JP2002504822A - Secreted proteins and polynucleotides encoding them - Google Patents

Abstract

  (57) [Summary] Disclosed are novel polynucleotides and the proteins encoded by them.

Description

DETAILED DESCRIPTION OF THE INVENTION             Secreted proteins and polynucleotides encoding them   No. 60 / XXXXXX filed on June 11, 1997 (not a provisional application) No. 08/873218 (changed to provisional application). And all are considered to be as described herein.                                Field of the invention   The present invention relates to novel polynucleotides and the use of such polynucleotides. Proteins, and therapeutic and diagnostic methods for these polynucleotides and proteins Provides catastrophic and research utility.                                Background of the Invention   Protein factors such as lymphokines, interferons, CSFs and The method aimed at the discovery of cytokines such as Matured rapidly over the years. Nowadays conventional hybridization cloning And expression cloning methods provide information directly related to the discovered protein (ie, In the case of hybridization cloning, the partial DNA / amino acid sequence of the protein Column; the activity of the protein in the case of expression cloning) The new polypeptide is cloned "directly". Signal sequence cloning ( DNA sequence based on the presence of the currently well-recognized secretory leader sequence motif And hybridization by various PCRs or with low stringency More recent "indirect" cloning methods, such as the dicing cloning method Is secreted in the case of cloning of the leader sequence. Or biological activity depending on the cell or tissue source in the case of the PCR method. Access to numerous DNA / amino acid sequences for proteins known to be Has improved the status quo. The present invention provides these proteins and their Mode Which are directed to the polynucleotide.                                Summary of the Invention   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising one nucleotide sequence;   (B) SEQ ID NO: A nucleotide from nucleotide 12 to nucleotide 800 of 1 A polynucleotide comprising an otide sequence;   (C) SEQ ID NO: A nucleotide from nucleotide 78 to nucleotide 800 of 1 A polynucleotide comprising an otide sequence;   (D) SEQ ID NO: Nucleotide from nucleotide 1 to nucleotide 547 of 1 A polynucleotide comprising a nucleotide sequence;   (E) clone bh389_1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of one full length protein coding sequence;   (F) clone bh389_1 deposited under accession number ATCC 98451 Polynucleic acid encoding full length protein encoded by one cDNA insert Leotide;   (G) Clone bh389_1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of one mature protein coding sequence;   (H) clone bh389_1 deposited under accession number ATCC 98451 Polynucleic acid encoding mature protein encoded by one cDNA insert Leotide;   (I) SEQ ID NO: Polynucleotide encoding a protein comprising amino acid sequence 2 Tide;   (J) SEQ ID NO: having biological activity: 2 A polynucleotide encoding the protein (the fragment is SEQ ID NO: 2 of 8 Contiguous amino acids);   (K) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (h) above Nucleotides;   (L) A polynucleotide encoding a species homolog of the protein of (i) or (j) above Otide; and   (M) any one of the polynucleotides (a) to (j) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 1 nucleotide 12 A nucleotide sequence from to nucleotide 800; SEQ ID NO: 1 nucleotide 7 A nucleotide sequence from 8 to 800 nucleotides; SEQ ID NO: 1 nucleotchi A nucleotide sequence from nucleotide 1 to nucleotide 547; Accession number ATCC 984 51 of the full-length protein coding sequence of clone bh38911 deposited as Nucleotide sequence; Or claw deposited under accession number ATCC 98451 Bh38911 contains the nucleotide sequence of the mature protein coding sequence. other In a preferred embodiment of The polynucleotide is Accession number ATCC 98451 Encoded by the cDNA insert of clone bh38911 deposited as Encodes the full-length or mature protein to be produced. In still other preferred embodiments , The present invention SEQ ID NO: Amino acid sequence from amino acid 1 to amino acid 178 of 2 And a polynucleotide encoding a protein comprising: Further preferred embodiments At The present invention SEQ ID NO: with biological activity 2 amino acid sequence Polynucleotide encoding the protein containing the fragment (the fragment has the sequence number: 2, Preferably eight, More preferably 20, Most preferably 30 (Consecutive amino acids), Alternatively, SEQ ID NO: having biological activity Ami of 2 A polynucleotide encoding a protein containing a fragment of the amino acid sequence (the fragment Is the sequence number: The amino acid sequence from amino acid 126 to amino acid 135 of Including).   Another specific example is SEQ ID NO: A gene corresponding to one cDNA sequence is provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: The amino acid sequence of 2;   (B) SEQ ID NO: An amino acid sequence of two amino acids 1 to 178;   (C) SEQ ID NO: Comprising two eight consecutive amino acids, SEQ ID NO: 2 amino Fragments of an acid sequence; and   (D) clone bh389_1 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert 1 Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such a protein array number: Amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 2 amino acids 1 to 178 Includes the amino acid sequence at In a further preferred embodiment, The present invention biology Having active activity: Protein containing a fragment of the amino acid sequence of Segment is SEQ ID NO: 2, Preferably eight, More preferably 20, Most preferred Or 30 consecutive amino acids), Or a sequence having biological activity number: A protein comprising a fragment of the amino acid sequence of SEQ ID NO: 2 comprising the amino acid sequence from amino acid 126 to amino acid 135) .   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising the nucleotide sequence of 3;   (B) SEQ ID NO: Includes 3 nucleotides 100 to 882 A polynucleotide;   (C) SEQ ID NO: Includes 3 nucleotides 635 to 867 A polynucleotide;   (D) clone bk1121 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of 5 of the full-length protein coding sequence;   (E) clone bk1121 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert 5 Tide;   (F) clone bk1121 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of 5;   (G) clone bk1121 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert 5 Tide;   (H) SEQ ID NO: Polynucleotide encoding a protein containing amino acid sequence 4 ;   (I) SEQ ID NO: having biological activity: 4 including a fragment of the amino acid sequence A polynucleotide encoding the protein (the fragment is SEQ ID NO: 4 of 8 Contiguous amino acid sequences);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Do; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: Nucleotide 3 of 100 A nucleotide sequence from to nucleotide 882; SEQ ID NO: 3 nucleotides A nucleotide sequence from 635 to nucleotide 867; Accession number ATCC98 Full length protein coding sequence of clone bk11215 deposited as 451 A nucleotide sequence of Or a black deposit deposited under accession number ATCC 98451. Bk112 15 contains the nucleotide sequence of the mature protein coding sequence. In another preferred embodiment, The polynucleotide is Accession number ATCC 9845 The cDNA insert of clone bk11215 deposited as Encodes the full-length or mature protein to be encoded. In still other preferred embodiments hand, The present invention SEQ ID NO: Amino acids from amino acid 200 to amino acid 256 of 4 A polynucleotide encoding a protein comprising an acid sequence is provided. More favored In a specific example, The present invention SEQ ID NO: with biological activity Four A polynucleotide encoding a protein comprising a fragment of the amino acid sequence (the polynucleotide The fragment is SEQ ID NO: 4, Preferably eight, More preferably 20, most Preferably 30 consecutive amino acids), Or have biological activity SEQ ID NO: Polynucleotide encoding a protein containing a fragment of amino acid sequence 4 Otide (the fragment is SEQ ID NO: 4 amino acids 125 to 134 Including the amino acid sequence at   Another specific example is SEQ ID NO: 3 provide the genes corresponding to the cDNA sequences.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: The amino acid sequence of 4;   (B) SEQ ID NO: Amino acid sequence from amino acid 200 to amino acid 256 of 4 ;   (C) SEQ ID NO: Comprising four consecutive eight amino acids; SEQ ID NO: Amino of 4 Fragments of an acid sequence; and   (D) clone deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of bk11215 Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins have the sequence number: Amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: Amino acid 200 to amino acid 25 of 4 Includes up to 6 amino acid sequences. In a further preferred embodiment, The present invention Raw SEQ ID NO: with physical activity Protein containing a fragment of the amino acid sequence of The fragment is SEQ ID NO: 4, Preferably eight, More preferably 20, Most favorable Preferably containing 30 consecutive amino acids), Alternatively, a biologically active Column index: Protein containing a fragment of the amino acid sequence of SEQ ID NO: 4 issue: 4 including the amino acid sequence from amino acid 125 to amino acid 134) I do.   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising the nucleotide sequence of 5;   (B) SEQ ID NO: 5 nucleotides from nucleotide 245 to nucleotide 520 A polynucleotide comprising a reotide sequence;   (C) SEQ ID NO: 5 nucleotides from nucleotide 181 to nucleotide 527 A polynucleotide comprising a reotide sequence;   (D) clone bk200 1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of 3 full length protein coding sequences;   (E) clone bk200 1 deposited under accession number ATCC 98451 Polynucleic acid encoding full length protein encoded by cDNA insert 3 Leotide;   (F) clone bk200 1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of 3;   (G) clone bk200 1 deposited under accession number ATCC 98451 Polynucleic acid encoding mature protein encoded by cDNA insert of No. 3 Leotide;   (H) SEQ ID NO: Polynucleotide encoding a protein containing the amino acid sequence of SEQ ID NO: 6 Tide;   (I) SEQ ID NO: having biological activity: 6 amino acid sequence fragments A polynucleotide encoding the protein (the fragment is SEQ ID NO: 6 of 8 Contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 5 nucleotides 245 A nucleotide sequence from to nucleotide 520; SEQ ID NO: 5 nucleotides A nucleotide sequence from 181 to nucleotide 527; Accession number ATCC98 Full length protein coding sequence of clone bk20013 deposited as 451 A nucleotide sequence of Or a black deposit deposited under accession number ATCC 98451. Bk200 13 contains the nucleotide sequence of the mature protein coding sequence. In another preferred embodiment, The polynucleotide is Accession number ATCC 9845 The cDNA insert of clone bk20013 deposited as No. 1 Encodes the full-length or mature protein to be encoded. In a further preferred embodiment, The present invention SEQ ID NO: with biological activity 6 fragments of the amino acid sequence A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: Six , Preferably eight, More preferably 20, Most preferably, 30 consecutive addresses Amino acids), Alternatively, SEQ ID NO: having biological activity 6 of the amino acid sequence A polynucleotide encoding a protein comprising a fragment (the fragment number: 6 amino acids 41 to 50). You.   Another specific example is SEQ ID NO: Genes corresponding to 5 cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: The amino acid sequence of 6;   (B) SEQ ID NO: Comprising 6 eight consecutive amino acids, SEQ ID NO: Amino 6 Fragments of an acid sequence; and   (C) clone deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of bk20013 Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: 6 amino acid sequences. In a further preferred embodiment, The present invention , SEQ ID NO: with biological activity Protein containing fragment of amino acid sequence 6 (The fragment has SEQ ID NO: 6, Preferably eight, More preferably 20, Most preferably contains 30 consecutive amino acids), Or have biological activity SEQ ID NO: A protein comprising a fragment of the amino acid sequence of Array number: 6 comprising the amino acid sequence from amino acid 41 to amino acid 50). You.   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising the nucleotide sequence of SEQ ID NO: 7;   (B) SEQ ID NO: A nucleotide from nucleotide 365 of nucleotide 7 to nucleotide 784 A polynucleotide comprising a reotide sequence;   (C) SEQ ID NO: A nucleotide from nucleotide 518 of nucleotide 7 to nucleotide 784; A polynucleotide comprising a reotide sequence;   (D) clone di386_3 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone di386_3 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone di386_3 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) Clone di386_3 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) SEQ ID NO: Polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 8 Tide;   (I) SEQ ID NO: having biological activity: 8 amino acid sequence fragments A polynucleotide encoding the protein (the fragment is SEQ ID NO: 8 of 8 Contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: Nucleotide 365 at 7 A nucleotide sequence from to nucleotide 784; SEQ ID NO: 7 nucleotides A nucleotide sequence from 518 to nucleotide 784; Accession number ATCC98 451 of the full-length protein coding sequence of clone di3863 deposited as 451 Nucleotide sequence; Or claw deposited under accession number ATCC 98451 And the nucleotide sequence of the mature protein coding sequence of di386_3. other In a preferred embodiment, The polynucleotide is Accession number ATCC 98451 and Encoded by the cDNA insert of clone di3863 deposited Encodes a full-length or mature protein. In still other preferred embodiments, Book The invention is SEQ ID NO: Contains the amino acid sequence from 8 amino acids 1 to 140 A polynucleotide encoding the protein. Still other preferred tools In the example, SEQ ID NO: with biological activity Fragment of amino acid sequence 8 A polynucleotide encoding a protein containing 8, Preferably eight, More preferably 20, Most preferably 30 consecutive Amino acids), Alternatively, SEQ ID NO: having biological activity 8 amino acid sequences A polynucleotide encoding a protein comprising a fragment of the sequence (the fragment SEQ ID NO: 8 (including the amino acid sequence from amino acid 65 to amino acid 74). Offer.   Another specific example is SEQ ID NO: 7 or SEQ ID NO: Genetics corresponding to 9 cDNA sequences Provide a child.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: The amino acid sequence of 8;   (B) SEQ ID NO: An amino acid sequence of 8 amino acids 1 to 140;   (C) SEQ ID NO: Comprising eight consecutive amino acids of eight, SEQ ID NO: 8 amino Fragments of an acid sequence; and   (D) clone di386_3 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: Amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 8 amino acids 1 to 140 Up to and including the amino acid sequence. In a further preferred embodiment, The present invention Creature SEQ ID NO: with biological activity Protein containing a fragment of the amino acid sequence of The fragment is SEQ ID NO: 8, Preferably eight, More preferably 20, Most favorable Preferably containing 30 consecutive amino acids), Alternatively, a biologically active Column index: A protein comprising a fragment of the amino acid sequence of SEQ ID NO: 8 issue: 8 amino acids 65 to 74 (including the amino acid sequence from amino acid 65 to amino acid 74). .   