe Ile100 105 110Phe Val Phe Pro Cys Gly Leu Glu Pro Phe115 120Sequence No.: 9Sequence length: 175Sequence type: Amino acidTopology: LinearSequence kind: ProteinHypothetical: NoOriginal source:Organism species: Homo sapiens15Asn AspVal LysLeu ThrThr Arg80Thr Trp95Glu TrpWO 98/11217CACell kind: Stomach cancerClone name:HP10368Sequence descriptionMet Glu Lys Ile Pro Val Ser Ala1Tyr ThrThr LysGly AspS0Ser Lys65ProCysIle GlnThr ThrMet Phe130Tyr Ser145Leu AspLeuAsp35GlnThrHisLysAsp115ValAsnAsnZ0SerLeuSerSerLeu100LysAspArgMet5ArgArgIleAsnGln85AlaHisProLeuLys165Sequence No.: 10AspProTrpLys70AlaGluLeuSerTyr150LysSequence length: 462ThrLysThr55ProLeuGlnSerLeu135AlaAlaSequence type: Nucleic acidThrLeu40GlnLeuLysPhePro120ThrTyrLeuPheVal25ProThrMetLysVal105AspValGluLys79Leu10LysGlnTyrIleVal90LeuGlyArgProLeu170.................... ..........s..a........¢...:..,.m.....m................ ‘LeuProThrGluIle75PheLeuGlnAlaAla155Leu02265923 1999-03-12LeuGlyLeuGlu60HisAlaAsnTyrAsp140AspLysValAlaSer45AlaHisGluLeuVal125IleThrThrAlaLys30ArgLeuLeuAsnVal110ProThrAlaGluPCT/JP97I03239Leu15LysGlyAspLys95TyrArgGlyLeuLeu175SerAspTrpLysGlu80GluGluIleArgLeu160CAW0 98/112178 0Strandedness: DoubleTopology: LinearSequence kind: cDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: FibrosarcomaCell line: HT-1080Clone name: HP00658Sequence descriptionATGAAGGTCT CCGCGGCAGC CCTCGCTGTC ATCCTCATTGGCATCTGCCT CCCCATATTC CTCGGACACC ACACCCTGCTCCACTGCCCC GTGCCCACAT CAAGGAGTAT TTCTACACCAGCAGTCGTCC ACAGGTCAAG GATGCCAAAG AGAGAGGGACCTGTATGACT CCCGGCTGAA CAAGGGCAAG CTTTGTCACCTGCCAACCCA GAGAAGAAAT GGGTTCGGGA GTACATCAACTGGAGAGTCC TTGAACCTGA ACTTACAGAA ATTTGCCTGTGCTTGGGAGG CTTCCCCTCA CTATCCTACC CCACCCGCTCSequence No.: 11Sequence length: 945Sequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KB02265923 1999-03-l2CTACTGCCCTGCTTTGCCTAGTGGCAAGTGAGCAAGTCTGCGAAAGAACCTCTTTGGAGATTCTGCTTGCCTPCT/JP97/03239CTGCGCTCCT 60CATTGCCCGC 120CTCCAACCCA 180GCAGGATTTC 240GCCAAGTGTG 300TGAGCTAGGA 360TCTTGTCCTA 420462WO 98/11217Clone name:HPOO714Sequence descriptionATGGACCTGCCCCACAGAAAGATGCTCAGATTTGATCAGCGATGGCGACACAAAAGCGCTGACGGCCTCGCCAGATCCTGAAAATGGCAGGACCCTGAGGGATAAGAATGGATGGGAATACGGGATAAGATCAGACTATGAAGGATGGCACAGGCCACAGGACAGTTTCTAGAAGGACCGGTTTTGATTATGACACCAGAAGGACGGGTTGGATTTACGATTTCCTGGGAATGATGGATTACAAGGATGGAGTATGACTACTGATGGTTTCTGATGAGCCACCGTGATGGATCATGCAGAAGCTTACCAAATTTTGGGGASequence No.: 12Sequence length: 474CATATGTGCCTGTGTACATCATTGACCATGATAGAGAGCAAGTGTCACTGTGGGATGTAGAGGGAGTATAAATAACTATAAAAGACCTCATTCATGAAAGATCATTGATCTAAGAATGGGTAGAAGATGGACGGCAGAAGCCGGAGGAGATCGGCCTTAGTASequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name:HP0087681TCCCTGTGCAGAGCCTCAGCGCCTTCTTGGGAAAGGCTTGGATGAGCTCACGACAGTGGAAATGCCACCTCAGATGATGGGCCACCAAGGATAGTAGTACGAAGAGTATAAAGACAGAGCAAGGAAGAGAAGGCACCTGGGTTGACAAGTCGGCATGATG02265923 1999-03-12CAGCLTTTGCTCAGTGACAAGTGCTGAAGAGAAAGATTGTAAGACTGGATAGGGGCATGAACGGCTACGTTTAGAGATGAAGGAGTTCACAGGAAACAATTTGGTGACATGAGAGCAGTTCCAAAGACTGTCTATGAATCATGACTTATTAGTTCPCT/JP97/03239CTTGAGCAAA 60GGTTCACAAT 120AGCAAAGACC 180AAGTAAAATA 240TAAATTTGCA 300CCTCAATGAG 360TTTAGATGAT 420GCGGAGGTTT 480AGCTTTCCTG 540GGAAGATATA 600GTACAGCCAT 660TGTTGAGTTT 720GATCCTTCCC 780AGACCAAAAC 840TGTTGGCAGC 900945W0 98/11217Sequence descriptionATGGCTTCCACTGGGTGATAGAAGCATGCGTCATCATGAGTGCTATGGTT ACTTCAGGAATACGGAAACGGAGTACATAAGAGCCCACCTGTGGCTATCAAAGAGGCAGC AGTGGCAGTGAAGTCCATGGGTGGGAACAATGGAGCAGCA ACGAATGCAASequence No.: 13Sequence length: 1128CAGCTGCTCCTAACCCAGCTGTGCTGAGGAACGGCATCTATCGAGAAGCCAGGATTGATGGGGCACTGTGCTCAAGCGCCAASequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: LiverClone name:HP01134Sequence descriptionATGGTTTGGAGATGATCCTGTATAATTATAATTCCTGACGCCCACTCCAGAAGGACTACAGCAGAAGCAGGTGTTCATTTAAGTAGCTGTAAGATGGAGGGGCACCAGGCAACAGATCGTGAATTGTGATCTGGAGAGGATGAAGGGCATACTTCACTGAATTCCTCAGTCAAGCACTGGAGACGCGTGCTGTGATGATGCAACAGGCCCTGTTACCCCAAGGATCCGGCCCATGGATCT82TTGCTGAGCTGCTCCTGGATTGGTCTGATGCTGAGTTTAACCGATATGGAGCCATGTATCGAGATGAGCTCACTTCCTGTGTGGCCCTGGGTGGTGATCGCATGCCTACCTACGATGACAAATGGCACAGCAAAATTTCCAAAGTCCTGAACTGGAATAC02265923 1999-03-12GCCTGGCCAAGGTTTTACCACCGAGCTCGAAGGAAGCGAGTTGGCCTGCATGTACAGATCCCAATAACAAGCAAGTACCGGCATTGGTGCTGGCAGGTTCAGATCATTCATTGCTTACTCATGTCTATCATTGCTGTGTTAGAGTGGCCCTGGTTTTTCCPCT/JP97/03239AACAGGAGTC 60CAAGTCCAAT 120GTGTCAGTCT 180CACCATAGCA 240CGACCCACAG 300CTGGTCTGGC 360CTTTTTAACT 420ACCA 474CGTTCCTAIA 60AAATGGCTGG 120CCGCAATGGG 180TGAAGACAAT 240GGGAGTCCCG 300GAGAGGCGAT 360CCAGGATCAC 420GAATGAAGAT 480W0 98/11217CTTCATGTAAAAGATGGTGTAACATCAATGTATGATGAGATCGGACGTGGCACACCAACAATGCAGTTTCCACCTTGACCAACACCAATGTACGAGTATGCTTCACAGGAAGGACCTGAATCTACATTGATTTATGCAACAGAGGTCCACAAGATCTGACCCAGCCACGTAGGGTATGAATCACCCCCAGATCTGGAGGACGTTGAGACATAAAATTGTCSequence No.: 14Sequence length: 519CATGAGACCATCAGCCTGTGAGTACTGCTGCCGTACCTGGGGTAAAGAGACCCATGCAGTATACGCAAAGCCCCCTGATGTGGTCCAGGCAGTTTGTACGTGCATGGACCACSequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiens83CATTACATGTTCTGGGTCCAAACCCCAGAGGACTGGTACACTGCACAAGCGGAAACAAAAAGTTCTCCCGCCTCTCACCACTCACGGAGGCTGGTCAACCGTGTGCCTTGCell kind: Epidermoid carcinomaCell line:KBClone name: HP10029Sequence description02265923 1999-03-l2ACAAACACAATGATGAACCAAGTCGTCCTAGCGTCAACTGAGTACCACCTCAATCTCCACTCCCCCTACCTCATGAAAAGAGATCCAGCGTTTGTGAGAAGTCACTACPCT/JP97/03239AATGTACCGA 540CCTGCCGGAT 600CGCCTGTTAC 660GATGGAAGAC 720GGTAAAATCG 780CATGAAAGTG 840TCCAGTCACA 900GAAACTGATG 960GCATCTGGAT 1020GCCGTATCCG 10801128ATGGCGGCGC CCAGCGGAGG GTGGAACGGC GTCCGCGCGA GCTTGTGGGC CGCGCTGCTCCTAGGGGCCG TGGCGCTGAG GCCGGCGGAG GCGGTGTCCG AGCCGACGAC CGTGGCGTTTGACGTGCGGC CCGGCGGCGT CGTGCATTCC TTCTCCCATA ACGTGGGCCC GGGGGACAAATATACGTGTA TGTTCACTTA CGCCTCTCAA GGAGGGACCA ATGAGCAATG GCAGATGAGTCTGGGGACCA GCGAAGACCA CCAGCACTTC ACCTGCACCA TCTGGAGGCC CCAGGGGAAG60120180240300CA 02265923 1999-03-l2W0 98/1121784TCCTATCTGT ACTTCACACA GTTCAAGGCA