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising the nucleotide sequence of 10;   (B) SEQ ID NO: 10 nucleotides 191 to 781 A polynucleotide comprising a nucleotide sequence;   (C) SEQ ID NO: Nuku from nucleotide 56 to nucleotide 492 of 10 A polynucleotide comprising a reotide sequence;   (D) Clone em3972 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone em3972 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone em3972 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) Clone em3972 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) SEQ ID NO: Polynucleotide encoding a protein comprising 11 amino acid sequences Otide;   (I) SEQ ID NO: having biological activity: Fragment of 11 amino acid sequence A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 11 Of 8 amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 10 nucleotides 19 A nucleotide sequence from 1 to nucleotide 781; SEQ ID NO: 10 nucleos A nucleotide sequence from nucleotide 56 to nucleotide 492; Accession number ATCC9 Full length protein coding sequence of clone em3972 deposited as 8451 A nucleotide sequence of Or a black deposit deposited under accession number ATCC 98451. The nucleotide sequence of the mature protein coding sequence of the gene em3972. other In a preferred embodiment of The polynucleotide is Accession number ATCC 98451 Encoded by the cDNA insert of clone em3972 deposited as Encodes the full-length or mature protein to be derived. In still other preferred embodiments, The present invention SEQ ID NO: Amino acid sequence from 11 amino acids 1 to 101 And a polynucleotide encoding a protein comprising: Further preferred embodiments At The present invention SEQ ID NO: with biological activity 11 amino acid sequence A polynucleotide encoding a fragment-containing protein (the fragment Column index: Eleven of Preferably eight, More preferably 20, Most preferably 30 Contiguous amino acids), Alternatively, SEQ ID NO: having biological activity 11 A polynucleotide encoding a protein comprising a fragment of the amino acid sequence of The fragment is SEQ ID NO: 11 amino acids from amino acid 93 to amino acid 102 (Including sequences).   Another specific example is SEQ ID NO: Genes corresponding to 10 cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 11 amino acid sequences;   (B) SEQ ID NO: 11 amino acid sequences from amino acid 1 to amino acid 101;   (C) SEQ ID NO: Comprising 11 eight consecutive amino acids SEQ ID NO: Eleven a Fragments of the amino acid sequence; and   (D) Clone em3972 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: 11 amino acid sequences or SEQ ID NO: 11 amino acids 1 to 1 Includes up to 01 amino acid sequences. In a further preferred embodiment, The present invention SEQ ID NO: with biological activity Protein containing a fragment of 11 amino acid sequences (The fragment has SEQ ID NO: Eleven of Preferably eight, More preferably 20 , Most preferably contains 30 consecutive amino acids), Or biological activity SEQ ID NO: Protein containing a fragment of the amino acid sequence of Is the sequence number: Contains the amino acid sequence from amino acid 93 to amino acid 102 of 11 ).   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising 12 nucleotide sequences;   (B) SEQ ID NO: The nucleotides from nucleotide 65 to nucleotide 1636 of 12 A polynucleotide comprising a nucleotide sequence;   (C) SEQ ID NO: 12 nucleotides 482 to 1636 A polynucleotide comprising a nucleotide sequence;   (D) SEQ ID NO: 12 nucleotides 487 to 1006 A polynucleotide comprising a nucleotide sequence;   (E) Clone fh170 7 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (F) Clone fh170 7 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (G) Clone fh170 7 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (H) clone fh170 7 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (I) SEQ ID NO: Polynucleotide encoding a protein containing 13 amino acid sequences Otide;   (J) SEQ ID NO: having biological activity: 13 amino acid sequence fragments A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 13 8 contiguous amino acids);   (K) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (h) above Nucleotides;   (L) A polynucleotide encoding a species homolog of the protein of (i) or (j) above Otide; and   (M) any one of the polynucleotides (a) to (j) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 12 nucleotides 65 A nucleotide sequence from to nucleotide 1636; SEQ ID NO: 12 nucleos A nucleotide sequence from Tide 482 to nucleotide 1636; SEQ ID NO: 12 A nucleotide sequence from nucleotide 487 to nucleotide 1006 of Commissioned Full length protein clone fh1707 deposited under accession number ATCC 98451 Nucleotide sequence of the loading sequence; Or as accession number ATCC 98451 Nucleotides of the mature protein coding sequence of the deposited clone fh1707 Contains an array. In another preferred embodiment, The polynucleotide is Accession number CDNA insert of clone fh1707 deposited as ATCC 98451 Encodes the full-length or mature protein encoded by the plate. Still other favors In a specific example, The present invention SEQ ID NO: 13 amino acids 142 to 3 A polynucleotide encoding a protein comprising up to 14 amino acid sequences is provided. In a further preferred embodiment, The present invention SEQ ID NO: with biological activity Polynucleotide encoding a protein comprising a fragment of 13 amino acid sequences C (the fragment is SEQ ID NO: Thirteen, Preferably eight, More preferably 20 Pieces, Most preferably contains 30 consecutive amino acids), Or biological activity SEQ ID NO: having Encodes a protein containing a fragment of 13 amino acid sequences A polynucleotide (the fragment is SEQ ID NO: Amino acid from 13 amino acids 257 (Including the amino acid sequence up to amino acid 266).   Another specific example is SEQ ID NO: Genes corresponding to the twelve cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 13 amino acid sequences;   (B) SEQ ID NO: Amino acid sequence from amino acid 142 to amino acid 314 of 13 Column;   (C) SEQ ID NO: Comprising 13 eight consecutive amino acids, SEQ ID NO: 13 a Fragments of the amino acid sequence; and   (D) clone fh170 7 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: 13 amino acid sequence or SEQ ID NO: 13 amino acids 142 to amino Includes the amino acid sequence up to acid 314. In a further preferred embodiment, The present invention Is SEQ ID NO: with biological activity Includes fragments of 13 amino acid sequences Protein (the fragment is SEQ ID NO: Thirteen, Preferably eight, More preferably 2 0, Most preferably contains 30 consecutive amino acids), Or biological activity SEQ ID NO: Protein containing a fragment of the amino acid sequence of Segment is SEQ ID NO: 13 amino acids from amino acid 257 to amino acid 266 (Including sequences).   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising 15 nucleotide sequences;   (B) SEQ ID NO: 15 nucleotides from nucleotide 41 to nucleotide 550 A polynucleotide comprising a reotide sequence;   (C) of clone fn534 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence;   (D) of clone fn534 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert Tide;   (E) of clone fn534 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence;   (F) of clone fn534 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert Tide;   (G) SEQ ID NO: Polynucleotide encoding a protein containing 16 amino acid sequences Otide;   (H) SEQ ID NO: having biological activity: Fragment of 16 amino acid sequence A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 16 8 contiguous amino acids);   (I) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (f) above Nucleotides;   (J) A polynucleotide encoding a species homolog of the protein of (g) or (h) above. Otide; and   (K) any one of the polynucleotides (a) to (h) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 15 nucleotides 41 A nucleotide sequence from to nucleotide 550; Accession number ATCC 98451 Of the full-length protein coding sequence of clone fn534 deposited as Tide sequence; Or clone fn5 deposited under accession number ATCC 98451 Contains the nucleotide sequence of the 34 mature protein coding sequences. Other preferred equipment In the example, The polynucleotide is Deposited under accession number ATCC 98451 Full length encoded by the cDNA insert of cloned fn534 or Encodes a mature protein. In a further preferred embodiment, The present invention Sequence number : Coding a protein containing an amino acid sequence from 16 amino acids 40 to 170 A polynucleotide to be loaded. In a further preferred embodiment, The present invention Is SEQ ID NO: with biological activity Includes fragments of 16 amino acid sequences A polynucleotide encoding the protein (the fragment is SEQ ID NO: 16 of Preferably eight, More preferably 20, Most preferably 30 contiguous nets Acid)), Alternatively, SEQ ID NO: having biological activity Of the 16 amino acid sequences A polynucleotide encoding a protein comprising a fragment (the fragment number: 16 amino acids from 80 to 89) I do.   Another specific example is SEQ ID NO: 15, SEQ ID NO: 14 or SEQ ID NO: 17 cDN A gene corresponding to the A sequence is provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 16 amino acid sequences;   (B) SEQ ID NO: Amino acid sequence from 16 amino acids 40 to 170 ;   (C) SEQ ID NO: Comprising 16 eight consecutive amino acids, SEQ ID NO: 16 a Fragments of the amino acid sequence; and   (D) of clone fn534 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: 16 amino acid sequences or SEQ ID NO: 16 amino acids 40 to amino acids Includes up to 170 amino acid sequences. In a further preferred embodiment, The present invention , SEQ ID NO: with biological activity A protein containing a fragment of 16 amino acid sequences White (the fragment is SEQ ID NO: 16 of Preferably eight, More preferably 20 Pieces, Most preferably contains 30 consecutive amino acids), Or biological activity SEQ ID NO: having A protein containing a fragment of 16 amino acid sequences (the fragment Is the sequence number: Includes the amino acid sequence from 16 amino acids 80 to 89 ).   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising 18 nucleotide sequences;   (B) SEQ ID NO: Nuku from nucleotide 84 to nucleotide 404 of 18 A polynucleotide comprising a reotide sequence;   (C) SEQ ID NO: Nuku from nucleotide 78 to nucleotide 493 of 18 A polynucleotide comprising a reotide sequence;   (D) clone fq505 4 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) clone fq505 4 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) clone fq505 4 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) clone fq5054 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) SEQ ID NO: Polynucleotide encoding a protein containing 19 amino acid sequences Otide;   (I) SEQ ID NO: having biological activity: Fragment of 19 amino acid sequence A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 19 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 18 nucleotides 84 A nucleotide sequence from to nucleotide 404; SEQ ID NO: 18 nucleoti Nucleotide sequence from nucleotide 78 to nucleotide 493; Accession number ATCC98 451 of the full-length protein coding sequence of clone fq5054 deposited as Nucleotide sequence; Or claw deposited under accession number ATCC 98451 And the nucleotide sequence of the mature protein coding sequence of fq5054. other In a preferred embodiment, The polynucleotide is Accession number ATCC 98451 and Encoded by the cDNA insert of clone fq5054 Encodes a full-length or mature protein. In still other preferred embodiments, Book The invention is SEQ ID NO: Amino acid sequence from 19 amino acids 23 to 107 And a polynucleotide encoding a protein comprising: Further preferred embodiments At The present invention SEQ ID NO: with biological activity 19 amino acid sequence A polynucleotide encoding a fragment-containing protein (the fragment Column index: 19, Preferably eight, More preferably 20, Most preferably 30 Contiguous amino acids), Alternatively, SEQ ID NO: having biological activity 19 A polynucleotide encoding a protein comprising a fragment of the amino acid sequence of The fragment is SEQ ID NO: Amino acid sequence from amino acid 48 to amino acid 57 of 19 Including columns).   Another specific example is SEQ ID NO: Genes corresponding to 18 cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 19 amino acid sequences;   (B) SEQ ID NO: Amino acid sequence from 19 amino acids 23 to 107 ;   (C) SEQ ID NO: Comprising 19 eight consecutive amino acids, SEQ ID NO: 19 a Fragments of the amino acid sequence; and   (D) clone fq505 4 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins have the sequence number: 19 amino acid sequences or SEQ ID NO: 19 amino acids 23 to amino acids 1 Includes up to 07 amino acid sequences. In a further preferred embodiment, The present invention SEQ ID NO: with biological activity Protein containing a fragment of 19 amino acid sequences (The fragment has SEQ ID NO: 19, Preferably eight, More preferably 20 , Most preferably contains 30 consecutive amino acids), Or biological activity SEQ ID NO: A protein containing a fragment of the amino acid sequence of 19 (the fragment Is the sequence number: Contains the amino acid sequence from 19 amino acids 48 to 57 )I will provide a.   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising 20 nucleotide sequences;   (B) SEQ ID NO: 20 nucleotides 1439 to 1744 A polynucleotide comprising the nucleotide sequence of   (C) SEQ ID NO: 20 nucleotides 1241 to 1754 A polynucleotide comprising the nucleotide sequence of   (D) of clone fw139 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence;   (E) of clone fw139 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert Tide;   (F) of clone fw139 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence;   (G) of clone fw139 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert Tide;   (H) SEQ ID NO: Polynucleotide encoding a protein comprising 21 amino acid sequences Otide;   (I) SEQ ID NO: having biological activity: 21 amino acid sequence fragments A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 21 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 20 nucleotides 14 A nucleotide sequence from 39 to nucleotide 1744; SEQ ID NO: 20 Nuku A nucleotide sequence from leotide 1241 to nucleotide 1754; Accession number Full length protein code of clone fw139 deposited as ATCC 98451 Nucleotide sequence of the signaling sequence; Or deposited under accession number ATCC 98451. Containing the nucleotide sequence of the mature protein coding sequence of clone fw139 No. In another preferred embodiment, The polynucleotide is Accession number ATCC98 451 deposited with the cDNA insert of clone fw139. Encodes the full-length or mature protein to be encoded. In still other preferred embodiments hand, The present invention SEQ ID NO: Amino acid sequence from amino acid 1 to amino acid 57 of 21 A polynucleotide encoding a protein comprising the sequence is provided. Further preferred specifics In the example, The present invention SEQ ID NO: with biological activity 21 amino acid sequences A polynucleotide encoding a protein containing a fragment of the sequence (the fragment Is the sequence number: 21 of Preferably eight, More preferably 20, Most preferred Contains 30 consecutive amino acids), Or SEQ ID NO: having biological activity : Polynucleotide encoding a protein comprising a fragment of 21 amino acid sequence (The fragment has SEQ ID NO: 21 amino acids 46 to 55 amino acids (Including a noic acid sequence).   