GAGGTGCGGG GCGCTGAGAT TGAGTACGCCATGGCCTACT CTAAAGCCGC ATTTGAAAGG GAAAGTGATG TCCCTCTGAA AACTGAGGAATTTGAAGTGA CCAAAACAGC AGTGGCTCAC AGGCCCGGGG CATTCAAAGC TGAGCTGTCCAAGCTGGTGA TTGTGGCCAA GGCATCGCGC ACTGAGCTGSequence No.: 15Sequence length: 219Sequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KBClone name: HP10189Sequence descriptionATGGGGGTGA AGCTGGAGAT ATTTCGGATG ATAATCTACC TCACTTTCCC TGTGGCTATGTTCTGGGTTT CCAATCAGGC CGAGTGGTTT GAGGACGATG TCATACAGCG CAAGAGGGAGCTGTGGCCAC CTGAGAAGCT TCAAGAGATA GAGGAATTCA AAGAGAGGTT ACGGAAGCGGCGGGAGGAGA AGCTCCTTCG CGACGCCCAG CAGAACTCCSequence No.: 16Sequence length: 3516Sequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: cDNA to mRNAOriginal source:PCT/JP97/0323936042048051960120180219W0 98/11217CA 02265923 1999-03-l2Organism species: Homo sapiensCell kind: LymphomaCell line:Clone name:U937HP10269Sequence descriptionATGAGACCATTGCTCCCGTGCTCCGAGCTTGAGTGGCAGACGAGTAGAGAGTGAACCCTGATGGAGTTCCAAGACCTGGCCGCCAGGGTCAATGCACGCCCCAGCAACTCTTCACCAGGCGTGTCCCAGCCCCAAGCCTGTGCCAGCACACCCTGGAGACCACTCAGAGAGGTGTGTGTGCACTATTTCCTGTGATCCGGTGCAAGGAGCACCTACGCCAGACATGCCGTAAATGTGACCTCTTCCTCTTGGGCCTGCTACATCTACCTGTGAAATGCTGATGTGGCTTCTCTCTCTGCAAGGGGCCCATGAGTGTACCAGGCCTCAGAGTAAATGGGGGAAAGTCAAAATGGCCCCTGTTCCGTCTGCAGGGCCTCTGCACACTGCCGGCGGCGGAGGGCATGTCACTTACAATTGCCGGGAACCGGCGATGGGGCAGTATGTGCAGGGACCCGCAGGGGTGACGAGGAAGTGTGCTCCvan’ .‘..........a..............»...a«m..r..............u........ GTGTTTTGCCTCCACCTGTTTGGACTGACCCAAGTGTGACATCCTCCGGCGCTGGACCTGGCCTGCCGGCGTACCTGGCTCTGGCAGGATGAAGGTCCAAAATTCAAGAGGCCCCAAAGGGGGGAGCTGCAGGCCCCTCCCCCAAATTGTCCAGGACGCCTGACCCCGCTGGACCACACCCCCGGGAGCTGCCAGGGGCTAGAGCGCTGTCTGCCACCGCGAGTGGGCGCCTACCACTGG85CTGCCTGGCCGGGGACCTGCAAGCCTGAGATCCAGGCAGCCCCATGCGCTGACAGGAGATATGCTGATTGGCCGACTGCAGTTCGGTGCCCTTAACCTTAGTGGGGGAGAGGCTACCACCTTCTGTCACGACCGCTGTGCGAGCGCTGTGCATGAATGCCGTGTTTGCCGGAAGGCAAGATCCATTCAGGCCCTGTGACCGACCTATGCATGTGACTGCATGCCTTTGTCAAGCTGGCCA TCCTGCATGCTTGTTGGGAGCCTACTGCACCTCACAACTAGGTGGCAGTCTCCAGCTTCAAGCGCTCCTCCCTCCACCTTAGTCCCTGCCTGGATTTAGTTCACAAACTTCTCCCAGCGCGCCATGCTGAAGGTCCACGACACCCTTCTAAAAGGTGCGACCAGCCAGGGACTGTGAGCGAGACCTGCATCAGTGACCGGAGCCGGGCTTACATCCTGGGTGCCCAACGTGTGGCCAGGGPCT/JP97/03239CCAACAAGCC 60GACCCGGTTT 120CCAGTATGGC 180CTACAGTCAC 240CCAGAATGAT 300AGAAGTCATG 360AGACTTCGGT 420CCCTCGGGTC 480TCAGAGGCCT 540GTCTGGGATT 600GAGAGTCAAT 660CTACTATGCT 720TCGCTGCGCA 780TGTCTGTGTC 840CAACAACCGG 900CTGCAATGGG 960GGCATATGGA 1020GTGTCAGCTG 1080CTCCTGCGAG 1140GCAGTGTGTG 1200CACTGGACTC 1260GTCCCGGAGG 1320GGTGGGTCCC 1380CTGTGAACCG 1440W0 98/11217TGTGCCTGCGCCCTGTCGGGGACCGGACCTACAGAGGGCCGGGCCCCGCTTGCCACCCTTAGACTCCGCAGCCTCCCGGACCCGCAGTCAACTCTCCAGGGACCTGGAGAGAGCAGTTTGGCCTACGAGCCAGCTCAGGGGGCACCGGCAACACCCACCTTGCCCTGGTGGTCCTTCCCAGGCTTCAATGTCACAGATTCATGGAGGAAGGACCCCGACACTGCCCACAGAGGCTCCCCACGGTTGCAGGGAAGATGTGGATGCAAGGCAGTACTGCGGCACACGGATGGACCCGCACAAAAGGCTTTGGATGGAGACGTCGGGCTGCGAGTGACCAGTGGCTTCCAGACATGCCACCGCTCCTAGATGCCAGAGCAGGAGCCTGCAGCTGTCTTGACAGAAAAAATAAGAGTCAGCCCAACAGCCGGAGGCCCCAAGCTTCAACAAGCTAGCTATGTCCGGGCCGGTGGCCCAGCTCCAAATCCAGTGCATGTCAGACGCTGATGCAGCACTCAGCTACACGTGGACTTCTGAGGCTGATTGGGAACCTCCAGCCGCTCCAGCAGAAAAAGGAGCTCCGCACTCCCTCAGCTGGCCTGATGGGCCACAGGACAAGGCATCACCAGCGAGGCCTATGATGCGCAGCCTGTGGAAAGAGTAAGGGTGGCTCAGGGATCTGCCCAAGCTTCAATCAGTGCTGATGGCTGCTCAGAGAGGCAGAGTGTGGCCCTGCTGTGGCAACCCAAGACAATGGCCTTCTTGGCGGACCAGGCCAGCGCTTGCACACGGCTCCACTATCCAGTGTTCTGCAGGGTGCTGTCCGGAAGCCAGGGCGGCAGGGGCCTTCGGCTTGCTGGTGACACCACCAAGCC86CCACAGTGCATGCAGCGCTGTGCCGAGCCTGGCCGCTGCCTACTGCAATCGACCTCCGGGTCAGGGCCTGATTGAGCAGAGTGGCCAGTGCTGGAGGAGGGGTCTCCTTACCTTCAGGAGCAGGTCTCCGAGGCTGGTGCAGGCTGGAGATCCAGGCAGAGGCACAGCCTATGGCGGGGCCAGATGATTAGAGACCCAGGCTAATCCAGCGAGGTCAGCGAAGATGAATGCAGACCAAGCAGCCGAGCCCACAGTGGCACATCCAGGACAAGCATGACCACGGCAGCAGG02265923 1999-03-l2ACCAGTTCACCAGCCATCCGGTGACTGTGATCTGCCGCCCGCTACCCGGTAGCAGGCCCTGGCTGGAGGATCCGAGCAGTCCATCCTCTCAGACGTTGTCCTATGTATCACCTTCCGGATACAGCTCGCGGGCAGGCGGGTGTCTTCGTTTGGCTTGCACGTGGCTCCCGAGGTGGCTGAGGGCAGCCGATGAGCGCCAGAGGTCCGGGAAGGCCGTGCTAGATCCAGGCAGGACATTGCATGCAGTGGATGCAGGAAGCGGGTTGCTGAAGCAGCTGGGGGGCAGAGGCPCTIJP97/03239AGGGCAGTGC 1500CCAGTGTCCA 1560TTTCCGGGGA 1620TGGCTTGACC 1680GTGCGTGGCC 1740GCGCTTTGGT 1800CCGTGGCCTG 1860TCTCAGCAGC 1920CCTCAGGCGA 1980CCTTCCGAGA 2040GAGGAAGAGG 2100GCTGAGCACA 2160CLTTTTGGAC 2220AGGAGGAGGA 2280GCCTGACCTG 2840CCCAATATCA 2400CTGCAGGGGT 2460GCAGCTGCGG 2520GGAATCTGCC 2580CCGCTCCCAG 2640CTTCCTAACA 2700GGCCCTGTGG 2760CATTGCAGCC 2820GCGTGCCCGC 2880GGGCCAGGTG 2940TCAGGACACC 3000GGTTCAGCAG 3060TGACTTCTGG 3120AGTCCAGGCC 3180W0 98/11217CAGCAGCTTG CGGAAGGTGCCA 02265923 1999-03-l2PCT/JP97/0323987CAGCGAGCAG GCATTGAGTG CCCAAGAGGG ATTTGAGAGAATAAAACAAA AGTATGCTGA GTTGAAGGAC CGGTTGGGTC AGAGTTCCAT GCTGGGTGAGCAGGGTGCCC GGATCCAGAGTGTGAAGACA GAGGCAGAGG AGCTGTTTGG GGAGACCATGGAGATGATGG ACAGGATGAA AGACATGGAG TTGGAGCTGC TGCGGGGCAG CCAGGCCATCATGCTGCGCT CAGCGGACCTATCAATGGGC GCGTGCTCTASequence No.: 17Sequence length: 366GACAGGACTG GAGAAGCGTG TGGAGCAGAT CCGTGACCACCTATGCCACC TGCAAGSequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: cDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name: HP10298Sequence descriptionATGGGCCTGT TGCTCCTGGTTACAACGGCT TCTACTACTCAAAGACCTCC TTAATGGAGTCGCATCCTAA CTGTGGGCCCAGAGCCGCTT GTACGGTGTTCCGCATTCCC TCACTGGCTGCCATTTSequence No.: 18Sequence length: 525CCCATTGCTC CTGCTGCCCG GCTCCTACGG ACTGCCCTTCCAACAGCGCC AACGACCAGA ACCTAGGCAA CGGTCATGGCGAAGCTGGTG GTGGAGACAC CCGAGGAGAC CCTGTTCACCCCAGAGCCTG GGGTCCGAAG CTTTGGCTTC CCCGACCCGCTACTGCTACC GCCAGCACTA GGACCTGGGG CCCTCCCCTGTGTATTTATT GAGTGGTTCG TTTTCCCTTG TGGGTTGGAGSequence type: Nucleic acid «..:.......r............‘ ._ ... NU v........:..-...o.......r..._.. .32403300336034203480351660120180240300360366W0 98/11217Strandedness:DoubleTopology: LinearCASequence kind: CDNA to mRNAoriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name:HP10368Sequence descriptionATGGAGAAAAAGAGATACCACCCCAGACCCGCTCTATATATGCCCACACAGCAGAGCAGTGATGGCCAGTATCACTGGAACTTGACAACATTCCAGTGTCCAGTCAAACCTCTCCAGAGGAATCCAAGACGTCAAGCTTTTTGTCCTCCTATGTCCCCAGGATATTCAAATGAAGAAAGCSequence No.: 19Sequence length: 1296AGCATTCTTGTGGAGCCAAATTGGGGTGACAAGCAACAAAAAAGAAAGTGCAATCTGGTTGATTATGTTTCCGTCTCTATTCTCAAGTTGSequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: FibrosarcomaCell line:Clone name:HT—108OHP0065888CTCCTTGTGGAAGGACACAACAACTCATCTCCCTTGATGATTTGCTGAAATATGAAACAAGTTGACCCATGCTTACGAAC02265923 1999-03-12PCT/JP97I03239CCCTCTCCTA CACTCTGGCCAGGACTCTCG ACCCAAACTGGGACTCAGAC ATATGAAGAATTATTCATCA CTTGGATGAGATAAAGAAAT CCAGAAATTGCTGACAAACA CCTTTCTCCTCTCTGACAGT TAGAGCCGATCTGCAGATAC AGCTCTGTTGCTGAAGACTG AATTG60120180240300360420480525WO 98/11217CASequence characteristics:89Code representing characteristics: CDSExistence site:56.. 520Characterization method: ESequence description02265923 1999-03-l2CCTGCAGAGG ATCAAGACAG CACGTGGACC TCGCACAGCCGTCLys ValTGC GCTCys AlaTGC TTTCys Phe35TAT TTCTyr Phe50TCA AGGSer ArgTAT GACTyr AspCCA AGTPro Serm.m...-....«........ . TCCSerCCTPro20GCCAlaTACTyrATGMetTCCSerGTGVal100GCGAlaGCAAlaTACTyrACCThrCCAProCGGArg85TGCCysGCAAlaTCTSerATTIleAGTSerAAGLys70CTGLeuCAAGlnGCCAlaGCCAlaGCCAlaGGCGly55ABAArgAACAsnCCCProCTCLeuTCCSerCGCArg40AAGLysGAGGluAAGLysAGAArgGCTAlaCCAPro25CCAProTGCCysGGAGlyGGCGlyGAAGlu105GTCVal10TATTyrCTGLeuTCCSerCAGGlnAAGLys90GAAGluATCIleTCCSerCCCProAACAsnCAAGln75CTTLeuATGMetCTCLeuTCGSerCGTArgCCAPro60GTCValTGTCysGGTGlyTCTCCCACAG GTACC ATGATTIleGACAspGCCAla45GCAAlaTGGTrpCACHisTCGSerGCTAlaACCThr30CACHisGTCValGlnCCGProGGAGly110ACTThr15ACAThrATCIleGTCValGATAspLys95GTAValPCT/JP97/03239GCCAlaCCCProAAGLysCACHisTTCPhe80GAAGluCATHisMetCTCLeuTGCCysGAGGluAGGArg65CTGLeuCCGProGln.‘...m.................—m..........,....~.....‘. . ,.‘.58106154202250298346394W0 98/11217CTC TTTLeu Phe115CAA ATTGln Ile130CCT CACPro HisTTCTACCACATGTAATCCCAACCAGCCTGGCGTGGTAGCGAACCCGGGAGACAGAGCGAGCGTGGTGGCCAACCCAGGAGACAAAGTGAGGAGCTTCTGACTTGGCTTTGGGGGAGGAACCAAACATGAAGGA GATGly AspTGC CTGCys Leu PheTAT CCTTyr ProGAGGluTTTLeuCTGLeuCAGly120CTT135ACCThr150CAGCAGCAGTGCACTTTGGGCCAACATGATGGCGCCTGTAGCGGAGCTTGACTCCGTCTCCACGCCTGTAGTGGAGGCTGACTCCGTCACGGCGCTGCTTCCAGGGCTCTGCTGCACTCTAAATCGGCTTSequence No.: 20Sequence length: 3311CCA CCCProProTACAAAAACCAGGCCAAGGTGAAACCCCATGTCCCAGCTACAGTGAGCCGAAAAAAAAAAATCCCAGCTACAGTGAGCTGAACAACAACATGTCAAAAGGGTGACGAGGATAAGCTTCCGACCATTAAAGSequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: cDNA to mRNA90Trp Arg Val Leu GluGCT CTT GTC CTA GCTLeu Ala Leu Val Leu Ala140Ala ProTTCCCCAGGCGGGTGGATCACTCTACTAAACTCGGGAGGCAGATCGCGCCAAAAAAAAAACTCGGGAGGCAGATTGTGCCACAAAAAGCTAAGTCTCTAGAGGAAGTCAGCCGTCTCAACTTCTCAATGC02265923 1999-03-12125GCT CCT TGAAGGGCCC AGATGGACGTGGTCTTGAGGTCAAATACAAAAATGAGGCAGGAACTGCACTCCAAATACAAAATAAGGCAGGAACTTCACTCCTCCCCAACTAGTTCTGAGCTCATGCCTCTACCCTCACAGGAACGATPCT/JP97l03239CTA GGA TGG AGA GTC CTT GAA CCT GAA CTT ACAPro Glu Leu ThrTGG GAG GCT TCCTrp Glu Ala Ser145GGCTCACGCCGGAGTTCGAGATTAGCCGGGGAATGGCGTGAGCCTGGGCOATTAGCCGGGAAATTGTTTGAGCCTGGGTGAAGCCTAGAACTGGCTTTGCGAGGCAAGGAAGCTTACTGG4424905305906507107708308900950101010701130119012501296CA 02265923 1999-03-l2W0 98/1121791Original source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line:Clone name :KBHP007l4Sequence characteristics :Code representing characteristics: CDSExistence site:57..1004Characterization method: ESequence descriptionGAGCGGCGGC CACGGCATCC TGTGCTGTGG GGGCTACGAGGACAspTTGLeuCTCLeuGATAsp50CCAProCTGLeuAGCSerAGTSer35GCCAlaGAAGluGACCGAArgLys20GACAspTTCPheGAGGluAAGCAGGlnCCCProAAGLysTTGLeuAGCSerGACTTTPheACAThrGTTValGGTGlyAAGLy s70. A> ._..............«......................4»W.........-A. CTTLeuGAAGluCACHisGCTAla55GAAGluTTTATGMetLysAATAsn40GAAGluAGGArgGTCTGCCysAAGLy s25GATAspGAAGluCTTLeuACTCTGLeu1 0GACAspGCTAlaGCAAlaGGAGlyGTGTCCSerCGTArgCAGGlnAAGLysAAGLys75GATCTGLeuGTAValAGTSerACCThr60ATTIleGAGPCT/JP97/03239GAAAGATCTA ATTATC ATGTGCCysCATHisTTTPhe1» 5TTTPheGTAValCTCACAThrCATHi s30GATAspGATAspAGTSerGCCAla15GAGGluTATTyrCAGGlnLysGACTTTPheCCTProGACAspCTGLeuATAIle80TGG‘ ...‘.—,i‘ ,.............u............... .MetGCCAlaCAGGlnCATHisACAThr6 5GATAspATT159107155203251299347CA 02265923 1999-03-l2W0 98/11217 PCT/JP97/0323992Gly Asp Lys Asp Gly Phe Val Thr Val Asp Glu Leu Lys Asp Trp Ile85 90 95AAA TTT GCA CAA AAG CGC TGG ATT TAC GAG GAT GTA GAG CGA CAG TGG 395Lys Phe Ala Gln Lys Arg Trp Ile Tyr Glu Asp Val Glu Arg Gln Trp100 105 110AAG GGG CAT GAC CTC AAT GAG GAC GGC CTC GTT TCC TGG GAG GAG TAT 443Lys Gly His Asp Leu Asn Glu Asp Gly Leu Val Ser Trp Glu Glu Tyr115 120 125AAA AAT GCC ACC TAC GGC TAC GTT TTA GAT GAT CCA GAT CCT GAT GAT 491Lys Asn Ala Thr Tyr Gly Tyr Val Leu Asp Asp Pro Asp Pro Asp Asp130 135 140 145GGA TTT AAC TAT AAA CAG ATG ATG GTT AGA GAT GAG CGG AGG TTT AAA 539Gly Phe Asn Tyr Lys Gln Met Met Val Arg Asp Glu Arg Arg Phe Lys150 155 160ATG GCA GAC AAG GAT GGA GAC CTC ATT GCC ACC AAG GAG GAG TTC ACA 587Met Ala Asp Lys Asp Gly Asp Leu Ile Ala Thr Lys Glu Glu Phe Thr165 170 175GCT TTC CTG CAC CCT GAG GAG TAT GAC TAC ATG AAA GAT ATA GTA GTA 635Ala Phe Leu His Pro Glu Glu Tyr Asp Tyr Met Lys Asp Ile Val Val180 185 190CAG GAA ACA ATG GAA GAT ATA GAT AAG AAT GCT GAT GGT TTC ATT GAT 683Gln Glu Thr Met Glu Asp Ile Asp Lys Asn Ala Asp Gly Phe Ile Asp195 200 205CTA GAA GAG TAT ATT GGT GAC ATG TAC AGC CAT GAT GGG AAT ACT GAT 731Leu Glu Glu Tyr Ile Gly Asp Met Tyr Ser His Asp Gly Asn Thr Asp210 215 220 225GAG CCA GAA TGG GTA AAG ACA GAG CGA GAG CAG TTT GTT GAG TTT CGG 779Glu Pro Glu Trp Val Lys Thr Glu Arg Glu Gln Phe Val Glu Phe Arg230 235 '24OWO 98111217GAT AAG AACAsp LysATC CTT CCCIle Leu Pro260GAAGTC TATVal Tyr Glu275ATGGTT GACIle Val Asp290GGGGAG GCCGly Glu