Another specific example is SEQ ID NO: Genes corresponding to the 20 cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 21 amino acid sequences;   (B) SEQ ID NO: 21 amino acid sequences from amino acid 1 to amino acid 57;   (C) SEQ ID NO: Comprising 21 eight consecutive amino acids; SEQ ID NO: 21 a Fragments of the amino acid sequence; and   (D) of clone fw139 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins are Distribution Column index: 21 amino acid sequence or SEQ ID NO: 21 amino acids 1 to 5 Includes up to 7 amino acid sequences. In a further preferred embodiment, The present invention Raw SEQ ID NO: with physical activity: A protein containing a fragment of the 21 amino acid sequence ( The fragment has SEQ ID NO: 21 of Preferably eight, More preferably 20, Most preferably contains 30 consecutive amino acids), Or have biological activity SEQ ID NO: A protein comprising a fragment of the 21 amino acid sequence (the fragment Is the sequence number: (Including the amino acid sequence from 21 amino acids 46 to 55) I will provide a.   In one specific example, The present invention An isolation port selected from the group consisting of: Provide a composition comprising a renucleotide:   (A) SEQ ID NO: A polynucleotide comprising 22 nucleotide sequences;   (B) SEQ ID NO: 22 nucleotides from nucleotide 47 to nucleotide 919 A polynucleotide comprising a reotide sequence;   (C) SEQ ID NO: 22 nucleotides from nucleotide 124 to nucleotide 452 A polynucleotide comprising a nucleotide sequence;   (D) clone gg6192 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone gg6192 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone gg6192 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) clone gg6192 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) SEQ ID NO: Polynucleotide encoding a protein comprising 23 amino acid sequences Otide;   (I) SEQ ID NO: having biological activity: 23 fragments of amino acid sequence A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 23 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions A polynucleotide capable of hybridizing to   Preferably, Such a polynucleotide is SEQ ID NO: 22 nucleotides 47 A nucleotide sequence from to nucleotide 919; SEQ ID NO: 22 nucleoti A nucleotide sequence from nucleotide 124 to nucleotide 452; Accession number ATCC9 Full length protein coding sequence of clone gg6192 deposited as 8451 Sequence nucleotide sequence; Or the deposit deposited under accession number ATCC 98451. Contains the nucleotide sequence of the mature protein coding sequence of Lone gg6192. In another preferred embodiment, The polynucleotide is Accession number ATCC 9845 Coded by cDNA insert of clone gg6192 deposited as No. 1. Encodes the full-length or mature protein to be produced. In still other preferred embodiments , The present invention SEQ ID NO: 23 amino acids 27 to 135 amino acids A polynucleotide encoding a protein comprising the sequence is provided. Further preferred equipment In the example, The present invention SEQ ID NO: with biological activity Amino acid sequence of 23 A polynucleotide encoding a protein comprising a fragment of Is the sequence number: 23 of Preferably eight, More preferably 20, Most preferably Containing 30 consecutive amino acids), Alternatively, SEQ ID NO: having biological activity A polynucleotide encoding a protein comprising a fragment of 23 amino acid sequences ( The fragment has SEQ ID NO: 23 amino acids 140 to 149 Including a amino acid sequence).   Another specific example is SEQ ID NO: Genes corresponding to 22 cDNA sequences are provided.   In another embodiment, The present invention A composition comprising a protein, The protein is   (A) SEQ ID NO: 23 amino acid sequences;   (B) SEQ ID NO: Amino acid sequence from amino acid 27 to amino acid 135 of 23 ;   (C) SEQ ID NO: Comprising 23 eight consecutive amino acids; SEQ ID NO: 23 a Fragments of the amino acid sequence; and   (D) clone gg6192 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of Comprising an amino acid sequence selected from the group consisting of: Other mammalian proteins A composition is provided that is substantially free. Preferably, Such proteins have the sequence number: 23 amino acid sequences or SEQ ID NOs: Amino acid 27 of the amino acid sequence of 23 To amino acid 135. In a further preferred embodiment hand, The present invention SEQ ID NO: with biological activity Fragmentation of 23 amino acid sequences Protein (the fragment is SEQ ID NO: 23 of Preferably eight, Better Preferably 20 Most preferably contains 30 consecutive amino acids), Or SEQ ID NO: with biological activity Protein containing a fragment of 23 amino acid sequences (The fragment has SEQ ID NO: 23 amino acids 140 to 149 Including an amino acid sequence).   In certain preferred embodiments, Polynucleotide can act on expression control sequences Linked to Noh. The present invention also provides Transformed with such a polynucleotide composition Was Bacteria, yeast, Host cells are provided, including insect and mammalian cells. Also , Of the gene corresponding to the polynucleotide sequence disclosed herein, Promotion, Decline, Also Is provided by the present invention for organisms having modified expression.   further, A method for producing a protein,   (A) culturing a host cell culture transformed with such a polynucleotide composition; Grown in the appropriate medium; Incidentally   (B) purifying the protein from the culture There is also provided a method comprising: Proteins produced by such methods are also Departure It is provided by Ming. As a preferred specific example, Manufactured by such a method And the protein to be produced is a mature form of the protein.   The protein composition of the present invention, It may further contain a pharmaceutically acceptable carrier. Or A composition comprising an antibody that specifically reacts with the protein, Provided by the present invention.   Administering a therapeutically effective amount of a composition comprising a protein of the invention and a pharmaceutically acceptable carrier. Administering to an animal subject, Prevention of medical conditions, For treatment or improvement A law is also provided.                             BRIEF DESCRIPTION OF THE FIGURES   1A and 1B show pED6 and pED6 used for depositing the clones disclosed herein. And pNOTs vectors are shown schematically.                                Detailed description Isolated proteins and polynucleotides   Nucleotides for each of the clones and proteins disclosed herein And amino acid sequences are reported below. Sequencing of the deposited clone by a known method To easily determine the actual nucleotide sequence of each clone Can be. The deduced amino acid sequence (both full length and mature) is then It can be determined from the leotide sequence. Express the clone in a suitable host cell. And collect the protein, then determine its sequence to determine The amino acid sequence of the encoded protein can also be determined. Each disclosed For proteins, applicants best identify using sequence information available at the time of filing Those determined to be possible reading frames were identified.   As used herein, the term "secreted" protein refers to a membrane when expressed in a suitable host cell. Refers to those that are transported through, and the result of the signal sequence in that amino acid sequence Transportation is also included. "Secreted" proteins are secreted entirely by the cells in which they are expressed. Proteins (eg, soluble proteins) or partially secreted proteins (eg, receptors) ), But not limited thereto. Also, "secreted" proteins pass through the membrane of the endoplasmic reticulum Including but not limited to those transported byClone "bh389 11"   The polynucleotide of the present invention has been identified as clone "bh38911". bh38911 is a method selective for cDNAs encoding secreted proteins (US From the adult thyroid cDNA library using Isolated or based on computer analysis of the amino acid sequence of the encoded protein. And encoding a secreted or transmembrane protein. bh389 11 is a full-length clone, which is a secretory protein (hereinafter referred to as "bh389 11 protein"). ) Is also included.   The nucleotide sequence of bh38911 determined this time is shown in SEQ ID NO: 1. The present applicant has determined that the bh38911 protein corresponding to the nucleotide sequence The reading frame and what is deemed to be the deduced amino acid sequence are shown in SEQ ID NO: 2. Ami Noic acids 10 to 22 are putative leader / signal sequences and putative mature amino acids The sequence starts at amino acid 23, or amino acids 10 to 22 are transmembrane The main. According to the TopPredII computer program, bh389 1 Potential transmembrane domain around amino acid 68 of SEQ ID NO: 2 in one protein sequence The main is predicted.   Another potential bh38911 reading frame and deduced amino acid sequence are It is encoded by base pair 757 to 1833 of No. 1, which corresponds to SEQ ID NO: 34. Nucleotides 803 to 803 of SEQ ID NO: 1 The reading frame of SEQ ID NO: 1 and SEQ ID NO: 34 reading frames may be linked. TopPredII computer program According to the sequence, amino acid 35 of SEQ ID NO: 34 in the amino acid sequence of SEQ ID NO: 34 A potential transmembrane domain centered around 7 is predicted.   EcoRI / N obtainable from the deposit containing clone bh38911 The otI restriction fragment should be approximately 1700 bp in length.   The nucleotide sequence of bh38911 disclosed herein can be replaced with BLASTN / BLAST GenBank and GenSeq nucleotide sequences using X and FASTA search protocols Searched against the database. bh389 11 is AA307880 (EST178733 Col oncarcinoma (HCC) cell line Homo sapiens cDNA 5'end), AA442426 (zv70f06. r1 Soares total fetus Nb2HF8 9w Homo sapiens cDNA clone 759011 5 '), H701 03 (yr92f04.r1 Homo sapiens cDNA clone 212767 5 '), R19820 (yg37f12.r1 Homo  sapiens cDNA clone 34771 5 '), and W46238 (zc30e10.s1 Soares senescent f Sequence identified as ibroblasts NbHSF Homo sapiens cDNA clone 323850 3 ') Showed at least some similarity to Based on sequence similarity, bh3 8911 protein and each similar protein or peptide share at least some activity. May have.Clone "bk112 15"   The polynucleotide of the present invention has been identified as clone "bk11215". bk11215 is a method selective for cDNAs encoding secreted proteins (US (See Patent No. 5,536,637)). Or based on computer analysis of the amino acid sequence of the encoded protein Thus, it was identified as encoding a secretory protein or a transmembrane protein. bk112 1 5 is a full-length clone, which is a secretory protein (also referred to herein as “bk112 15 protein”). ) Is included.   The nucleotide sequence of bk11215 determined this time is shown in SEQ ID NO: 3. The present applicant has determined that the correct bk11215 protein corresponding to the nucleotide sequence The reading frame and what is considered the deduced amino acid sequence are shown in SEQ ID NO: 4.   EcoRI / N obtainable from the deposit containing clone bk11215 The otI restriction fragment should be approximately 1300 bp in length.   The nucleotide sequence of bk11215 disclosed herein can be obtained using BLASTA / BLASTX GenBank and GeneSeq databases using the FASTA and FASTA search protocols Searched against. bk112 15 is AA307119 (EST178031 Colon carcinoma ( HCC) cell line Homosapiens cDNA 5'end), AA318352 (EST20422 Retina II Hom o sapiens cDNA 5'end similar to similar to C. elegans hypothetical prot ein, cosmid ZK688.2), L20941 (Human ferritin heavy chain mRNA, complete c ds), M97164 (Human ferritin heavy chain mRNA, complete cds), N25339 (yx55d0 8.s1 Homo sapiens cDNA clone 265647 3 '), N31453 (yx55d08.r1 Homo sapiens cDNA clone 265647 5 '), and N33227 (yy07d02.s1 Homo sapiens cDNA clone 27 0531 3'similar to gb: L20941 FERRITIN HEAVY CHAIN (HUMAN)) Showed at least some similarity to the sequence. About bk112 15 The deduced amino acid sequence disclosed herein was compared to GenPept using the BLASTX search protocol. And GeneSeq amino acid sequence database. Estimated bk112 Fifteen protein has a sequence identified as Z68335 (C29F4.2 [Caenorhabditis elegans]). Showed at least some similarity to Based on sequence similarity, The bk11215 protein and each similar protein or peptide are at least partially active. May share a gender.Clone "bk200 13"   The polynucleotide of the present invention has been identified as clone "bk20013". bk20013 is a method selective for cDNA encoding secreted proteins (US (See Patent No. 5,536,637)). Or based on computer analysis of the amino acid sequence of the encoded protein Thus, it was identified as encoding a secretory protein or a transmembrane protein. bk200 1 3 is a full-length clone, which is a secretory protein (also referred to herein as “bk200 13 protein”). ) Is included.   The nucleotide sequence of bk20013 determined this time is shown in SEQ ID NO: 5. The present applicant has determined that the correct bk200 13 protein The reading frame and what is considered the deduced amino acid sequence are shown in SEQ ID NO: 6.   EcoRI / N obtainable from the deposit containing clone bk20013 The otI restriction fragment should be approximately 1000 bp in length.   The nucleotide sequence disclosed herein for bk20013 was used as a BLASTA / BLASTX GenBank and GeneSeq databases using the FASTA and FASTA search protocols Searched against. bk200 13 is AA098915 zk84f06.s1 Soares pregnant uterus NbHPU Homo sapiens cDNA clone 489539 3 '), AA150367 z1 07b06.r1 So ares pregnant uterus NbHPU Homo sapiens cDNA clone 491603 5 '), AA235904 ( zs40h05.r1 Soares NhHMPu S1 Homo sapiens cDNA clone 687705 5 '), N32487 (y x79g10.r1 Homo sapiens cDNA clone 268002 5 '), and T47862 (yb17g03.r1 Hom o At least for the sequence identified as sapiens cDNA clone 71476 5 ') It showed a degree of similarity. Based on sequence similarity, the bk200 13 protein and each Similar proteins or peptides may share at least some activity . Nucleotide sequence of bk200 13 may contain CAAAAA repeat-like There is.Clone "di386-3"   The polynucleotide of the present invention has been identified as clone di386-3. di3863 is a method selective for cDNA encoding secreted proteins (US No. 5,536,637) from an adult testis cDNA library. Or based on computer analysis of the amino acid sequence of the encoded protein Encoding a secretory or transmembrane protein. di386 3 is A full-length clone, which is a secretory protein (also referred to herein as "di386_3 protein"). ) Contains the entire coding sequence.   The nucleotide sequence of di386_3 determined this time is shown in SEQ ID NO: 7. now Arrange what the applicant considers to be the correct reading frame for the coding area No .: 8 Putative amino acid sequence of di386_3 protein corresponding to the above nucleotide sequence The amino acid sequence is shown in SEQ ID NO: 8. Amino acids 39 to 51 are putative leaders / Signal sequence, the predicted mature amino acid sequence starting at amino acid 52 or Is a transmembrane domain from amino acids 39 to 51. Amino acid of SEQ ID NO: 8 The leader / signal sequence could be as high as 17-29, suggesting a mature mature amino acid. The acid sequence starts at amino acid 30 or starts at amino acid 17 of SEQ ID NO: 8. Up to 29 are transmembrane domains. 3 'of di386_3, including a poly A tail The additional nucleotide sequence from the portion is shown in SEQ ID NO: 9.   EcoRI / No obtainable from the deposit containing clone di3863 The tI restriction fragment should be approximately 2000 bp long.   The nucleotide sequence of di386_3 disclosed herein can be modified using BLASTA / BLASTX and Against GenBank and GeneSeq databases using FAST and FASTA search protocols And searched. di386_3 is similar to the known sequences in these databases. No similarity was shown.Clone "em397 2"   The polynucleotide of the present invention has been identified as clone "em3972". e m3972 is a method that is selective for cDNAs encoding secreted proteins (US Pat. No. 5,536,637) from a human fetal kidney cDNA library. Or based on computer analysis of the amino acid sequence of the encoded protein And encoding a secreted or transmembrane protein. em397 2 is a full-length clone, which is a secretory protein (also referred to herein as "em3972 protein"). ) Contains the entire coding sequence.   