AlaCATTTCCTCAACTGAGACTGCCCCATTCCTAATTAGTACAATTTTTGTATCATGTAGACATCACTTAACTAAAAAATATAAAGTCCAACACAACTGAACCCAAATTGATTCAGCTGTGGTTCTCTTTGCATCGGGGCATAAsnCGTArg245TCASerTCASerAAGLysTTALeuGATAspGACAspGACAspTATTyrGTAVal310AAAGTAATTTTTACTACAAACCTCCTCTCTCTTGTGTTTGTTTTCTCTGGAACATTAGCTAATTTTGTAATGCTCCACAATTTCATAGGTTGCCATTACCTTCTTCTTTTGGGAAGAGTTGAGCTATAGACATTTTTTTTGGGGlyTATTyrCAAGlnGACAsp295CGGArgCAAAGLysGATAspAACAsn280TTALeuCATHisATGMetCATHis265AAGLysTTTPheGATAspATTTTTACAGCTTTTTAAGAGAGGGACTGGTAGATTTACATTGGGAGTATCTTTACTCTTGCCTGAGATCTTTATATTTAAGTAGGGGCCTGGGCAAGGATCCCCCTGTAAGGGCCAGTGTAGAAACAGCCTGGGTGTGCGACAsp250GCAAlaGATAspGTTValGAGGlu93AAGLysGAGGluGGCGlyGGCGlyTTCPhe315GAAGluGCAAlaAAGLysAGCSer30002265923 1999-03-l2GAGGluGAAGluCTTLeu285CAGGlnACC GACThr Lys Asp255GCC AGG CACAla Arg His270ACC AAG GAGThr Lys GluGCC ACA GATAla Thr AspTGAGCTACGG AGGAACCCTCTTCTGGTTTCATGAAAAGGAGGGAAGCCGCTTTGTATTAGATATGAAGGTCTCAACCCCAATAAGAAATGAGAGAGAACACATATTACAAAGATCCCTTGGACTGACTGTCTTGAAAATTGGAAAACTAATCTGTTGAACACATGAAATCGTAATGAAATGCTTCTGAGTGTATTAACAATCAAGATCCTTTTATGATTGTTCAGGAGAACTTAGTCTTTTCAGTTGCTTGCTCTAGGATTGGCTAATTCAATCAAGTAAAGGAAAAATATGCTCAAGATGTTTGCGCTACCATCCCGTGAACAACTCTTGGCGTGTTTTCAACTCACATTAATAATTCGAGGAAAGAAGCCTGTCAAAATAGGTCCAGAAGCTTGGCCTTGTCAAGCAGTGAATGTGAACAAGTGTTTCTTAATTATT. 17 .......4.....‘...................w.-..... .. ,PCTIJP97/03239TGG 827TrpCTG 875LeuGAG 923GluTTT 971Phe305102010801140120012601320138014401500156016201680174018001860W0 98/11217TGCCTTTTGAGGAATTAATCGTGCCTTTAAAAAAAAGACTTTTTTCTTCTTGGTTGCAGTCAGGGATCCTTGGAGAGCTTAGGACCATGGTCTCCCCGCTAGTCCTTATCACTTTACCCAGACCTCTTGAATATGTATATTGGGTGATTTccrccccrccCTAAGCTCTTTTTCCTGCCCGCCACCAACTCTCACTAGGTTAATCTGCAATTTTTTTGTTATTGTGTGTTTGTAAACCAATGTTTACATTAATCACTGTATTGGTTTCACCGAAAGAAATATTTGGATAATCCCTTTCTCGTTCTTATCTCATACCTCACGAGCTCACACCTTACCTTTCGCCAAAAAAAAAAGAGAGATTATTTTATGCGAAGAATTATATAACCTTTAATTATAATCTCTGGTATGGTGATAGTGGATTCTGGGTTCCCTGGCTTAGTGCAGAGAGCCAGACAGCAGCTGTTTGTTTACTGTGAATGCGTTTTATATTCSequence No.: 21Sequence length: 1152CAAATGCCCCCATACAATTAAAGGTCACTGAACTTATAGGAATTTTGGACAATGTGGGCTGAAATGCAAACCTCAAAGATCACTGCCTTTGAAAAAAAAAAGGTGGAAAGAGAACACAAACACGTATTCCACTTATTGCTATGAACCTAGGTAAAAAGCCAGATACTCTTTTCCATTTTTACTAAGTGAGAGCAGGCCTTATAAGCATTATAAATCAAGCCTTAGCTTTCTTCTGCAATGCGSequence type: Nucleic acid94TCCGGTTCCTATTCACTCCTTGGGAATTCTAGCCTAGAACTAGTTAAATTTTTCCAAAAAACTTACTACCGAGGACCTACCCCATCACACGAAACGTTTACTAAAGAAACCTGTCCTTTTGTTTTTAGCCATCTTTGTGGATATCCTTTGGTATAATGTAAAGTTTAGCCTATTAAGAAGTGTGAACTGTGTTAAAATCACGGTCATCTTGAGGCTGGTGGAATTTGGATAACAGGTACC02265923 1999-03-12CTTCTTCCCATTCCAATCATCTTAAGAAACCTCCCAGTAGAGCAGTATTACCACATGCTGAGGCCTTTTTAGAGAGGGCTCCCATTTCCTTCATGAATCACACCCTTTGTGGGTCCCTTTCTCAGGTTACATAATACATTGTCTTCCACAACTTCACCCCCCAATATAGGACCAGTGATAGTGGCAAGAGTGCACTTGAAGAATGATCCCAACAGTAGCTATTGGTTATTTATCTGTTTCPCT/JP97/03239GGTGTGCCAA 1920GTCATTGAAA 1980CCTGAGATTA 2040AGTGGGGATT 2100GTTATGAGTT 2160CTGAATTTAC 2220CTGTGTCCAC 2280CTTTGGTTTG 2340CCTCTTTCCC 2400ACAGGGTTTC 2460TCCCAACTCC 2520CTTACAGATG 2580CAAGATAAAT 2640CAGGTGGTGC 2700GTCATGTTGA 2760AGCCTTTGTA 2820GTAATGGAAA 2880ATTTAATAAT 2940AGCCTCACAC 3000AAGCAAACCT 3060TTTGAAATTT 3120ACACACCCAT 3180TTTTATAGAG 3240TAAATAAAAC 33003311W0 98lll217Strandedness:Topology: LinearDoubleCASequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name:HPO0876Sequence characteristics:95Code representing characteristics: CDSExistence site:147..623Characterization method: ESequence descriptionACTGGAGACA CTGAAGAAGG CAGGGGCCCT TAGAGTCTTG GTTGCCAAAC AGATTTGCAGATCAAGGAGA ACCCAGGAGT TTCAAAGAAG CGCTAGTAAG GTCTCTGAGA TCCTTGCACTAGCTACATCC TCAGGGTAGG AGGAAG ATG GCT TCC AGA AGC ATG CGG CTG CTCCTA TTGLeu Leu10ATG AGAMet ArgTATTyr GlyTGT CAGCys GluCTGLeuCCCProTACTyrTCTSer60AGCSerAGCSerTTCPhe45TACTyrTGCCysTGTCys30AGGArgGGAGlyCTGLeu15GCTAlaAAGLysAACAsnGCCAlaCCTProCTGLeuGGAGlyMet Ala Ser Arg Ser Met Arg Leu LeuLysGGAGlyAGGA178GCCAla65ACAThrTGGTrpAACAsn50CACHisGGAGlyTTTPhe35TGGTrpCTGLeu. .. ..w—..a................. ....._‘... ....~‘ 14 ..GTCVal20TACTyrTCTSerGCAAla02265923 1999-03-12CTGLeuCACHisGATAspTCTSerGGTGlyAAGLysGCCAlaATCIle70GATAspTCCSerGAGGlu55CTGLeuPCT/JP97/032395ATCIleAATAsn40CTCLeuAGTSerATCIle25TGCCysGAGGluTTALeu60120173221269317365W0 98/11217GCCGlu Ala75CCG ATAGln Pro Ile90ATTCAG TGGGln Trp IleTCC ATG GGTSer Met GlyTTT TTA ACTPhe Leu Thr140TGCAAG TACCys Lys Tyr155TGCACAGCCCGGGAAACCTAAGACAGAAACTCCCTTTCCAGAAGAGTGCAGAAGACAGAACTGCCCTCTCTTGGCCATGGTTTAATAAACAGCSerTGGTrpGATAspGGGGly125TGGTrpCGA CCAArgACCThrATTIleGGGGly110AACAsnAGCSerProCGTCCTCTTCCAATA GCA GAGIle Ala Glu80GGC CTG CACGly Leu His95GCC ATG TATAla Met TyrAAG CAC TGTLys His CysAGC GAASer Asn Glu145TACTyrGACAspCTGLeuGCTAla130TGGCys96ATAIleCCAProTACTyr115GAGGluAACAsnAGTSerCAGGln100AGAArgATGMetAAGLys02265923 1999-03-12GGCGly85AAGLysTCCSerAGCSerCGCArgPCT/JP97/03239TAT CAG AGA AGCTyr Gln Arg SerAGG CAG CAG TGGArg Gln Gln Trp105TGG TCT GGC AAGTrp Ser Gly Lys120TCC AACSer Asn Asn Asn135CAA CAC TTC CTGGln His Phe Leu150TAGAGCAAGA ATCAAGATTC TGCTAACTCCCTTTCTGCTAGCCTGGCTAA ATCTGCTCATTATTTCAGAGGCAAACTAAGTTTAGCATTGCAGTATCCTTTCTCCAGCCTGGAAGAAACTTCCATTGCCTGAAGGTTTACCATTGTGTACSequence No.: 22AGTGATAAGGGCCCAGTAGTCTTCCCTCCTATGAAACAGCCAGGAGTAAGGCACCCCACCCAGTAGAATCATGCCCTACTACGGCTTCTAGCCCCCTGTCTCTGGGTCTTTGCTTCTAGCCCCGAGCCACTCCTTGCTAGGTACTGGCTTTTTCTAAATGTTTGGCTGTCTCGCCATAAGAACCTTCAGCTTAACTCCTGCTTGATGTGGGCTTAGGCTTAGTGCCCCGCCAGAGCAGTCTAGTAAAGATTTCTACACCCTTTGTTTTTCCTCATACATTCC4134615095576056507107708308909501010107011301152W0 98/11217CASequence length: 1749Sequence type: Nucleic acidStrandedness:Topology: LinearDoubleSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: LiverClone name:HP01134Sequence characteristics:97Code representing characteristics: CDSExistence site:117.. 1247Characterization method: ESequence description02265923 1999-03-l2AATCACAGCA GTNCCGACGT CGTGGGTGTT TGGTGTGAGGCACTGCCACC ACGGTCGCCT GCCACAGGTG TCTGCAATTGGTT TGGVal TrpGTT CCTVal ProGTG GCAVal Ala35TGC CATCys His................. ................o..»..:....-...........4.:..::...._c »LysATAIle20GGTGlyGCCAlaGTAValGATAspTCASerTACTyrGCTAlaGATAspAATAsnGAGGlnGTAValCCTProGGCGlyATCIleTTCPheGAAGluTGGTrp40ATTIleCTCLeuGATAsp25TATTyrCACHisAGTSer10GGAGlyAATAsnCGCArgGTGValGGCGlyTATTyrAATAsn,...v,.......m...-........,..........: :GCCAlaAAGLysAGGArgGGGGlyPCT/JP97I03239CTGCGAGCCG CCGCCGCCACAACTCCAAGG TGCAGA ATGCTGLeuCACHisCACHis45ATTIleGGCTGGTrp30CAGGlnCCTProATTIle15GTGValGCAAlaGACAspGlyGTGValGACAspGAAGluMetGCCAlaATCIleGCGAlaCAGGln160119167215263311CA 02265923 1999-03-l2W0 98/11217 PCT/JP97/0323998so 55 so 65ATC GTT GTG ATG ATG TAC GAT GAC ATT GCT TAC TCT GAA GAC AAT ccc 359Ile Val Val Met Met Tyr Asp Asp Ile Ala Tyr Ser Glu Asp Asn Pro70 75 80ACT CCA GGA ATT GTG ATC AAC AGG CCC AAT GGC ACA GAT GTC TAT CAG 407Thr Pro Gly Ile Val Ile Asn Arg Pro Asn Gly Thr Asp Val Tyr Gln85 90 95GGA GTC CCG AAG GAC TAC ACT GGA GAG GAT GTT ACC CCA CAA AAT TTC 455Gly Val Pro Lys Asp Tyr Thr Gly Glu Asp Val Thr Pro Gln Asn Phe100 105 110CTT GCT GTG TTG AGA GGC GAT GCA GAA GCA GTG AAG GGC ATA GGA TCC 503Leu Ala Val Leu Arg Gly Asp Ala Glu Ala Val Lys Gly Ile Gly Ser115 120 125GGC AAA GTC CTG AAG AGT GGC CCC CAG GAT CAC GTG TTC ATT TAC TTC S51Gly Lys Val Leu Lys Ser Gly Pro Gln Asp His Val Phe Ile Tyr Phe130 135 140 145ACT GAC CAT GGA TCT ACT GGA ATA CTG GTT TTT CCC AAT GAA GAT CTT 599Thr Asp His Gly Ser Thr Gly Ile Leu Val Phe Pro Asn Glu Asp Leu150 155 160CAT GTA AAG GAC CTG AAT GAG ACC ATC CAT TAC ATG TAC AAA CAC AAA 647His Val Lys Asp Leu Asn Glu Thr Ile His Tyr Met Tyr Lys His Lys165 170 175ATG TAC CGA AAG ATG GTG TTC TAC ATT GAA GCC TGT GAG TCT GGG TCC 695Met Tyr Arg Lys Met Val Phe Tyr Ile Glu Ala Cys Glu Ser Gly Ser180 185 190ATG ATG AAC CAC CTG CCG GAT AAC ATC AAT GTT TAT GCA ACT ACT GCT 743Met Met Asn His Leu Pro Asp Asn Ile Asn Val Tyr Ala Thr Thr Ala195 200 205GCC AAC CCC AGA GAG TCG TCC TAC GCC TGT TAC TAT GAT GAG AAG AGG 791W0 98/11217Ala210TCCSerGACAspGTAValACAThrGCCAla290CCCProACCThrHisCTTLeuAsnACGThrGTGValLysATCIle275AGTSerAGCSerAATAsnCTGLeuTGTCys355Pro ArgTAC CTGTyr LeuGAA GATGlu Asp245TCG CACSer His260TCC ACCSer ThrTCT CCCSer ProCCT GATPro AspGAT CTGAsp Leu325GAT TACAsp Tyr340GAG AAGGlu LysGluGGGGly230CTGLeuACCThrATGMetGTCValGTGVal310GAGGluGAGGluCCGProSer215GACAspACTThrAsnLysCCCPro295CCTProGAGGluTATTyrTATTyrCASerTGGTrpLysACCThrGTGVal280CTALeuCTCLeuTCCSerGCGAlaCCGPro36002265923 1999-03-12TyrTACTyrGAGGluAGCSer265ATGMetCCTProACCThrAGGArgTTGLeu345CTTLeuAlaAGCSerACCThr250CAGHisCAGGlnCCAProATCIleCAGGln330AGAArgCACHis99CysGTCVal235CTGLeuGTCValTTTPheGTCValATGMet315CTCLeuCATHisAGGArgTyr220TyrAspAAC TGG ATGAsn Trp MetCACHisATGMetCAGGlnACAThr300LysACGThrTTGLeuATAIleAAGLysCAGGlnGGTGly285CAGHisAGGArgGAGGluTACTyrLys365CAGGlnTATTyr270ATGMetCTTLeuLysGAGGluGTGVal350TTGLeu, .............-....—............................._ . .GluGAAGluTACTyr255GGALysGACAspCTGLeuATCIle335CTGLeuTCCSerLysGACAsp240CAGHisAACASHCGCArgCTCLeuATGMet320CAGGlnGTCValATGMetPCT/JP97/03239Arg225TCG 839SerCTG 887LeuAAA 935LysAAA 983LysACC 1031Thr305AAC 1079AsnCGG 1127ArgAAC 1175AsnGAC 1223AspW0 98lll217CA 022659231999-03-12100CAC GTG TGC CTT GGT CAC TAC TGAAGAGCTG CCTCCTGGAA GCTTTTHis Val Cys Leu Gly His Tyr370CCAAGTGTGAGTCTCCGCTGTTCACAAGATTTAGGGTGGGTTTTGCCTGTAGGAGTCTTTTTGAAGAGGGTTGCTTTTGT375GCGCCCCACCCTCGGGCCCTGACTTGCTCGAAAAGCTCTGTAGTTTTGAGATTCTGAGAACCGCAAGCCCATTTAATTCTSequence No.: 23Sequence length: 988GACTGTGTGCCCTGGGGAGCCTGTTACCTGTATTGAGAAGGAGCAGGAAGTTTGAAGCTGCAAATGGAAAGCAGGTGTTCSequence type: Nucleic acidStrandedness:DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensTGATCAGAGACCCCGCTCCACTTCCCCAGTGGTCATATTTCTCATGGGGGAAACCTCTTTACTGTTTTTAAAGTCTTAAACell kind: Epidermoid carcinomaCell line: KBClone name:HP10029Sequence characteristics:Code representing characteristics: CDSExistence site:9..530Characterization method: ESequence descriptionCTGGAGAGGTGGGCTCGCTCCTTTTCTGAAGCTTTCTAGGCTTCTGTAGCAAATCTTCAGGAAAATATGAAAATAAAGATPCT/JP97/032391270GGAGTGAGAA 1330CAGGACCTTC 1390AAACTACAAA 1450AGGTTTGTTG 1510CCCTCTCAAA 1570AATGATTTTA 1630TGATTTTTGA 1690TTATAACAG 1749AGTCCAAC ATG GCG GCG CCC AGC GGA GGG TGG AAC GGC GTC CGC GCG AGC50CA 02265923 1999-03-l2W0 98/1 1217 PCT/JP97/03239101Met Ala Ala Pro Ser Gly Gly Trp Asn Gly Val Arg Ala Ser1 5 10TTG TGG GCC GCG CTG CTC CTA GGG GCC GTG GCG CTG AGG CGG GCG GAG 98Leu Trp Ala Ala Leu Leu Leu Gly Ala Val Ala Leu Arg Pro Ala Glu15 20 25 30GCG GTG TCC GAG CCC ACG ACC GTG GCG TTT GAC GTG CGG CCC GGC GGC 146Ala Val Ser Glu Pro Thr Thr Val Ala Phe Asp Val Arg Pro Gly Gly35 40 45GTC GTG CAT TCC TTC TCC CAT AAC GTG GGC CCG GGG GAC AAA TAT ACG 194Val Val His Ser Phe Ser His Asn Val Gly Pro Gly Asp Lys Tyr Thr50 55 60TGT ATG TTC ACT TAC GCC TCT CAA GGA GGG ACC AAT GAG GAA TGG CAG 242Cys Met Phe Thr Tyr Ala Ser Gln Gly Gly Thr Asn Glu Gln Trp Gln65 70 75 AATG AGT CTG GGG ACC AGC GAA GAC CAC CAG CAC TTC ACC TGC ACC ATC 290Met Ser Leu Gly Thr Ser Glu Asp His Gln His Phe Thr Cys Thr Ile80 85 90TGG AGG CCC CAG GGG AAG TCC TAT CTG TAC TTC ACA CAG TTC AAG GCA 338Trp Arg Pro Gln Gly Lys Ser Tyr Leu Tyr Phe Thr Gln Phe Lys Ala95 100 105 110GAG GTG CGG GGC GCT GAG ATT GAG TAC GCC ATG GCC TAC TCT AAA GCC 386Glu Val Arg Gly Ala Glu Ile Glu Tyr Ala Met Ala Tyr Ser Lys Ala115 120 125GCA TTT GAA AGG GAA AGT GAT GTC CCT CTG AAA ACT GAG GAA TTT GAA 434Ala Phe Glu Arg Glu Ser Asp Val Pro Leu Lys Thr Glu Glu Phe Glu130 135 140GTG ACC AAA ACA GCA GTG GCT CAC AGG CCC GGG GCA TTC AAA GCT GAG A82Val Thr Lys Thr Ala Val Ala His Arg Pro Gly Ala Phe Lys Ala Glu145 ' 150 155 %% .mm-‘.l. ...__._..........