The nucleotide sequence of em3972 determined this time is shown in SEQ ID NO: 10. Correct reading frame and estimation of em3972 protein corresponding to the above nucleotide sequence SEQ ID NO: 11 shows what the applicant considers to be the amino acid sequence.   EcoRI / No obtainable from the deposit containing clone em3972 The tI restriction fragment should be approximately 1250 bp in length.   The nucleotide sequence of em3972 disclosed herein can be modified using BLASTA / BLASTX and Against GenBank and GeneSeq databases using FAST and FASTA search protocols And searched. em3972 is AA092876 (m0851.seq.F Fetal heart, Lambda  ZAP Express Homo sapiens cDNA 5 '), AA180952 (zp41b06.r1 Stratagene muscl e 937209 Homo sapiens cDNA clone 611987 5 '), AA463323 (zx71f01.r1 Soares total fetus Nb2HF8 9w Homo sapiens), H87081 (ys74f01.r1 Homo sapiens cDNA  clone 220537 5 '), W56381 (zc57a01.r1 Soares parathyroid tumor NbHPA Homo  sapiens cDNA clone 326376 5 '), W88527 (zh73g02.s1 Soares fetal liver spl een 1NFLS S1 Homo sapiens cDNA clone 417746 3 '), and Z64565 (H. sapiens C pG island DNA genomic Msel fragment, clone 13d12, reverse read cpg13d12. It showed at least some similarity to the sequence identified as (rtlc). Distribution Based on sequence similarity, the em3972 protein and each similar protein or pair Peptides may share at least some activity.Clone "fh170 7"   The polynucleotide of the present invention has been identified as clone "fh1707". f h1707 is a method selective for cDNAs encoding secreted proteins (US Pat. No. 5,536,637) from a human fetal brain cDNA library. Or based on computer analysis of the amino acid sequence of the encoded protein Encoding a secretory or transmembrane protein. fh170 7 Is a full-length clone, and is a secretory protein (also referred to herein as "fh1707 protein"). ) Contains the entire coding sequence.   The nucleotide sequence of fh1707 determined this time is shown in SEQ ID NO: 12. This time, the applicant has read the correct reading of the fh1707 protein corresponding to the above nucleotide sequence. The sequence considered as the open frame and deduced amino acid sequence is shown in SEQ ID NO: 13. Amino acid 1 27 through 139 are a predicted leader / signal sequence, The amino acid sequence starts at amino acid 140, or amino acid 127 to amino acid Up to 139 are transmembrane domains.   EcoRI / No obtainable from the deposit containing clone fh1707 The tI restriction fragment should be approximately 2200 bp in length.   The nucleotide sequence of fh1707 disclosed herein can be modified using BLASTA / BLASTX and Against GenBank and GeneSeq databases using FAST and FASTA search protocols And searched. fh1707 is AA112479 (zn69a02.s1 Stratagene HeLa cell  s3 937216 Homo sapiens cDNA clone 563402 3 '), AA593402 (nn57g10.s1 NCI_C GAP_Kid6 Homo sapiens cDNA clone IMAGE: 1088034), Q76795 (Human genome fra gment), T26136 (Human gene signature HUMGS08373), and Z19759 (H. sapiens p utatively transcribed partial sequence; UK-HGMP sequence IDAAAALWX; single read) showed at least some similarity to the sequence identified as read. f The deduced amino acid sequence disclosed herein as h1707 was compared to the BALSTX search Search against GenPept and GeneSeq amino acid sequence databases using protocol did. The putative fh1707 protein is D32253 (MagA [Magnetospirillum sp.]) And At least some similarity to the sequence identified as WO1520 (MagAprotein) Showed sex. The putative fh1707 protein is other prokaryotic membrane transport protein (potassium flux). Export system proteins kefB and NaH-antiporter protein) Both showed some similarity. Based on sequence similarity, the fh1707 protein and And similar proteins or peptides share at least some activity Could be. According to the TopPredII computer program, fh170   7 amino acid 130 of SEQ ID NO: 13 in protein sequence; 160, 210, 230, 280, 310, 360, 380, 420, and 5 Ten potential transmembrane domains centered around each amino acid of 00 are predicted You.Clone "fn53 4"   The polynucleotide of the present invention has been identified as clone "fn534". fn 534 is a method selective for cDNA encoding a secreted protein (US Pat. No. 5,366,637) from a human fetal brain cDNA library; Alternatively, based on computer analysis of the amino acid sequence of the encoded protein, It was identified as encoding a secretory or transmembrane protein. fn534 is full length Loan and all secretory proteins (also referred to herein as “fn534 protein”). Contains the coding sequence.   The nucleotide sequence of fn534 determined this time is shown in SEQ ID NO: 14. now The further determined internal nucleotide sequence is shown in SEQ ID NO: 15. This application The correct reading frame and deduced amino acid sequence encoded by such an internal sequence No. 16 is shown in SEQ ID NO. Fh534-3, including poly-A tail The additional nucleotide sequence of the 'portion is shown in SEQ ID NO: 17.   EcoRI / Not obtainable from the deposit containing clone fn534 The I restriction fragment should be approximately 4100 bp in length.   The nucleotide sequence disclosed herein for fn534 is compared to BLASTA / BLASTX and GenBank and GeneSeq databases using the I searched. fn534 is AA179207 (zp46c11.s1 Stratagene HeLa cell s3 937216 Homo sapiens cDNA clone 612500 3 '), AA279207 (zs83e06.s1 NCI_CGAP_ GCB1 Homo sapiens cDNA clone IMAGE: 704098 3 ', mRNA sequence), H87151 (yw15 a06.s1 Homo sapiens cDNA clone 252274 3 '), and H83373 (ys90a09.r1 Homo s apiens cDNA clone 222040 5'similar to SP: BIC_DROME P16568 CYTOSKELETON- LIKEBICAUDALD) shows at least some similarity to the sequence identified as did. The deduced amino acid sequence disclosed herein as fn534 Columns were compared to GenPept and GeneSeq amino acid sequence data using the BALSTX search protocol. Searched against the database. Putative fn534 proteins are M31684 and X51652 (bic audalD protein [Drosophila melanogaster]) and R66930 (AMMLchromosome inv ( 16) show at least some similarity to the sequence identified as product) Was. Based on sequence similarity, the fn534 protein and each similar protein or The peptides may share at least some activity.Clone "fq505 4"   The polynucleotide of the present invention has been identified as clone fq5054. f q5054 is a method selective for cDNA encoding a secreted protein (US Pat. No. 5,536,637) from an adult testis cDNA library. Or based on computer analysis of the amino acid sequence of the encoded protein, It was identified as encoding a secreted or transmembrane protein. fq505 4 is all Long clone, secreted protein (also referred to herein as "fq5054 protein") Contains the entire coding sequence.   The nucleotide sequence of fq5054 determined this time is shown in SEQ ID NO: 18. Here, the applicant has determined that the correct reading of the fq5054 protein corresponding to the above nucleotide sequence The open frame and deduced amino acid sequence are shown in SEQ ID NO: 19.   EcoRI / No obtainable from the deposit containing clone fq5054 The tI restriction fragment should be approximately 512 bp in length.   The nucleotide sequence of fq5054 disclosed herein can be modified using BLASTA / BLASTX and Against GenBank and GeneSeq databases using FAST and FASTA search protocols And searched. fq5054 is expressed as Z71861 (C.hircus mRNA for EST2-31) It showed at least some similarity to the identified sequences. fq505 4 Using the deduced amino acid sequence disclosed herein as the BALSTX search protocol GenPept and GeneSeq amino acid sequence databases. Estimate f q5054 protein is P92141 (Recombinant human adult T cell leukaemia derived factor polypeptide), X54539 (thioredoxin [Homo sapiens]), and X77 584 (ATL-derived factor / thioredoxin [Homo sapiens]) It showed at least some similarity. FQ505 4 protein is surface bound A sequence identified as a sulfhydryl protein (GenProt accession number 135773) The columns also showed at least some similarity. The similarity between these proteins is It contains the WCGPC catalytic site, which is amino acid 3 of the putative fq505 4 protein. Present as RCGPC from 1 to 35. Has thioredoxin catalytic activity In addition, at least one thioredoxin-related protein is an "IL-2 receptor / Tac inducer ”(Tagaya et al., 1989, EMB) O J. 8 (3): 757-764). At least one thioredoxin-related protein on the plasma membrane It is reported that it is associated with, "The protein is one of the members of this membrane family. And are shown to act as essential growth factors. " (Martin and Dean, 1991, Biochem. Biophys. Res. Commun. 175 (1): 123-128) . Based on sequence similarity, the fq5054 protein and each similar protein or The peptides may share at least some activity.Clone "fw139"   The polynucleotide of the present invention has been identified as clone fw139. fw 139 describes a method selective for cDNA encoding a secreted protein (US Pat. 536637)) from an adult testis cDNA library. Or secretion based on computer analysis of the amino acid sequence of the encoded protein. It was identified as encoding a protein or transmembrane protein. fw139 is full length black And all the secretory proteins (also referred to herein as "fw139 protein"). Contains the coding sequence.   The nucleotide sequence of fw139 determined this time is shown in SEQ ID NO: 20. now Applicants have determined that the correct reading frame of the fw139 protein corresponding to the above nucleotide sequence And those considered to be deduced amino acid sequences are shown in SEQ ID NO: 21.   EcoRI / obtainable from the deposit containing clone fw139 NotI restriction fragments should be approximately 1900 bp in length.   The nucleotide sequence of fw139 disclosed herein can be compared to the BLASTX search protocol. Against the GenPept and GeneSeq amino acid sequence databases . The estimated fw139 is AA047557 (zf13f08.r1 Soares fetal heart NbHH19W Hom o sapiens cDNA clone 376839 5 '), AA284524 (zt20d07.s1 Soares ovary tumor NbHOT Homo sapiens cDNA clone 713677 3 '), AA502778 (ne43e04.s1 NCI_CGAP_C o3 Homo sapiens cDNA clone IMAGE: 900126), J04743 (M. musculus Ms6-hm locus , Repeat elements), R35040 (yh86a10.r1 Homo sapiens cDNA clone 136602 5 ') , T21414 (Human gene signature HUMGS02783), and U91318 (Human chromosome 16p13 BAC clone CIT987SK-962B4 complete sequence) It showed at least some similarity. Based on sequence similarity, fw13   9 proteins and each similar protein or peptide are at least partially active May have shared. According to the TopPredII computer program, potential around amino acid 30 of SEQ ID NO: 21 in the fw139 protein sequence A transmembrane domain is predicted.Clone “gg6192”   The polynucleotide of the present invention has been identified as clone gg6192. g g6192 is a method selective for cDNAs encoding secreted proteins (US Pat. No. 5,536,637) from a human fetal kidney cDNA library. Or based on computer analysis of the amino acid sequence of the encoded protein Thus, it was identified as encoding a secretory protein or a transmembrane protein. gg6192 Is a full-length clone and is a secreted protein (also referred to herein as "gg6192 protein"). ) Contains the entire coding sequence.   The nucleotide sequence of gg6192 determined this time is shown in SEQ ID NO: 22. Applicants have now correctly read the gg6192 protein corresponding to the above nucleotide sequence. The frame and what is considered the deduced amino acid sequence are shown in SEQ ID NO: 23.   EcoRI / obtainable from the deposit containing clone gg6192 / NotI restriction fragments should be approximately 1350 bp in length.   The nucleotide sequence of gg6192 disclosed herein was modified using BLASTA / BLASTX and Against GenBank and GeneSeq databases using FAST and FASTA search protocols And searched. gg6192 is obtained from N42957 (yy12bl2.r1 Homo sapiens cDNA clon e 271007 5'similar to SW: ALG5_YEAST P40350 dolichyl-phosphate beta-glu cosyltransferase), N50844 (yy91g05.s1 Homo sapiens cDNA clone 280952 3's imilar to SW: ALG5_YEAST P40350 dolichyl-phosphate beta-glucosyltransfera se), and N62597 (yz75a06.s1 Homo sapiens cDNA clone 288850 3'similar t o SW: ALG5_YEAST P40350 Dolichyl-phosphate beta-glucosyltransferase) Showed at least some similarity to the identified sequences. gg619 2 using the deduced amino acid sequence disclosed herein as the BALSTX search protocol. And used to search against GenPept and GeneSeq amino acid sequence databases. Estimation gg6192 protein is R38093 (nodC N-terminal portion [Bradyrhizobium sp. . (Parasponia)]) and X77573 (dolichyl-phosphate beta-glucosyl-transferas e [Saccharomyces cerevisiae]) It showed a degree of similarity. Enzyme UDP-glucose: dolicyl-glucosyl phosphate Transferase is an endoplasmic reticulum membrane-bound enzyme involved in N-linked glycosylation of proteins Catalyzes the transfer of glucose from UDP-glucose to doricyl phosphoric acid You. Based on sequence similarity, the gg6192 protein and each protein with similarity Or peptides may share at least some activity. TopPredI According to the I computer program, SEQ ID NO: in the gg6192 protein sequence: A potential transmembrane domain centered around 23 amino acids 188 is predicted.   Depositing clones   Clone bh389 11, bk112 15, bk200 13, di38 63, em397 2, fh170 7, fn53 4, fq505 4, f w139 and gg6192 are based on the Budapest Treaty in 1997 On June 10, American Type Culture Collection (10801 University Boulevard , Manassas, Virginia 20110-2209 U.S.A.) with accession number ATCC 98451. And the clone is available therefrom. For public use of deposited materials All restrictions that apply to 37 C.I. F. R. Except for the provisions of § 1.808 (b), patents Will be terminated upon grant, and the deposit period will be 37C. F. R. 61.806 Will follow.   Each clone is transfected into a separate bacterial cell (E. coli) as this complex deposit. Was transfected. EcoRI / NotI digestion (5 'site, EcoRI; 3' Site, NotI), and a fragment of appropriate size for such a clone. Thus, each clone can be obtained from the deposited vector. Each clone was placed in either the pED6 or pNOTs vector shown in FIG. Deposited. Insert a new polylinker to facilitate cDNA cloning Derived pED6dpc2 vector (pED6) from pED6dpc1 (Kaufman et al. (1991). NAR 19: 4485-4490). DHFR is deleted and a new By inserting a unique polylinker and inserting the M13 origin of replication into the ClaI site. The pNOTs vector was converted to pMT2 (Kaufman et al. 1989. Mol. Cell. Biol. 9: 1741-1750). In some cases, the deposited clone has been Flip "(that is, in the opposite direction). Even in such a case Alternatively, the cDNA insert can be isolated by EcoRI and NotI digestion. I However, in that case, the cDN must be in the correct orientation for expression in a suitable vector. To place A, NotI creates a 5 'site and EcoRI creates a 3' site. Will do. Expression of cDNA from vector where cDNA is deposited Is also good.   Obtaining bacterial cells, including individual clones, from the complex deposit as follows Can:   Oligonucleotides should be against known sequences for individual clones. Otide probes or probes should be designed. This sequence is It can be derived from a sequence, or a combination of those sequences. Each full length claw The oligonucleotide probe sequences used to isolate the , They should be the most reliable in isolating the clone of interest.clone Probe sequence bh389 11 SEQ ID NO: 24 bk112 15 SEQ ID NO: 25 bk200 13 SEQ ID NO: 26 di386 3 SEQ ID NO: 27 em397 2 SEQ ID NO: 28 fh170 7 SEQ ID NO: 29 fn53 4 SEQ ID NO: 30 fq505 4 SEQ ID NO: 31 fw13 9 SEQ ID NO: 32 gg6192 2 SEQ ID NO: 33   The sequence listed above contains an N at position 2, which position is a preferred probe / pump. Biotinylated phosphoramidites rather than nucleotides in primers Residues such as biotin phosphoramidite (1-dimethoxytrityloxy-2 -(N-biotinyl-4-aminobutyl) -propyl-3-O- (2-cyanoe Tyl)-(N, N'-diisopropyl) -phosphoramidite (Glen Research catalog Obtained by using log numbers 10-1953))).   