‘.. ..................... .W0 98/11217CA 02265923 1999-03-12102PCT/JP97/03239CTG TCC AAG CTG GTG ATT GTG GCC AAG GCA TCG CGC ACT GAG CTGLeu Ser Lys Leu Val Ile Val Ala Lys Ala Ser Arg Thr Glu Leu160165170TGA CCAGCAGCCC TGTTGCGGGT GGCACCTTCT CATCTCCGGT GAAGCTGAAGGGGCCTGTGG CCCTGAAAGGTTCTACCTGG GCTGACGTTGGCAGAGAACA GAGGGTCCAGTGCTGAGCTC TTCTGGACTCGGGGCTATGC TGGGGAAAGCAGCCTGCAGA ACTGCTTTCCGAGATGAAAT GTTTTTTCATSequence No.: 24Sequence length: 390GCCAGCACAT CACTGGTTTTCCTTGTCCGG AGGGGCTTGCGGCCCTCCTG GCTCCCAACAAGGATCGCAG ATCCGGGGCAAGCCATGCTC CCCCCGACCTTATGTTTACC CAGGGGACCTATTTAAATAA ATAAGAACATSequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Epidermoid carcinomaCell line: KBClone name:HP10189Sequence characteristics:Code representing characteristics: CDSExistence site: 102.. 323Characterization method: ESequence descriptionAATCAGCTTC AGCAATGGAG CGTGCAAAAC ACCAGTGAGC TTCTGTCTTG CTGGAGGGTCCTAGGAGGGA CTCTTAAGTTAGGGTGGCTG AAGCCCTGGGGCTTCTCAGT TCCCACTTCCCAAAGAGGGT GGGGAACATGCCAGCCGAGC ATCCTTCATGCCTTTCAGAT GAACTGGGAATAAAAAGC52758064070076082088094098860W0 98/11217CA02265923 1999-03-12103PC1VJP9%M3239GGCTTTGGGC GGAACTGGCT TTGTTGACCG GGAGAAACGA G ATG GGG GTG AAG CTGGAG ATAGlu IleTGG GTTTrp ValAGGLys ArgAAA GAGLys Glu55GAGGln Gln70TTTPheTCCSerGAGGlu#0AGGArgAACAsnUGG ATGArg Met10AAT CAGAsn Gln25CTG TGGLeu TrpTTA CGGLeu ArgTCCSerATAIleGCCAlaCCAProAAGLysATCIleGAGGluCCTProCGGArg60TACTyrTGGTrpGAGGlu45CGGArgCTGLeuTTTPhe30AAGLysGAGGluACT TTCThr Phe15GAG GACGlu AspCTT CAALeu GlnGAG AAGGlu LysCCCCTGATGA AATATACATA TACTCAGTTC CTTGTTATTCSequence No.: 25Sequence length: 4667Sequence type: Nucleic acidStrandedness:Topology: LinearDoubleSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Lymphoma .W............»..—uu-au.nuuu---..n.......... ., ,Met Gly Val Lys LeuCCTProGATAspGAGGluCTCLeu651GTGValGTCValATAIle50CTTLeuTGAGGCCTCC AAGTGGGAGT CCTAGCCCCTGCTAlaATAIle35GAGGluCGGArgATGMet20CAGGlnGAAGluGACAspTTCPheCGCArgTTCPheGCCAla5116164212260308350390WO 98111217Cell line:Clone name:CA 02265923 1999-03-12Sequence characteristics:Code representing characteristics: CDSExistence site:754.. 4272Characterization method: ESequence descriptionCATTTAGTTA CTCTGCTCAT TTCTCTTAAGTTCCTGATGA ACCTTGCCTT TTAAGGATCCATTTTTTTTT TCACTGGGGA GGGGAATGGTCTCACCTTCC AGCCCGGTGATGTGTTCTCTTGCTGGCTTTCCCTGTGAATGCCCCTTGCACCGACCGACCATGGGTGTGAGGGAGTCTCCCATTCAAGAGGGTCCTTTCTTGT TTT GCC CTG CCT GGC CTCCys Phe Ala Leu Pro Gly Leu10GGG GCC TGC TAT CCA CCT GTTGly Ala Cys Tyr Pro Pro Val25TTT CTC CGA GCT TCA TCT ACCGCCTGATCTTGGGAAAATGCTCTGGTCTCTGCCCCCACAGAACCCACTTGCGGCTGCCAGAGAGGTGAGGGAGCTTTCAGGGGGATCACCTATGTCTGGACTGTCTGGGGTGAGTTCATTGATGATCACTGCAGGTGGGCCCCAGTCCCGATTCCTGAGACTGTTGTTTAGCGATCTGGACCATTGGCTG1530PCT/JP97/03239104CTTTCCTTGG ATGAGTTGAG CTTTGAATCC 60TCCAAATGCC CCAAGAAGCT GGGATTTTTC 120GCTTTCCAGG GTCCTGGATG TTTGAGTCTT 180GCTTTAACTC TCTATATAAG CCCTAATCTT 240TGGTCCAGGT CACAAGAAGA AGCTGACCCC 300GCCTGGCACA AATGCAAGGG CCCTTCCCCA 360TACATGTGCC TTGTGCTTTC TGTTTGAGGG 420ATTGTGGAGC TCACTACAAG AACTCTGGGA 480TCCTGGGAGG TGGGGGTGCA GTGACGACAG 540CCCGCCCTGC GGTGGGGCTA CACCCAGCCA 600AAAACCTGGA GCCGGGAGGG GAGACCCCCA 660GAAAGAACGG CAGAACACAC AGCAAGGAAA 720AAG ATG AGA CCA TTC TTC CTC TTG 774Met Arg Pro Phe Phe Leu Leu1 5CTG CAT GCC CAA CAA GCC TGC TCC CGT 822Leu His Ala Gln Gln Ala Cys Ser Arg20GGG GAC CTG CTT GTT GGG AGG ACC CGG 870Gly Asp Leu Leu Val Gly Arg Thr Arg35TGT GGA CTG ACC AAG CCT GAG ACC TAC 918W0 98/11217Phe4 0TGCCysAGGArgTCCSerGTCValATGMe t120TCCSerGACAspTGGTrpCTALeuLeuACCThrCAGGlnTCCSerTCTSer105ATGMetTCASerTGCCysCAGGlnAATAsn185ArgCAGGlnCCTProGGCGly90CTGLeuGAGGluGACAspACCThrGATAs p170AlaTATTyrCACHis75CCCProCAGGlnTTCPheTTCPheTCCSer155GTTValGGGGlySerGGCGly60AsnATGMetCTGLeuGlnGGTGly1140ACCThrCGGLysSer45GAGGluTACTyrCGCArgGACAspGGGGly125AAGLysTTCPheTGCCysGTCValCAThrTGGTrpTACTyrTGGTrpCTGLeu110CCCProACCThrCCTProCAGGlnGln19002265923 l999-03- l2CysCAGGlnAGTSerTGGTrp95GACAspATGMetTGGTrpCGGArgTCCSer175CTTLeuGlyATGMetCACH i s8 0CAGGlnAGGArgCCTProCGAArgGTCVal160CTGLeuAACAsn105LeuLys65CGAArgTCCSerAGAArgGCCAlaGTGVal145CGCArgCCTProCTTLeuThr50TGCCysGTAValCAGGlnTTCPheGGCGly130TACTyrCAGGlnCAGGlnATGMetLysTGCCysGAGGluAATAsnCAGGln115ATGMetCAGGlnGGTGlyAGGArgGATAsp195ProAAGLysAATAsnGATAsp100CTTLeuCTGLeuTACTyrCGGArgCCTPro180TTALeuGluTGTCysGTGVal85GTGValGlnATTIleCTGLeuCCTPro165AATAsnGTGValThrGACAsp70GCTAlaAAGAsnGluGAGGluGCTAla150CAGGlnGCAAlaTCTSerPCT/JP97/03239Tyr55TCC 966SerTCA 1011+SerCCT 1062ProGTC 1110ValGGC 1158Arg135GCC 1206AlaAGC 125!»SerCGC 1302ArgGGG 1350GlyW0 98/11217ATTIle200AsnTACTyrGlyGTCVal280TTCPheGAAGluGACAspGACAspCCAProTTGLeuCACAGCSerGCCAla265TGCCysTACTyrTGCCysCCCProAATAsnGCAAlaAGAArgCCTProTGCCys250TCTSerCAGGlnAACAsnGlnGCTAla330TGCCysACTThrGTCValCCCPro235TTCPheGCAAlaCACHisAACAsnAGGArg315cmValCGGArgCAAGlnAATAsn220AGCSerTGTCysGGCGlyAACAsnCGGArg3 0 0TGCCysTTTPheGACAspAGTSer205TTCPheGCCAlaCACHisCCCProACTThr28 5CCCProGACAspGCCAlaCACHisCACAAGlnACCThrTACTyrGGCGlyTCCSer270GCCAlaTGGTrpTGCCysGCCAlaACCThr02265923 l999-03- l2LysAGGArgTATTyrCATHi s255ACCThrGGCGlyAGAArgAATAsnAGCSer335GAAGluATTIleCTGLeuGCTAla2140GCTAlaGCTAlaCCAProCCGProGGGGly320CAGGlnGGCGly106CAA GAG GTG GGGGlnGCCAla225GTGValGATAspGTGValAATAsnGCGAla305CACHisGlyAAGLysGlu210CCTProTCCSerGGCArgCAGGlnTGTCys29 0GAGGluTCASerGCAAlaAACAsnValGTGValCAGGlnTGCCysGTCVal275GAGGluGGCGlyGAGGluTATTyrTGTCysGlyCCCProCTCLeuGCAAla2 6 0CACHisCGCArgCAGGlnACAThrGGAGly31; 0GAGGluGAGGluCAAGlnCGTArg245CCCProGATAspTGTCysGACAspTGTCys325GGTGlyCGGArgATCIleAGGArg230CTGLeuAAGLysGTCValGCAAlaGCCAla310CAGHisGTGValTGTCysPCT/JP97/03239ACA 1398Thr215GGC 1446GlyCAG 1494GlnCCT 151:2ProTGT 1590CysCCC 1638Pro295CAT 1686HisTTT 1734PheTGT 1782CysCAG 1830GlnW0 98/11217CTGLeu360TGCCysTGTCysGAGGluAsnAGGArg440AsnCTGLeuTCCSerGAA345CACHisATCIleGACAspCGCArgCCGPro425GACAspGTGValGCCAlaCTCLeuGGCTATTyrTCCSerCCAProTGTCys410CAGGlnATGMetGTGValAGTSerAGCSer490TTTTTCPheTGCCysGTGVal395GACAspGGCGlyCCGProGGTGlyGGCGly475CCAProGGTCGGArgGAGGlu380ACCThrCTALeuTGCCysTGTCysCCCPro460CAGGlnCAGGlnGGCAACAsn365TGTCysGGGGlyTGCCysCACHisGACAsp445LysGGCGlyTGCCysCTGCA350CGGArgGATAspCAGGlnAAGLysCGCArg430GAGGluTGTCysTGTCysAACAsnATGCGCArgCCGProTGTCysCCGPro415TGTCysGAGGluGACAspGAAGluCAGGln495TGCCCGProGATAspGTGVal400GGCGlyGACAspAGTSerCAGGlnCCGPro480TTCPheAGC107GGAGlyGGGGly385TGCCysTTCPheTGCCysGGGGlyTGTCys465TGTCysACAThrGCTGCTA18370GCAAlaAAGLysACTThrAACAsnCGCArg450GCTAlaGCCAlaGlyGCA02265923 1999-03-12355TCCSerGTGValGAGGluGGAGlyATCIle435TGCCysCCCProTGCCysCAGGlnGCCATTIleCCAProCATHisCTCLeu420CTGLeuCTTLeuTACTyrGACAspTGCCys500ATCCAGGlnGGGGlyGTGVal405ACCThrGGGGlyTGTCysCACHisCCGPro485CCCProCGCPCT/JP97l03239GAG ACC 1878Glu Thr375GCT CCC 1926Ala Pro390CAG GGA 1974Gln GlyTAC GCC 2022Tyr AlaTCC CGG 2070Ser ArgCTG CCC 2118Leu Pro455TGG AAG 2166Trp Lys470CAG AAC 2214His AsnTGT CGG 2262Cys ArgCAG TGT 2310WO 98111217GluGCAPro520TGTCysGGCArgCAGGlnTGCCysGly600GAGGluGAGGluGTGValGly505GACAspGATAspTGCCysCGAArgTTCPhe585AGAArgGACAspCAGGlnGCTAlaPheCGGArgTTCPheCTCLeuGGCGly5 70CAGGlnCTCLeuCGTArgATCIleCAGGln650GlyACCThrCGGArgTGCCysS55TACTyrACCThrCGCArgGGCGlyCGAArg635GTGValGlyTATTyrGGAGly540CGCArgTGCCysTATTyrAATAsnCTGLeu620GCAAlaGCCAlaLeuGGAGly525ACAThrCCTProAATAsnGATAspGCCAla605GCCAlaGTTValAGTSerCAMet510GACAspGAGGluGGCGlyCGCArgGCGAla590ACCThrTCCSerCTCLeuGCCAla02265923 l999-03- 12CysGTGValGlyTTGLeuTACTyr5 7 5GACAspGCCAlaCGGArgAGCSerATCIle655SerGCCAlaCCGProACCThr560CCGProCTCLeuAGCSerATCIleAGCSer640CTCLeu108AlaACAThrGGCGly545GGGGlyGTGValCGGArgCTGLeuCTALeu625CCCProTCCSerAlaGGAGly530TGCCysCCCProTGCCysGAGGluTGGTrp610GATAspGCAAlaCTCLeuAla515TGCCysGACAspCGCArgGTGValCAGGln595TCASerGCAAlaGTCValAGGArgIleCGAArgAAGLysTGTCysGCCAla580GCCAlaGGGGlyAAGLysACAThrCGAAr g660ArgGCCAlaGCAAlaGACAsp565TGCCysCTGLeuCCTProAGTSerGAGGlu645ACTThrGlnTGTCysSer550CAGGlnCAGHisCGCArgGGGGlyAAGLy s6 3 0CAGGlnCTCLeuPCT/JP97/03239CysGAC 2358Asp535GGC 24 06GlyTGC Z454CysCCT 2502ProTTT 2550PheCTG 2598Leu615ATT 26!; 6IleGAG 2694GluCAG 2742GlnW0 98/1 1217GlyAGAAr g680TATTyrTCASerGCTAlaGACAspGGAGly760TCGSerAGGGlnCTGLeu665GACAspCAGGlnGGAGlyGCTAlaAGCSer745GGCGlyTTGLeuCAGGlnGACAspCAGGlnCTGLeuAGGArgGCCAlaCAGGln730CGGArgACCThrCCTProATGMetAsnCTGLeuGAGGluAAGLysTTCPhe7 1 5CAGGlnAGAArgGGCGlyGACAspGCTAla795GGCGlyGATAspAGTSerAGGArg7 0 0CGGArgGTCValGAGGluAGCSerCTGLeu780TGCCysACAThrCTGLeuCTTLeu685GAGGluATGMetTCCSerGCAAlaCCCPro765ACAThrACCThrGCCAlaCACCCPro670GACAspCAGGlnCTGLeuGACAspGAGGlu750AAGLysCCCProCCAProTGTCysCTGLeuAGAArgTTTPheAGCSerAGCSer735AGGArgCTTLeuACCThrATAIleGGCGly109GAGGluAGCSerGAAGluACAThr720TCGSerCTGLeuGTGValTTCPheTCASer800TCCSerGAGGluTTCPheLys705GCCAlaCGCArgGTGValGCCAlaAACAsn785TGCCysCGCArgGAGGluAATAsn690ATAIleTACTyrCTTLeuCGGArgCTGLeu770AAGLysCCTProTGCCys02265923 l999-03- l2ACGThr6 7 5GGTGlyAGCSerGAGGluTTGLeuCAGGln7 5 5AGGArgCTCLeuGGTGlyAGGArgTTGLeuCTCLeuAGTSerCAGGlnGACAsp7140GCGAlaCTGLeuTGTCysGAGGluGGTGlyTCCSerCTTLeuGCTAlaTCASer725CAGGlnGGAGlyGAGGluGGCGlyCTALeu805GTCValCTTLeuACTThrGATAsp710GCCAlaCTCLeuGGAGlyATGMe tAACAsn790TGTCysCTTLeu .....4.....»..m....a............_.........Y .PCTIJP97/03239CCG 2790ProATG 2838Met695CCT 2886ProCAG 2934GlnAGG 2982ArgGGA 3030GlyTCT 3078Ser775TCC 3126SerCCC 3174ProCCC 3222ProCA 02265923 1999-03-l2W0 98/ 11217 PCT/JP97/03239110810 815 820AGG GCC GGT GGG GCC TTC TTG ATG GCG GGG CAG GTG GCT GAG CAG CTG 3270Arg Ala Gly Gly Ala Phe Leu Met Ala Gly Gln Val Ala Glu Gln Leu825 830 835CGG GGC TTC AAT GCC CAG CTC CAG CGG ACC AGG CAG ATG ATT AGG GCA 3318Arg Gly Phe Asn Ala Gln Leu Gln Arg Thr Arg Gln Met Ile Arg Ala840 845 850 855GCC GAG GAA TCT GCC TCA CAG ATT CAA TCC AGT GCC CAG CGC TTG GAG 3366Ala Glu Glu Ser Ala Ser Gln Ile Gln Ser Ser Ala Gln Arg Leu Glu860 865 870ACC CAG GTG AGC GCC AGC CGC TCC CAG ATG GAG GAA GAT GTG AGA CGC 3414Thr Gln Val Ser Ala Ser Arg Ser Gln Met Glu Glu Asp Val Arg Arg875 880 885ACA CGG CTC CTA ATG CAG CAG GTC CGG GAC TTC CTA ACA GAC CGC GAC 3462Thr Arg Leu Leu Ile Gln Gln Val Arg Asp Phe Leu Thr Asp Pro Asp890 895 900ACT GAT GCA GCC ACT ATC CAG GAG GTC AGC GAG GCC GTG CTG GCC CTG 3510Thr Asp Ala Ala Thr Ile Gln Glu Val Ser Glu Ala Val Leu Ala Leu905 910 915TGG CTG CCC ACA GAC TCA GCT ACT GTT CTG CAG AAG ATG AAT GAG ATC 3558Trp Leu Pro Thr Asp Ser Ala Thr Val Leu Gln Lys Met Asn Glu Ile920 925 930 935CAG GCC ATT GCA GCC AGG CTC CCC AAC GTG GAC TTG GTG CTG TCC CAG 3606Gln Ala Ile Ala Ala Arg Leu Pro Asn Val Asp Leu Val Leu Ser Gln940 945 950ACC AAG CAG GAC ATT GGG GGT GCC CGC CGG TTG CAG GCT GAG GCT GAG 3654Thr Lys Gln Asp Ile Ala Arg Ala Arg Arg Leu Gln Ala Glu Ala Glu955 960 965GAA GCC AGG AGC CGA GCC CAT GCA GTG GAG GGC CAG GTG GAA GAT GTG 3702WO 98/11217Glu Ala Arg Ser970GTT GGG AAC CTGVal Gly Asn Leu985ACC ATG GGCThr Met Gln Gly1000GCT GAG GTT CAGAla Glu Val GlnATG ACC CAGMet Thr Lys GlnArgCGGArgACCThrCAGGlnAlaCAGGlnAGCSer1005GTAVal1020CTGLeu1035CAA GCC CGGHis Gln Ala Arg1050GCG GCCGAA GGTAla Glu Gly Ala1065AGA ATA AAA CAAArg Ile Lys Gln1080TCC ATG CTG GGTSer Met Leu GlyGCA GAG GAG CTGAla Glu Glu LeuCAGGlnAGCSerAAGLysGAGGluGGTGlyCAGGlnGAGGluTATTyrCAHisGGGGly990CGCArgCTGLeuGACAspGGGGlyCAGGln1070GCTAla1085CAGGln1100GGTGlyTTT GGG GAGPhe Gly Glu111502265923 1999-03-l2PCT/JP97/03239111Ala Val Glu Gly Gln Val Glu Asp Val975 980ACA GTG GCA CTG CAG GAA GCT CAG GAC 3750Thr Val Ala Leu Gln Glu Ala Gln Asp995TCC CTT CGG CTT ATC CAG GAC AGG GTT 3798Set Leu Arg Leu Ile Gln Asp Arg Val1010 1015CGG CCA GCA GAA AAG CTG GTG ACA AGC 3846Arg Pro Ala Glu Lys Leu Val Thr Ser1025 1030TTC TGG ACA CGG ATG GAG GAG CTC GGC 3894Phe Trp Thr Arg Met Glu Glu Leu Arg1040 1045GCA GAG GCA GTC CAG GCC CAG CAG CTT 3942Ala Glu Ala Val Gln Ala Gln Gln Leu1055 1060GCA TTG AGT GCC CAA GAG GGA TTT GAG 3990Ala Leu Ser Ala Gln Glu Gly Phe Glu1075GAG TTG AAG GAC CGG TTG GGT CAG AGT 4038Glu Leu Lys Asp Arg Leu Gly Gln Ser1090 1095GCC