Preferably, the design of the oligonucleotide probe follows these parameters. Should be:   (A) The region of the sequence where the number of unclear bases (N), if any, is minimal Should be designed to:   (B) Tm is about 80 ° C. (2 ° C. for A or T, 4 ° C. for G or C) (Assume ° C).   Preferably, a method widely used for oligonucleotide labeling is used, Oligonucleotides are converted to γ-³²P-ATP (specific activity 6000 Ci / mmole). Other labeling methods may be used it can. Preferably, the unincorporated label is gel filtered or otherwise established. Should be removed by any method The amount of radioactivity incorporated into the probe It should be quantified by measuring with a titration counter. Preferably, The specific activity of the probe obtained should be about 4e + 6 dpm / pmole .   Preferably, a bacterial culture containing a pool of full-length clones is thawed and 100 μl of Stock was added to 25 ml of sterile L-broth containing 100 μg / ml ampicillin Should be used to inoculate sterile culture flasks containing. Preferably, the culture is It should be grown at 37 ° C. to saturation, and preferably, the saturated culture should be fresh L Should be diluted with broth. Preferably, some of these dilutions are plated 100 μg / ml ampicillin in a 150 mm Petri dish and Grow overnight at 37 ° C. on solid bacterial culture medium containing L broth containing 5% agar Dilution rate yields 5000 distinct and well-separated colonies The volume should be determined. Others to get clear, well-separated colonies Can also be used.   The colonies are then nitted using standard colony hybridization techniques. Transfer to a low cellulose filter for dissolution, denaturation and baking. You.   Then, preferably, 0.5% SDS, 100 μg / ml yeast RNA, and 6X SSC containing 10 mM EDTA (205.3 x 175.3 gN aCl / liter, 88.2 g sodium citrate, pH 7.0 with NaOH ) (About 10 ml per 150 mm filter) with gentle stirring Incubate at 65 ° C for 1 hour. The probe is then preferably hived. Add to the redidation mix and add a concentration greater than 1e + 6 dpm / ml Should be equal to this. Then, preferably the filter is at room temperature Wash without stirring with 500 ml of 2X SSC / 0.5% SDS, preferably Followed by 500 ml of 2X SSC / 0.1 with gentle shaking at room temperature. % Wash with SDS. 65 ° C, 30 minutes to 1 hour, 0.1X SSC / 0.5% A third wash with SDS is optimal. Then preferably dry the filter After sufficient time for autoradiography, positives were visualized on X-ray film. Let Other known hybridization methods can also be used.   Positive colonies are picked, grown in medium, and then positively added using standard procedures. Isolate the mid DNA. Then, restriction analysis, hybridization analysis or Clones can be verified by DNA sequencing.   A fragment of the protein of the present invention that can exhibit biological activity is also included in the present invention. You. Protein fragments may be linear or, for example, H.U.Saragovi Etal., Bio / Technology 10, 773-778 (1992) and R.S. McDowell, et al., J. Am. Amer. Chem. Soc. 114, 9245-9253 (1992) (both references are incorporated herein by reference) Cyclization using known methods such as those described in No. For many purposes, including increasing the number of valencies at the protein binding site, Such a fragment may be fused to a carrier molecule together with the immunoglobulin. An example For example, a protein fragment can be linked to the Fc portion of an immunoglobulin via a “linker”. They may be fused. For the bivalent form of the protein, such a fusion is made to the Fc of the IgG molecule. Can be done for parts. Use other immunoglobulin isotypes A fusion may be obtained. For example, a protein-IgM fusion is a 10-valent form of a protein of the invention. Will result.   The invention also provides the full length and mature forms of the disclosed proteins. Full length form of such a protein Is identified in the sequence listing by translation of the nucleotide sequence of the disclosed clone. I have. The mature form of such a protein can be found in a suitable mammalian cell or other host cell. To release the disclosed full-length polynucleotides (preferably those deposited with the ATCC). It may be obtained by exposing. Amino acid sequence of full-length form It may be determined from the column.   The present invention also provides a gene corresponding to the cDNA sequence disclosed herein. " A "corresponding gene" is a region of the genome that is transcribed to produce mRNA, CDNA is derived from the RNA and the genes required for regulated expression of such genes. Flanking regions (including coding sequences, 5 'and 3' untranslated regions) or Are spliced exons, introns, promoters, enhancers, As well as silencer or suppressor elements. Disclosure in this specification The corresponding gene can be isolated using the information of the sequence. Sequences disclosed herein The corresponding gene can be isolated using this information. Such a method is disclosed Prepare a suitable genomic library by preparing probes or primers from sequence information Or identifying and / or amplifying genes in other sources of genomic material I do. An "isolated gene" is present in the genome of the organism from which the gene was isolated. Genes separated from flanking coding sequences (if present).   Enhance, decrease, or increase the gene corresponding to the polynucleotide sequence disclosed herein. Provides an organism having an altered expression. Antisense polynucleotide Or to bind and / or bind mRNA transcribed from the gene. The desired change in gene expression is achieved by using a ribozyme that cleaves (Albert and Morris, 1994, Trends Pharmacol. Sci. 15 (7): 250-25 4; Lavarrosky et al., 1997, Biochem. Mol. Med 62 (1): 11-22; and Hampel, 1998 , Prog. Nucleic Acid Res. Mol. Biol. 58: 1-39; all of which are book by reference It is regarded as described in the specification). For the polynucleotides disclosed herein, A transgenic animal having a corresponding multicopy gene, preferably a transformed cell. Transform cells with genetic constructs that are stably maintained in cells and their progeny A transgenic animal obtained by the conversion is provided. Gene expression Increase or decrease levels, or the temporal or spatial pattern of gene expression Transgenic animals having altered genetic control regions that alter the genes (See European Patent No. 0 649 464 B1; see all of these As described herein). Furthermore, by inserting an external sequence Or the deletion of all or part of the corresponding gene, Provided by organisms in which the gene corresponding to the leotide sequence is incomplete or completely inactivated Is done. Insertion, preferably after incorrect resection of the transposable element (Plasterk, 1992, Bioessays 14 (9): 629-633; Zwaal et al., 1993, Proc. Natl. Acad. Sci. USA 90 (16): 7431-7435; Clark et al., 1994, Proc. Na tl. Acad. Sci. USA 91 (2): 719-722; all of which are described herein by reference. Or by homologous recombination, preferably positive / negative By homologous recombination detected by sexual genetic selection (Mansour et al., 1988 U.S., Nature 336: 348-352; Patent Nos. 5,464,764; 5,487,992; 5,627,059; 5,63 1,153; 5,614, 396; 5,616,491; and 5,679,523; all of which are herein incorporated by reference. Incomplete or complete gene inactivation be able to. Those organisms with altered gene expression are preferably eukaryotic And more preferably a mammal. Such organisms are associated with the corresponding gene To develop non-human models for the study of disease It is useful for developing an assay system for identifying a molecule that interacts with a substance.   When the protein of the present invention is membrane-bound (eg, a receptor), the present invention Soluble forms are also provided. In such a form, the intracellular and transmembrane domains of the protein And remove all or part of the protein so that it is sufficiently secreted from the host where the protein was expressed. To do. Intracellular and transmembrane domains of the protein of the present invention are determined from sequence information. The domain can be identified by a known method for determining the domain.   The proteins and protein fragments of the present invention have at least the amino acid sequence of the disclosed protein. 25% (more preferably at least 50%, most preferably at least 75%) At least 60% sequence identity to the disclosed proteins. (More preferably at least 75% identity, most preferably at least 90% Or 95% identity). Sequence identity is a measure of sequence gap. When sequences are juxtaposed to maximize overlap and identity while minimizing It is determined by comparing the amino acid sequences of the proteins. Seg of any disclosed protein At least 75% sequence identity (more preferably at least 75% 85% identity, most preferably at least 95% identity). 8 or more (more preferably 20 or more, most preferably Is a protein containing a segment containing 30 or more contiguous amino acids Alternatively, protein fragments are also included in the present invention.   Species homologs of the disclosed polynucleotides and proteins are also provided by the invention. Book The term "species homolog" as used herein refers to a species different from the source of the protein or polynucleotide. A protein or polynucleotide, but as determined by one skilled in the art, Those having significant sequence similarity. Preferably, a polynucleotide species homolog Is at least 60% (more preferably less Both have a sequence identity of 75%, and most preferably at least 90%). Isozymes are at least 30% (more preferably at least 45%) relative to a particular protein. %, Most preferably at least 60%). Sequence identical here Sex is aligned so that overlap and identity are maximized and sequence gaps are minimized The nucleotide sequence of the polynucleotide or the amino acid sequence of the protein Is determined by Suitable probes or primers from the sequences provided herein And then screening for an appropriate nucleic acid source from the desired species. More species homologs may be isolated and identified. Preferably, the species homolog is from a mammalian species It is isolated. Most preferably, the species homolog is, for example, Pan troglodyte s, Gorilla gorilla, Pongo pygmaeus, Hylobates concolor, Macaca mulatta, Papio papio, Papio hamadryas, Cercopithecus aethiops, Cebus capucinus, A otus trivirgatus, Sanguinus oedipus, Microcebus murinus, Mus musculus, R attus norvegicus, Crisetulus griseus, Felis catus, Mustela vison, Canis familiaris, Oryctolagus cuniculus, Bos taurus, Ovisaries, Sus scrofa and And isolated from specific mammals such as Equus caballus Genetic maps have been created to map the genomic organization of genes in one species and The association of gene sequence order with genomic organization of related genes in (O'Brien and Seuanez, 1988, Ann. Rev. Genet. 22: 323-351; O'Br ien et al., 1993, Nature Genetics 3: 103-112; Johansson et al., 1995, Geno mics 25: 682-690; Lyons et al., 1997, Nature Genetics 15: 47-56; O'Brien et al., 1997, Trends in Genetics 13 (10): 393-399; Carver and Stubbs, 1997, Ge nome Research 7: 1123-1137 (all of which are incorporated herein by reference). Is considered to be))).   The invention also relates to allelic variants of the disclosed polynucleotides, i.e., the disclosed polynucleotides. Identical, homologous or related to the protein encoded by the nucleotide Includes naturally occurring alternative forms of the isolated polynucleotide encoding the protein. Preferred Alternatively, an allelic variant has at least 60% (for a particular polynucleotide) More preferably at least 75%, most preferably at least 90%) identity Where the sequence identity is the maximum overlap and identity, Compare nucleotide sequences of aligned polynucleotides to minimize It is determined by Suitable probes or primers from the sequences described herein And screen for appropriate sources of nucleic acids from individuals of appropriate species. And the allelic variant may be isolated and identified.   Also, the present invention has a sequence complementary to the sequence of the polynucleotide disclosed herein. Also encompasses polynucleotides.   The invention also relates to the use of the present invention under reduced stringency conditions, more preferably under stringent conditions. The polynucleotides described herein may also be hybridized, preferably under very stringent conditions. Also encompasses polynucleotides that can be redistributed. The following table shows examples of strictness conditions. Shown in The very strict conditions are, for example, at least as strict as conditions A to F. Yes, the strict conditions are, for example, at least as strict as the conditions GL, The condition for reducing the density is, for example, at least as strict as the conditions M to R. ^‡: The hybrid length is the length of the hybridizing polynucleotide. Expected length for hybridized region (s). Polinu Hybridize a nucleotide to a target polynucleotide of unknown sequence If so, the hybrid length is the length of the polynucleotide to be hybridized. Suppose When a polynucleotide of known sequence hybridizes Aligns polynucleotide sequences to identify region (s) of optimal sequence complementarity By doing so, the hybrid length can be determined.^† : SSPE (1 × SS) in hybridization and wash buffer PE was 0.15 M NaCl, 10 mM NaH_TwoPO_Four, And 1.25 mM ED TA, pH 7.4, was converted to SSC (1 × SSC was 0.15 M NaCl and 1 5 mM sodium citrate). Hybridization After the completion of the washing, the washing is performed for 15 minutes. * T_B-T_R: For hybrids that are expected to be shorter than 50 base pairs in length The hybridization temperature is the melting temperature of the hybrid (T_m5) than 10) C should be lowered. T by the following equation_mIs determined. Less than 18 base pairs in length For hybrids, T_m(° C.) = 2 (number of A + T bases) +4 (number of G + C bases). Length 18 For a 49 base pair hybrid, T_m(° C) = 81.5 + 16.6 (log_Ten[Na⁺) +0.41 (% G + C)-(600 / N), where N is the hybrid The number of bases and the concentration of sodium ions in the hybridization buffer [(Na for 1 × SSC⁺] = 0.165M).   Further examples of stringency conditions for polynucleotide hybridization Is Sambrook, J., E.F. Fritsch, and T.W. Maniatis, 1989, Molecular Cloning: A  Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Har bor, NY, chapters 9 and 11, and Current Protocols in Molecular Biology, 1995, F.M. Ausubel et al., Eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4 and are considered to be hereby incorporated by reference. Eggplant   Preferably, each of such hybridizing polynucleotides Is at least 25% of the polynucleotide of the invention to be hybridized (More preferably at least 50%, most preferably at least 75%) A length that is small relative to the polynucleotide of the invention to be hybridized. At least 60% sequence identity (more preferably, at least 75% identity; And preferably also at least 90% or 95% identity). Sequence identity Are sequenced to maximize overlap and identity, while minimizing sequence gaps. Are determined by comparing the amino acid sequences of the proteins when are aligned.   