CGG ATC CAG AGT GTG AAG ACA GAG 4086Ala Arg Ile Gln Ser Val Lys Thr Glu1105 1110ACC ATG GAG ATG ATG GAC AGG ATG AAA 4134Thr Met Glu Met Met Asp Arg Met Lys1120 1125CA 02265923 1999-W0 98/11217112GAC ATG GAG TTG GAG CTG CTG CGG GGC AGCAsp Met Glu Leu Glu Leu Leu Arg Gly Ser1130 1135TCA GCG GAC CTG ACA GGA CTG GAG AAG CGTSer Ala Asp Leu Thr Gly Leu Glu Lys Arg1145 1150CAC ATC AAT GGG GGC GTG CTC TAC TAT GCCHis Ile Asn Gly Arg Val Leu Tyr Tyr Ala1160 1165GATGCTACAG CTTCCAGCCC GTTGCCCCAC TCATCTGCAGATTGGGT TGGAATGCTT TCCATCTCCA GGAGACTTGGACCACCC CTGGTGTGTA GCTAGTAAGA TTACCCTATGGGACAGTAGCTCTCAAG TCAAGGAAGC TGGGCTGGGC AGTATCCGAGGAA1CCT GGACCAAGCA CAAAAACTTA ACAAAAGTAAAAATCTT TGGAAAAGAG CCTGGAGGTT CAACGAGSequence No.: 26Sequence length: 1086Sequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: cDNA to mRNAOriginal source:Organism species: Hamo sapiensCell kind: Stomach cancerClone name: HP10298Sequence characteristics:Code representing characteristics: CDS03-l2PCT/JP97/03239CAG GCC ATC ATG CTG GGCGln Ala Ile Met Leu Arg1140GTG GAG GAG ATC CGT GACVal Glu Gln Ile Arg Asp1155ACC TGC AAG TThr Cys Lys1170CCG CCTTTGCTTT TGGTTGGGGGTTC ATGCAGCCTA AAGTACAGCCGAG CTGCAGCTGA GCCTGAGCCATACACTTGAC AGACAAAGAT GGTGGAGATT GGCATGCCAT TGAAACTAAGCCC GCCTTTAGTT CTCCACTGGGTGA TGTAAAAATG AAAAGCCAAA4182423042704330439044504510457046304667CA 02265923 1999-03-l2W0 98/11217113Existence site: 138.. 506Characterization method : ESequence descriptionTTTAATTTCC CCGAAATCAG ACTGCTGCCT TGGACCGGGA CAGCTCGCGG CCCCCGAGAGCTCTAGCCGT CGAGGAGCTG CCTGGGGACG TTTGCCCTGG GGCCCCAGCC TGGCCCGGGTPCT/JP97/03239CACCCTGGCA TGAGGAG ATG GGC CTG TTG CTC CTG GTC CCA TTG CTC CTGMet Gly Leu Leu Leu Leu Val Pro Leu Leu Leu1 5CTG CCC GGC TCC TAC GGA CTG CCC TTC TACLeu Pro Gly Ser Tyr Gly Leu Pro Phe Tyr15 20AAC AGC GCC AAC GAC CAG AAC CTA GGC AACAsn Ser Ala Asn Asp Gln Asn Leu Gly Asn30 35CTT AAT GGA GTG AAG CTG GTG GTG GAG ACALeu Asn Gly Val Lys Leu Val Val Glu Thr45 50ACC GGC ATC CTA ACT GTG GGC CCC CAG AGCThr Arg Ile Leu Thr Val Gly Pro Gln Ser60 65GCT TCC CCG ACC CGC AGA GCC GCT TGT ACGAla Ser Pro Thr Arg Arg Ala Ala Cys Thr80 85AGC ACT AGG ACC TGG GGC CCT CCC CTG CCGSer Thr Arg Thr Trp Gly Pro Pro Leu Pro95 100GTA TTT ATT GAG TGG TTC GTT TTC CCT TGTVal Phe Ile Glu Trp Phe Val Phe Pro Cys110 115AsnGGTGlyCCCProCTGLeu70GTGValCATHisGGGGlyGGCGlyCATHisGAGGlu55GGGGlyTTTPheTCCSerTTGLeuTTCPheGGCGly40GAGGluTCCSerACTThrCTCLeuGAGGlu120TACTyr25LysACCThrGAAGluGCTAlaACTThr105CCAPro1 0TACTyrGACAspCTGLeuGCTAlaACCThr90GGCGlyTTTPheTCCSerCTCLeuTTCPheTTGLeu75GCCAlaTGTCys60120170218266311+362410458503CA 02265923 1999-03-12W0 98/1 1217 PCT/JP97/03239114TAACTGT TTTTATACTT CTCAATTTAA ATTTTCTTTA AACATTTTTT TACTATTTTT 560TGTAAAGCAA ACAGAACCCA ATGCCTCCCT TTGCTCCTGG ATGCCCCACT CCAGGAATCA 620TGCTTGCTCC CCTGGGCCAT TTGCGGTTTT GTGGGCTTCT GGAGGGTTCC CCGCCATCCA 680GGCTGGTCTC CCTCCCTTAA GGAGGTTGGT GCCCAGAGTG GGCGGTGGCC TGTCTAGAAT 740GCCGCCGGGA GTCCGGGCAT GGTGGGCACA GTTCTCCCTG CCCCTCAGCC TGGGGGAAGA 800AGAGGGCCTC GGGGGCCTCC GGAGCTGGGC TTTGGGCCTC TCCTGCCCAC CTCTACTTCT 860CTGTGAAGCC GCTGACCCCA GTCTGCCCAC TGAGGGGCTA GGGCTGGAAG CCAGTTCTAG 920GCTTCCAGGC GAAAGCTGAG GGAAGGAAGA AACTCCCCTC CCCGTTCCCC TTCCCCTCTC 980GGTTCCAAAG AATCTGTTTT GTTGTCATTT GTTTCTCCTG TTTCCCTGTG TGGGGAGGGG 1040CCCTCAGGTG TGTGTACTTT GGACAATAAA TGGTGCTATG ACTGCC 1086Sequence No.: 27Sequence length: 866Sequence type: Nucleic acidStrandedness: DoubleTopology: LinearSequence kind: CDNA to mRNAOriginal source:Organism species: Homo sapiensCell kind: Stomach cancerClone name: HP10368Sequence characteristics:Code representing characteristics: CDSExistence site: 73.. 600Characterization method: ESequence descriptionACTCAGAAGC TTGGACCGCA TCCTAGCCGC CGACTCACAC AAGGCAGGTG GGTGAGGAAA 60TCCAGAGTTG CC ATG GAG AAA ATT CCA GTG TCA GCA TTC TTG CTC CTT GTG 111Met Glu Lys Ile Pro Val Ser Ala Phe Leu Leu Leu ValW0 98/1 1217GCCAlaLys30AGACTALeuTTGLeuAsnGTTVal110CCCProACTThrGCTCTCLeu15LysGGTGlyTATTyrGATAspLys95TATTyrAGGAISGGAGlyCTGTCCSerGACAspTGGTrpLysGAGGlu80GAAGluGAAGluATTIleAGAArgTTGTACTyrACAThrGGTGlyTCCSer65TGCCysATCIleACAThrATGMetTATTyr145CTTACTThrAAGLysGACAsp50AAGLysCCAProCAGGlnACTThrTTTPhe130TCASerGACCTGLeuGACAsp35CAAGlnACAThrCACHisLysGACAsp115GTTValAsnAACCAGCCAla20TCTSerCTCLeuAGCSerAGTSerTTGLeu100LysGACAspCGTAraATG115AGA GATArg AspCGA CCCArg ProATC TGGIle TrpAACAsn Lys70CAA GCTGln Ala85GCA GAGAla GluCAC CTTHis LeuCCA TCTPro SerCTC TATLeuTyr150ACCThrLysACTThr55CCCProTTALeuCAGGlnTCTSerCTGLeu135GCTAlaGCTACAThrCTGLeu40CAGGlnTTGLeuAAGLysTTTPheCCTPro120ACAThrTACTyrCTC02265923 1999-03-l2GTCVal25CCCProACAATGMetLysGTCVal105GATAspGTTValGAAGluAAGLysCAGGlnTATTyrATTIleGTGVal90CTCLeuGGCGlyAGAArgCCTProTTG10CCTProACCThrGAAGluATTIle75TTTPheCTCLeuCAGGlnGCCAlaGCAAla155CTGGGAGlyCTCLeuGlu60CATHisGCTAlaAATAsnTATTyrGATAsp140GATAspPCT/JP97/03239GCC 159AlaTCC 207Ser45GCT 255AlaCAC 303HisGAA 351GluCTG 399LeuGTC 447Val125ATC 495IleACA 543ThrACT 591CA 02265923 1999-03-l2W0 98/11217116Ala Leu Leu Leu Asp Asn Met Lys Lys Ala Leu Lys Leu Leu Lys Thr160 165 170GAA TTG TAAAGAAAAA AAATCTCCAA GCCCTTCTGT CTGTCAGGCC TTGGlu Leu175AGACTTGAAA CCAGAAGAAG TGTGAGAAGA CTGGCTAGTG TGGAAGCATA GTGAACACACTGATTAGGTT ATGGTTTAAT GTTACAACAA CTATTTTTTA AGAAAAACAA GTTTTAGAAATTTGGTTTCA AGTGTACATG TGTGAAAACA ATATTGTATA CTACCATAGT GAGCCATGATTTTCTAAAAA AAAAAATAAA TGTTTTGGGG GTGTTCTGTT TTCTCCPCT/JP97/03239640700760820866

Claims (4)

Claims

1. Proteins containing any of the amino acid sequences represented by Sequence No. 1 to Sequence No. 9.

2. DNAs encoding any of the proteins as described in Claim 1.

3. cDNAs containing any of the base sequences represented by Sequence No. 10 to Sequence No. 18.

4. cDNAs described in Claim 3 which comprise any of the base sequences represented by Sequence No. 19 to Sequence No. 27.