The isolated polynucleotide encoding the protein of the present invention is described in Kaufman et al., Nucl. eic Acids Res. PMT2 or pED expression vector disclosed in 19, 4485-4490 (1991) Operably linked to an expression control sequence such as Good. Many suitable expression control sequences are known in the art. Many fit Various expression control sequences are known in the art. One for recombinant protein expression General methods are also known. Kaufman, Methods in Enzymology 185, 537-566 ( 1990) is a typical example. “Operably linked,” as defined herein, refers to the isolation port of the present invention. The polynucleotide and the expression control sequence are placed and ligated into a vector or cell. (Transfection) with the polynucleotide / expression control sequence It is meant to be expressed by a host cell.   Many types of cells can serve as suitable host cells for expression of the proteins of the present invention. Mammalian cells include, for example, monkey COS cells, Chinese hamster ovary (CH O) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells Vesicles, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid Cells, cell lines obtained from in vitro culture of primary tissues, primary explants, H eLa cells, mouse cells, BHK, HL-60, U937HaK or Jurkat cells Vesicles.   Alternatively, in lower eukaryotic cells such as yeast or prokaryotic cells such as bacteria. It is possible to produce proteins. A potentially suitable yeast strain is Saccharomyces ce revisiae, Schizosaccharomyces pombe, Kluyveromyces strain, Candida, or Includes yeast strains capable of expressing the seed protein. A potentially suitable bacterial strain is Escherichia capable of expressing E. coli, Bacillus subtilis, Salmonella typhimurium, or heterologous proteins Functional bacterial strains. If the protein is produced in yeast or bacteria, so The resulting protein is converted, for example, by phosphorylation or glycosylation of the appropriate site. It may need to be modified to obtain a functional protein. Known chemical or enzymatic method The covalent bonding may be performed using a method.   The isolated polynucleotides of the present invention can be used in one or more insect expression vectors to The protein can be obtained by operably linking to an appropriate control sequence and using an insect expression system. Good. Materials and methods for baculovirus / insect cell expression systems are described, for example, in In Kit form from vitrogen, San Diego, California, USA (MaxBac^RKit) Commercially available, such methods are well known in the art and include Summers and And Smith, Texas Agricu1tural Experiment Station Bulletin No. 1555 (1987) (Such as described herein by reference) You. As used herein, insect cells capable of expressing the polynucleotide of the present invention include "Transformed".   Culturing transformed host cells under culture conditions suitable for expressing the recombinant protein The protein of the present invention may be produced more. Next, the obtained expressed protein was subjected to gel filtration and filtration. Such cultures using known purification processes, such as ion exchange chromatography (I.e., medium or cell extract). Also, protein purification Is an affinity column containing an agent that will bind to the protein; Valine A-agarose, Heparin-Toyopearl^ROr Cibacromblue 3GA Sepha Loin^ROne or more column steps with an affinity column such as Use resin such as phenyl ether, butyl ether or propyl ether One or more steps using hydrophobic interaction chromatography; Or immunoaffinity chromatography.   Alternatively, the protein of the invention may be expressed in an easily purified form. For example, Lactose binding protein (MBP), glutathione-S-tonspherase (GST) Or expressed as a fusion protein such as a fusion protein with thioredoxin (TRX) You may. Kits for expression and purification of such fusion proteins are available from New En from glan BioLab (Beverly, MA), Pharmacia (Piscataway, NJ) and InVitrogen It is commercially available. Tag a protein with an epitope, and then tag such epitope Pointing Purification can also be performed by using the specific antibody thus obtained. Epitome of 1 ("Flag") is commercially available from Kodak (New Haeven, CT).   Finally, a hydrophobic RP-HPLC medium such as a pendant methyl or other aliphatic group is added. One or more reversed-phase high quality liquid chromatography using silica gel with The protein can be further purified using the-(RP-PLC) step. A few Or a substantially homogeneous isolation system using various combinations of all of the above purification steps. A recombinant protein can also be obtained. The protein thus purified can be derived from other mammalian proteins. It is not qualitatively included and is defined as "isolated protein" in the present invention.   The protein of the present invention may be used as a product of a transgenic animal. Characterized by somatic or germ cells containing the nucleotide sequence Expressed as an ingredient in milk of transgenic cows, goats, pigs, or sheep Is also good.   The protein may be produced by known conventional chemical synthesis. The present invention by synthetic means Methods for constructing proteins are known to those skilled in the art. Synthetically constructed protein sequences are primary Sharing secondary or tertiary structure and / or conformational properties Thus, they may have common biological properties, including protein activity. Yo For the screening of therapeutic compounds and the immunology for the production of antibodies. Process to replace the biological activity or immunological replacement of the naturally occurring purified protein May be used.   The protein shown in the present specification has an amino acid sequence similar to that of the purified protein. Which are modified naturally or by derivatization Is also good. For example, modification of a peptide or DNA sequence can be accomplished by one of ordinary skill in the art using known methods. More can be done. The desired modification in the protein sequence depends on the choice in the coding sequence. Includes amino acid residue changes, substitutions, exchanges, insertions or deletions. For example, up to one Or more cysteine residues have been deleted or replaced with another amino acid. The conformation of the child may be changed. Such changes, replacements, exchanges, insertions, etc. Methods for deletion or deletion are well known to those skilled in the art (see, for example, US Pat. No. 8584). Preferably, such changes, substitutions, exchanges, insertions or deletions Loss retains the desired activity of the protein.   Expected to retain protein activity in whole or in part, thus screening Or other fragments of the protein sequence that may be useful for immunological or other immunological methods. Derivatives can also be made by those skilled in the art from the disclosure herein. Such modifications are the subject of the present invention. Is believed to be encompassed byApplications and biological activities   The polynucleotides and proteins of the present invention may have one or more of the following uses or Exhibiting biological activity (including those associated with the assays cited herein) Conceivable. The uses or activities described for the proteins of the present invention may be attributed to the administration of such proteins. Supply or use, or of a polynucleotide encoding such a protein. Administration or use (eg, for any vector suitable for gene therapy or DNA transfer) C).Research applications and usefulness   The polynucleotide provided by the present invention can be used for various purposes depending on the research population. Can be used. Preferential expression of the corresponding protein for analysis, characterization or therapeutic use (Constitutively, at a specific stage of tissue differentiation or development, or As tissue markers (expressed in disease states) as well as Southern gel molecules As a quantity marker, it can be used to identify chromosomes or map related gene locations. Compared to the patient's endogenous DNA as a chromosome marker or tag (if labeled) Probes to identify potential genetic diseases Genetic fingerprinting to discover new related DNA sequences As a source of information for obtaining PCR primers for Probes to subtract known sequences in the process of nucleotide discovery And select the oligomer to bind to a “gene chip” or other support To test for expression patterns, use DNA immunization to To generate antibodies, as well as to generate anti-DNA antibodies, or Polynucleotides can be used as antigens to induce an immune response You. Binds or potentially binds another protein (e.g., If the protein encodes a protein that binds to Or interaction trap assays to identify inhibitors of binding interactions A (for example, as described in Gyuris et al., Cell 75: 791-803 (1993)). And polynucleotides can be used.   The proteins provided by the present invention are a family of multiple proteins for high-throughput screening. For assays to determine biological activity, including proteins of interest; production of antibodies or other A protein (or its receptor) in a biological fluid Reagents (including labeling reagents) in assays designed to quantitatively determine The corresponding protein is preferentially expressed (constitutively or with tissue differentiation or Is expressed at a particular stage of development or in a disease state) As well as used to, of course, isolate related receptors or ligands You may. Bind when a protein binds or potentially binds to another protein Proteins to identify other proteins and / or inhibitors of binding interactions White can be used. Using proteins involved in these binding interactions, Of peptide or small molecular inhibitors or agonists for binding interactions Training can also be performed.   Any or all of these research uses may be commercialized as research products. Can be developed into reagent grade or kit formats.   Methods for performing the above uses are well known to those skilled in the art. Open this method The literature shown is "Molecular Cloning: A Laboratory Manual", 2nd ed., Cold Spri. ng Harbor Laboratory Press, Sambrook, J., E.F. Fritsch and T. Maniatis e ds., 1989, and "Methods in Enzymology: Guide to Molecular Cloning Techni ques ", Academic Press, Berger, S.L. and A.R. Kimrnel eds., 1987 But not limited to these.   Nutritional uses   Use of the polynucleotide and protein of the present invention as a nutrient source or additive Can be. Such uses include the use as a protein or amino acid additive and the use as a carbon source. All uses, as a nitrogen source and as a carbohydrate source. Not limited to these. In such a case, the protein or polynucleotide of the present invention is Food, pills, solutions, suspensions or capsules. It can also be administered as a separate solid liquid formulation, such as in the form of a solid. Microbial In this case, the protein or polynucleotide of the present invention is added to the medium in which the microorganism is cultured. be able to.   Cytokines and cell proliferation / differentiation activity   The protein of the present invention has cytokine activity, cell growth activity (induction or inhibition) or cell activity. Can show blast differentiation activity (induction or inhibition) or in certain cell populations To induce the production of other cytokines. Many proteins found to date Sex factors (including all known cytokines) are dependent on one or more factors Showing activity in cell proliferation assays, and thus the assay Serves as a convenient way to confirm activity. The activity of the protein of the present invention is determined in cell lines (32D, DA 2, DA1G, T10, B9, B9 / 11, BaF3, MC9 / G, M + (pr eBM +), 2E8, RB5, DA1, 123, T1165, HT2, CTLL 2, including but not limited to TF-1, Mo7e and CMK) As confirmed by any of a number of conventional factor-dependent cell proliferation assays.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Assays for T cell or thymocyte proliferation are described in Current Protocols in I mmunology, Ed by J. E. Coligan, A.M.Kruisbeek, D.H.Margulies, E.M.Shevach, W Strober, Pub.Greene Publishing Associates and Wiley-Interscience (Chapte r 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, I mmunologic studies in Humans); Takai et al. Immunol. 137: 3494-3500, 1 986; Bertagnolli et al., J. Am. Immunol. 145: 1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133: 327-341, 1991; Bertagnolli, et al., J. Am. Immun ol. 149: 3778-3783, 1992; Bowman et al., J. Am. Immunol. 152: 1756-1761, in 1994 Includes but is not limited to those described.   Cytokine production and / or expansion of spleen cells, lymph node cells or thymocytes Assays for propagation are described in Polyclonal T cell stimulation, Kruisbeek, A.M. and  Shevach, E.M. In Current Protocols in Immunology. J.E.e.a. Coligan eds . Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measu rement of mouse and human Interferon γ, Schreiber, R.D. In Current Prot ocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John W iley and Sons, Toronto. Includes, but is not limited to those described in 1994 No.   Assays for proliferation and differentiation of hematopoietic and lymphogenic cells ent of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., D avis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a . Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 199 1; deVries et al. Exp. Med. 173: 1205-1211, 1991; Moreau et al., Nature  336: 690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80: 2931-2938, 1983; Measurement of mouse and human interleukin 6-Nordan, R.A. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.6. 1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Nat1. Ac ad. Sci. U.S.A. 83: 1857-1861, 1986; Measurement of human Interleukin 11-B ennett, F., Giannotti, J., Clark, S.C. and Turner, K. J. In Current Prot ocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.15.1 John Wiley a nd Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9-Ciar letta, A., Giannotti, J., Clark, S.C. and Turner, K.J. In Current Protoc ols in Imlunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.13.1, John Wiley an d Sons, Toronto. Includes, but is not limited to, those described in 1991.   Assays for the response of T cell clones to antigens (particularly proliferation and APC-T cell interaction as well as direct To identify the effects of T cells) is described in Current Protocols in Immunology, Ed. E . Coligan, A.M.Kruisbeek, D.H.Margulies, E.M.Shevach, W Strober, Pub.Greene P ublishing Associates and Wiley-Interscience (Chapter 3, In Vitroassays fo r Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular rece ptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77: 6091-6095, 1980; Weinberger et al., Eur. J. Immun . 11: 405-411, 1981; Takai et al., J. Am. Immunol. 137: 3494-3500,1986; Takai e t al., J.S. Immunol. 140: 508-512, 1988, including those described in Not limited to   Immunostimulatory or suppressive activity   In addition, the protein of the present invention has an activity (including but not limited to ), And may exhibit immunostimulatory or immunosuppressive activity. Protein is In various deficiencies and disorders, including severe immunodeficiency complications (SCID) May be useful, for example, to increase the proliferation of T and / or B lymphocytes In regulating or down-regulating, and N Useful in enhancing the cytolytic activity of K cells and other cell populations It is possible. These immunodeficiencies can be genetic and can include viral ( HIV, as well as those caused by bacterial or fungal infections. Or may be caused by an autoimmune disease. Yo More specifically, the susceptibility caused by viruses, bacteria, fungi or other infectious agents Infectious diseases such as HIV, hepatitis virus, herpes virus, mycobacteria A variety of fungal infections such as Leishmania, Malaria and Candida species It can be treated with myoprotein. Of course, in this regard, the immune system When a protein is required, that is, in the treatment of cancer, the protein of the present invention may be used.   Autoimmune diseases that may be treated using the protein of the present invention include, for example, multiple sclerosis, Systemic deep elitomades, rheumatoid arthritis, autoimmune pneumonia, Guilla in-Barre syndrome, autoimmune thyroiditis, insulin-dependent diabetes, severe muscle Includes asthenia, graft versus host disease and autoimmune inflammatory eye diseases. Book Such proteins can be used to treat allergic reactions such as asthma or other respiratory disorders And may be used for the treatment of symptoms. Other conditions for which immunosuppression is desired (eg, asthma (Especially allergic asthma) and related respiratory problems) And may be treated. Other conditions for which immunosuppression is desired (including, for example, organ transplantation) May be treated using the protein of the present invention.   The proteins of the present invention can also be used to enable an immune response in a number of ways. Da Unregulation can block or block an immune response already in progress Or includes interfering with the induction of an immune response. There may be. By suppressing the T cell response, or Inhibits activated T cell function by inducing resistance or both May be. Generally, immunosuppression of T cell responses is an active, non-antigen specific Process, which requires continuous exposure of T cells to the inhibitor. Resistance and Means non-responsive or anergic in T cells, generally antigen-specific In that it persists after exposure to the tolerizing agent has ceased. Operationally, the lack of a T cell response when exposed to a specific antigen in the absence of a resistance agent More resistance may be shown.   One or more antigen functions (eg, B lymphocyte antigen function (eg, B7) Including, but not limited to, down-regulating For example, blocking high levels of lymphokine synthesis by activated T cells Useful in tissue, skin and organ transplantation and graft versus host disease (GVHD) There will be. For example, blocking T cell function reduces tissue destruction in tissue transplantation Should be. Typically, in tissue transplants, graft rejection is Initiated by T cells being recognized as foreign and then breaking the graft A destructive immune response occurs. B7 Lymphocyte Antigen on Immune Cells and Its Native Riga A molecule that inhibits or blocks interaction with another B lymphocyte antigen (eg, , B7-1, B7-3), in the form of a monomer having the activity of Or a single, soluble, monomeric peptide having B7-2 activity) Planting The previous administration provides a natural response on immune cells without transmitting responsive costimulatory signals. May induce binding of the molecule to the ligand. In this regard, B lymphocyte anti- Blocking the primary function involves cytokine synthesis by immune cells, such as T cells. And thus acts as an immunosuppressant. Moreover, the lack of co-stimulation It may be sufficient to cause a loss of T cell response. B lymphocyte antigen blocking reagent Induction of long-term tolerance by The need can be avoided. To achieve sufficient immunosuppression or tolerance in the subject May also need to block the function of the B lymphocyte antigen combination .   Individual blocking in preventing organ transplant rejection or GVHD Evaluate the effectiveness of the reagents using animal models that can predict their effectiveness in humans be able to. Examples of suitable systems that can be used include allografts in rats and allografts. Xenogeneic pancreatic islet cell grafts in mice and Was used to test the immunosuppressive effect of the CTLA4Ig fusion protein (Lenscho w et al., Science 257: 789-792 (1992) and Turka et al., Proc Natl. Acad. Sci. USA, 89: 11102-11105 (1992)). In addition, GVHD mice Mimodel (Paul ed., Fundamental Immunology, Ravan Press, New York, 1989) , Pp. 846-847) using B lymphocytes to progress the disease in vivo. The blocking effect of the antigen function can be determined.   In addition, blocking antigen function is therapeutically useful for treating autoimmune diseases It can be. Many autoimmune diseases are responsive to self- Inappropriate activity of T cells to promote the production of cytokines and autoantibodies involved in It is the result of sexualization. Interfering with the activation of self-reactive T cells reduces the symptoms of the disease. Less or may be eliminated. Disrupting B lymphocyte antigen receptor: ligand interaction Inhibit T cell activation using administration of a reagent that blocks T cell costimulation Production of autoantibodies or T cell-derived cytokines that can harm and participate in the disease process Can interfere with life. In addition, blocking reagents can provide long-term remission of disease It may induce antigen-specific resistance of autoreactive T cells that may lead. Autoimmune disease The effectiveness of blocking reagents in the prevention or amelioration of Can be determined using a number of well-characterized animal models You. Examples are murine experimental autoimmune encephalitis, MRLlpr / lpr mice or N Systemic deep erythematosus and murine self-immunity in ZB hybrid mice Plague collagen arthritis, diabetes in NOD mice and BB rats, and Experimental rat myasthenia gravis (Paul ed., Fundamental Immunology, Raven Press) , New York, 1989, pp. 840-856).   Antigen function as a means of up-regulating the immune response (preferred Alternatively, up-regulation of B lymphocyte antigen function) is also therapeutically useful. Up-regulation of the immune response may be May be in a form that eliminates the initial immune response. For example, B lymphocyte antigen function Enhancing the immune response by stimulating may be useful in the case of a viral infection. In addition, systemic viral such as influenza, common cold, and encephalitis Disease may be ameliorated by systemic administration of a stimulatory form of B lymphocyte antigen .   Alternatively, T cells are taken from a patient and tagged with ACPs that express a peptide of the invention. Co-stimulate T cells in vitro with added viral antigens, or Is combined with a stimulating form of the soluble peptide of the invention and then activated in vitro Re-introduced T cells into the patient, the anti-virus in infected patients It may enhance the immune response. Another method of promoting an antiviral immune response is Infected cells are taken from the patient and the nucleic acid encoding the protein of the invention described herein is To allow cells to express all or part of the protein on their surface. And then reintroduce the transfected cells into the patient. U. The infected cells then transmit a costimulatory signal to the T cells in vivo. Could thereby activate T cells.   In another application, antigen function (preferably B lymphocyte antigen function) Up-regulation or promotion may be useful in inducing tumor immunity . Transfection with a nucleic acid encoding at least one peptide of the invention Tumor cells (eg, sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, cancer Tumor) can be administered to a subject to overcome tumor-specific resistance in the subject. Desired If you Transfect tumor cells to express a combination of peptides it can. For example, a tumor cell obtained from a patient is treated with a peptide having B7-2-like activity. Or a peptide having a B7-1-like activity and / or a B7-3-like activity Expression vector that directs expression in combination Can be sfected. Transfected tumor cells into patient To express the peptide on the surface of the transfected cells. Alternatively, for transfection in vivo using gene therapy Tumor cells can be targeted.   Existence of the peptide of the present invention having B lymphocyte antigen activity on the surface of tumor cells Provides the necessary co-stimulatory signals for T cells to provide T cell-mediated trafficking. Induces an immune response against the transfected tumor cells. In addition, MHC Tumor cells lacking class I or MHC class II molecules, or sufficient MHC Tumor cells that cannot reexpress class I or MHC class II molecules are I α chain protein and β_TwoMicroglobulin protein or MHC class II α chain or Or all or part of the MHC class II β chain protein (eg, Transfection with the nucleic acid encoding the Class I or class II MHC proteins can be expressed on the cell surface . A marker having the activity of a B lymphocyte antigen (eg, B7-1, B7-2, B7-3) Expression of the appropriate class I or class II HMC in combination with the peptide is Elicits an immune response to transfected tumor cells mediated by vesicles Lead. If desired, expression of MHC class II binding proteins, such as invariant chains, can be blocked. The gene coding for the antisense construct to be detected can be linked to the activity of the B lymphocyte antigen. Co-transfection with DNA encoding a peptide having To promote the presentation of tumor-associated antigens and induce tumor-specific immunity. Therefore Induction of an immune response mediated by T cells in a human subject can be caused by tumors in the subject. It may be sufficient to overcome tumor-specific resistance.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Suitable assays for thymocyte or spleen cell cytotoxicity are described in Current Protocols in Immunology, Ed by J.E.Coligan, A.M.Kruisbeek, D.H.Margulies, E.M.Shevach, WS trober, Pub.Greene Publishing Associates and Wiley-Interscience (Chapter 3 , In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immu nologic studies in Humans); Herrmann et al., Proc. Natl. Acad. Sci. USA 7 8: 2488-2492, 1981; Herrmann et al., J. Am. Immunol. 128: 1968-1974, 1982; Handa  et al., J. Amer. Immunol. 135: 1564-1572, 1985; Takai et al., J. Am. Immunol. 137: 3 494-3500, 1986; Takai et al., J. Am. Immunol. 140: 508-512, 1988; Herrmann et a l., Proc. Natl. Acad. Sci. USA 78: 2488-2492, 1981; Herrmann et al., J. Am. Im munol. 128: 1968-1974, 1982; Handa et al., J. Am. Immunol. 135: 1564-1572, 1985 ; Takai et al., J .; Immunol. 137: 3494-3500, 1986; Bowman et al., J. Am. Virolog y 61: 1992-1998; Takai et al., J. Am. Immunol. 140: 508-512, 1988; Bertagnollie t al., Cellular Immunology 133: 327-341, 1991; Brown et al., J. Am. Immunol. 1 53: 3079-3092, including but not limited to the assays described in 1994.   Updates for T cell-dependent immunoglobulin response and isotype switching Say (especially to modulate the T cell-dependent antibody response to a Th1 / Th2 profile Influencing proteins are identified in Maliazewski, J. Immunol. 144: 3028-3033, 1990. Includes, but is not limited to, the assays described, and further enhances B cell function Say, In vitro antibody production, Mond, J.J. and Brunswick, M. In Current  Protocols in Immunology J.E.Coliganeds.Val 1 pp.3.8.1-3.8.16, John Wiley  and Sons, Tronto 1994.   Mixed lymphocyte reaction (MLR) assays (especially primarily Th1 and CTL Identify the protein that produces the answer), Current Protocols in Immunology, Ed by  J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober , Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In  Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunolo gic studies in Humans); Takai et al. Immunol. 137: 3494-3500, 1986; Tak ai et al. Immunol. 140: 508-512, 1988; Bertagnolli et al., J. Am. Immunol . 149: 3778-3783, including but not limited to the assays described in 1992.   Dendritic cell-dependent assays (especially for dendritic cells that activate untreated T cells) To identify proteins that are more expressed) are described in Guery et al., J. Am. Immunol. 134: 536-544 Inaba et al., Journal of Experimental Medicine 173: 549-559, 1991; Macatonia et al., Journal of Immunology 154: 5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182: 255-260, 1995; Nair et al., Jou rnal of Virology 67: 4062-4069, 1993; Huang et al., Science 264: 961-965, 1 994; Macatonia et al., Journal of Experimental Medicine 169: 1255-1264, 19 89; Bhardwaj et al., Journal of Clinical Investigation 94: 797-807, 1994; a nd Inaba et al., Journal of Experimental Medicine 172: 631-640, 1990. Includes, but is not limited to, the assays listed.   Lymphocyte survival / apoptosis assays (especially apoptosis after superantibody induction) Identify Proteins That Prevent Lysis and that Regulate Lymphocyte Homeostasis ) Is Darzynkiewicz et al., Cytometry 13: 795-808, 1992; Gorczyca et al., Leukemia 7: 659-670, 1993; Gorczyca et al., Cancer Research 53: 1945-1951, 1993; Itoh et al., Cell 66: 233-243, 1991; Zacharchuk, Journal of Immunolog. y 145: 4037-4045, 1990; Zamai et al., Cytometry 14: 891-897, 1993; Gorczyca et al., International Journal of Oncology 1: 639-648, 1992. Includes, but is not limited to:   Early stage T cell commitment and development assays Antica et al., Blood 84: 111-117, 1994; Fine et al., Cellular Immunology 155: 111-122, 1994; Galy et al., Blood 85: 2770-2778, 1995; Toki et al., Proc. Natl. A cad. Sci. USA 88: 7548-7551, 1991, including but not limited to No.   Hematopoietic regulatory activity   The proteins of the present invention are useful in regulating hematopoiesis and are therefore Useful in the treatment of bulb deficiency. Colony forming cells or factor-dependent cell lines Even minimal biological activity in support of has been implicated in regulating hematopoiesis. For example, to support the growth of erythroid progenitor cells alone, or to In combination with, for example, treatment of various anemias, or release Production of erythroid progenitors and / or erythroblasts in combination with radiation therapy / chemotherapy Stimulating viability; proliferation of bone marrow cells such as granulocytes and monocytes / macrophages Support (ie, traditional CSF activity), eg, in combination with chemotherapy In addition, it is useful in preventing subsequent myelosuppression; Breeding, then supporting platelet growth, and thereby thrombocytopenia It is useful for preventing or treating various platelet diseases, and Used instead of or in addition to platelet infusion; and / or hematopoietic stem Cells (mature to all of the above hematopoietic cells, and therefore various stem cell diseases ( Diseases that are usually treated by transplantation, such as aplastic anemia and development To support the growth of nocturnal hemoglobinuria) And after radiation / chemotherapy in vivo or ex vivo That is, combined with bone marrow transplantation), or genetically engineered for gene therapy Also useful in repopulating the stem cell compartment as normal cells after is there.   In particular, the activity of the protein of the present invention may be measured by the following method.   Assays suitable for proliferation and differentiation of various hematopoietic cell lines have already been cited .   Assays for embryonic stem cell differentiation, specifically identifying proteins that affect embryonic hematopoiesis ) Is based on Johansson et al. Cellular Biology 15: 141-151, 1995; Keller et al., Molecular and Cellular Biology 13: 473-486, 1993; McClanahan et al., Blood  81: 2903-2915, 1993, including, but not limited to.   Assays for stem cell survival and differentiation, specifically identifying proteins that regulate lymphoper hematopoiesis ) Is described in Methylcellulose colony forming assays, Freshney, M.G. In Cultu re of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 265-268, W iley-Liss, Inc., New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. S ci. USA 89: 5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A. In Cultur e of Hematopoietic Cells.R.I.Freshney, et al.eds.Vol pp.23-39, Wiley-Liss, Inc., New York, NY. 1994; Neben et al., Experimental Hematology 22: 353-35 9, 1994; Cobblestone area forming cell assay, Ploemacher, R.E. In Culture  of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 1-21, Wiley- Liss, Inc .., New York, NY. 1994; Long term bone marrow cultures in the pr esence of stromal cells, Spooncer, E., Dexter, M. and Allen, T .; In Cultu re of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 163-179, W iley-Liss, Inc., New York, NY. 1994; Long term culture initiating cell as say, Sutherland, H.J. In Culture of Ilematopoietic Cells. R.I. Freshney , Et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, NY. Recorded in 1994 Includes, but is not limited to, the assays listed.   Tissue proliferation activity   The protein of the present invention may be used to grow or regenerate bone, cartilage, keys, ligaments and / or nerve tissue. And compositions used for wound healing and tissue repair, further including burns, lacerations And has utility in the treatment of ulcers.   Book that induces cartilage and / or bone growth in an environment where bone is not formed normally Inventive proteins cure healing of fractures and cartilage damage or defects in humans and other animals There are applications in Such formulations using the protein of the present invention include closed fractures and It is useful for reducing open fractures and improving fixation of artificial joints. Bone De novo bone formation induced by plasticizers can be congenital, traumatic or tumor Contributes to the repair of craniofacial deficits induced by radiological resection and further It is also useful in general surgery.   The proteins of the present invention may be used in the treatment of periodontal disease and other tooth restoration processes. Heel Agents provide an environment to attract osteogenic cells, stimulate the growth of osteogenic cells, Alternatively, it can induce osteogenic cell precursor differentiation. For example, the protein of the present invention And / or mediated by inflammatory or inflammatory processes Block the process of tissue destruction (collagenase activity, osteoclast activity, etc.) This may be useful in the treatment of osteoporosis or osteoarthritis.   Another category of tissue developmental activity that may be attributed to the proteins of the invention is the key. / Ligament formation. Environments where key / ligament-like or other tissues are not formed properly The protein of the present invention that induces the formation of such a tissue in humans is Applied to healing of key or ligament lacerations, deformations and other key or ligament defects You. Such a formulation using a key / ligament-like tissue-inducing protein may be used for key or ligament-like tissue. To prevent key or ligament fixation to bone or other tissue It may be. The de novo key / ligament-like tissue formation induced by the composition of the present invention Sexual, traumatic, or oncological resection-induced craniofacial defects Cosmetic surgery for contributing to the repair and also for attaching or repairing keys or ligaments It is also useful in The composition of the present invention attracts key- or ligament-forming cells Provide an environment for stimulating the growth of key- or ligament-forming cells, Induction of precursors of band-forming cells or tissue repair when returned to vivo. Ex vivo can induce the growth of key / ligament cells or progenitors ex vivo. The compositions of the present invention can be used to treat keratitis, carpal tunnel syndrome and other key or ligament defects. Is also useful. The composition of the present invention may comprise a suitable matrix and / or It may include a sequestering agent, such as a well-known carrier.   The protein of the present invention is used for proliferation of nerve cells and regeneration of nerve and brain tissue, , Central and peripheral nervous system diseases and neuropathy and mechanical diseases and Treatment of traumatic diseases (including degeneration, death or trauma to nerve cells or nerve tissue) May also be useful for treatment. More specifically, peripheral nerve injury, peripheral neuropathy and Diseases of the peripheral nervous system such as neuropathy and localized neuropathy, and Alzheimer's disease , Parkinson's disease, Huntington's disease, amyotrophic lateral spinal sclerosis and Shy-Drager Proteins may be used in the treatment of diseases of the central nervous system, such as the syndrome. By the present invention Additional conditions that may be treated include mechanical disorders such as spinal cord disorders and traumatic disorders And cerebrovascular diseases such as head trauma and stroke. Chemotherapy or other Peripheral neuropathy caused by medical therapy of Cure Can be treated.   The protein of the present invention may also be used for pressure ulcer, ulcer associated with vascular dysfunction, More preferred for non-healing wounds, including (but not limited to) wounds due to trauma It may also be useful for promoting quick closure.   The protein of the present invention includes organs (eg, pancreas, liver, intestine, kidney, skin, endothelium). ), Muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue To promote the development of other tissues or the proliferation of cells that make up such tissues. Activity. Part of the desired effect is by inhibiting fibrotic scarring. Regeneration of normal tissue. The proteins of the present invention may also exhibit angiogenic activity.   The protein of the present invention is useful for protecting or regenerating intestine, and for fibrosis of lung or liver, Treatment of tissue reperfusion injury and symptoms caused by systemic cytokine damage May also be useful for treatment.   The protein of the present invention promotes or suppresses differentiation of the above-mentioned tissue from precursor tissue or cells; Alternatively, it may be useful for suppressing the growth of the tissue.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Assay for tissue regeneration activity is described in WO 95/16035 (bone, cartilage, key) International Publication WO95 / 05846 (nerves, neurons); International Publication WO91 / 05 7491 (skin, endothelium), including but not limited to .   Assays for wound healing activity are described in Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), Year Book Medical Publishers, Inc., C hicago (Eaglstein and Mertz, J. Invest. Dermatol 71: 382-384 (1978) (Modified) but not limited thereto.   Activin / inhibin activity   Also, the protein of the present invention may exhibit activin- or inhibin-related activity. I Inhibins are characterized by their ability to inhibit follicle stimulating hormone (FSH) release, Activins are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). You. Therefore, the protein of the present invention may be used alone or as a member of the inhibin α family. In the form of a heterodimer with a female mammal, which reduces the fertility of a female mammal May be useful as an infertility drug based on the ability of inhibin to reduce spermatogenesis in animals You. Administration of sufficient amounts of other inhibins may result in infertility in these mammals. Can be guided. Alternatively, the proteins of the present invention may be homodimers or Is a heterodimer with other protein subunits of the inhibin-β group Based on the ability of activin molecules to stimulate FSH release from anterior pituitary cells And may be useful as a therapeutic agent that induces fertility. For example, US Pat. See 98885. In addition, the protein of the present invention is useful for reproduction in sexually immature mammals. It may be useful for enhancement and, as a result, homes such as cattle, sheep and pigs Increased fertility during the life of the animal.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Assays for activin / inhibin activity are described in Vale et al., Endocrinology 91: 562-572, 1972; Ling et al., Nature 321: 779-782, 1986; Vale et al., Nature 321: 776-779, 1986; Mason et al., Nature 318: 659-663,1985; Forage et al., P roc. Natl. Acad. Sci. USA 83: 3091-3095, 1986. However, it is not limited to these.   Chemotaxis / chemokinesis activity   The protein of the present invention can be used for mammalian cells such as monocytes, neutrophils, T cells, mast cells, and eosinophils. Chemotactic or chemokinetic activity of spheres and / or endothelial cells (eg, Acting as in). Uses chemotactic and chemokinetic proteins And recruit or attract the desired cell population to the desired site of action. Chemotaxis Alternatively, chemokinesis proteins may be used to treat and localize tissue injuries and other trauma. It is particularly advantageous for treating localized infections. For example, tumors of lymphocytes, monocytes or neutrophils Attraction to tumor or infected site may improve immune response to tumor or infectious agent You.   Certain proteins or peptides have chemotactic activity for specific cell populations. Direct or indirect, if stimulated, the direction or behavior of such cell populations. Command movement. Preferably, the protein or peptide has a directed movement of the cell. Have the ability to directly stimulate Specific proteins have chemotactic activity on cell populations Is used to determine whether such proteins or peptides have known chemotaxis Can be easily determined.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Assay for chemotaxis activity (an assay to identify proteins that induce or interfere with chemotaxis) Say) describes the ability of the protein to induce cell translocation across the membrane as well as the Includes assays that measure the ability of a protein to induce adhesion to other cell populations. Moving Assays suitable for adhesion and adhesion are described in Current Protocols in Immunology, Ed by J.E.C. oligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober, Pub. Gre ene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measuremen t of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin.Invest . 95: 1370-1376, 1995; Lind et al. APMIS 103: 140-146, 1995; Muller et al Eu r. J. Immunol. 25: 1744-1748; Gruber et al. J. of Immunol. 152: 5860-5867, 1994; Johnston et al. J. of Immunol. 153: 1762-1768, assay described in 1994. But not limited to these.   Hemostasis and thrombolytic activity   In addition, the protein of the present invention may exhibit hemostatic or thrombolytic activity. As a result Thus, such proteins are useful in the treatment of various clotting disorders, including genetic disorders such as hemophilia. Or in the treatment of injury caused by trauma, surgery or other causes. Blood clots and other hemostasis. The protein of the present invention may be used to dissolve or form a thrombus. Growth inhibition and the symptoms resulting therefrom (eg, myocardial infarction and central nervous system blood) It may be useful in the treatment and prevention of vascular infarcts (eg, stroke).   The activity of the protein of the invention may be measured, inter alia, by the following method:   Assays for haemostatic and thrombolytic activity are described by Linet et al., J. Am. Clin. Pharmacol. 26: 131-140, 1986; Burdick et al., Thrombosis Res. 45: 413-419, 1987; Humphre y et al., Fibrinolysis 5: 71-79 (1991); Schaub, Prostaglandins 35: 467-474,198. 8 including, but not limited to.Receptor / ligand activity   Further, the protein of the present invention may be a receptor, a receptor ligand or a receptor / ligand interaction. May exhibit activity as inhibitors or agonists. Such receptors and Examples of gand are cytokine receptors and their ligands, receptor kinases and And their ligands, receptor phosphatases and their ligands, cells Receptors involved in cell interactions and their ligands (cell adhesion molecules (SELEC , Integrin and their ligands) and antigen presentation, antigens Receptor / ligand pairs involved in the development of cognitive, cellular and humoral immune responses Inclusive) but not limited to. Receptors and ligands are related receptors Screening of potential peptide or small molecule inhibitors for body / ligand interactions It is also useful for training. The protein of the present invention (receptor and ligand fragments Include, but are not limited to, blocking the receptor / ligand interaction itself. May be useful as a harmful agent.   The activity of the protein of the invention may be measured, inter alia, by the following method:   Suitable assays for receptor-ligand activity are described in Current Protocols in Immunolog. y, Ed by J. E. Coligan, A.S. M. Kruisbeek, D.S. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Cha pter 7.28, Measurement of Cellular Adhesion under static conditions 7.28 .1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84: 6864-6868, 1987 Bierer et al., J .; Exp. Med. 168: 1145-1156, 1988; Rosenstein et al., J. Am. E xp. Med. 169: 149-160 1989; Stoltenborg et al., J. Am. Immunol. Methods 175: 59 -68, 1994; includes the assay described in Stitt et al., Cell 80: 661-670, 1995. However, it is not limited to these.   Anti-inflammatory activity   The protein of the present invention can exhibit anti-inflammatory activity. Anti-inflammatory activity is involved in the stimulus response By stimulating cells, cell-cell interaction (eg, attachment) Chemotaxis of cells involved in the inflammatory process by inhibiting or promoting By inhibiting or promoting, by inhibiting or promoting cell extravasation, Alternatively, it stimulates the production of other factors that more directly inhibit or promote the inflammatory response or Is exhibited by suppressing. Symptoms of inflammation ( Includes chronic or acute symptoms, infection-related inflammation (including septic shock, sepsis) Or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, Fatal injury by dotoxin, arthritis, hyperacute rejection mediated by complement, Nephritis, lung injury induced by cytokines or chemokines, inflammatory bowel disease Disease, Crohn's disease or overproduction of cytokines such as TNF or IL-1 (Including but not limited to diseases resulting from). Departure Myelin protein is a cure for anaphylaxis and hypersensitivity to antigenic substances or materials. May also be useful for treatment.   Cadherin / tumor entry inhibitory activity   Cadherin is a calcium-dependent adhesion molecule, Plays a major role in determining specific cell types, in particular I think that the. Loss or alteration of normal cadherin expression is associated with tumor growth and metastasis. It can induce a change to the relevant cell adhesion properties. Cadherin dysfunction is vulgaris Pemphigus and pemphigus foliaceus (autoimmune cutaneous blistering disease), Crohn's disease, and It is also involved in other human diseases, such as some developmental abnormalities.   The cadherin superfamily contains over 40 members, each of which is distinct. Expression patterns. All members of the superfamily Have a common conserved extracellular repeat (cadherin domain), but There are structural differences in other parts. Cadherin domain binds to calcium Calcium is necessary for their attachment as they combine to form their tertiary structure. You. Few amino acids in the first cadherin domain are due to homophilic attachment Base Modification of this recognition site can alter the specificity of cadherin, providing a foundation As a result, the mutant molecule not only recognizes itself, but also Be able to bind to doherin. In addition, some cadherins are It is also involved in heterophilic attachment to phosphorus.   E-cadherin, one of the members of the cadherin superfamily, It is expressed in cell types. Pathologically, E-cadherin expression is If lost, the malignant cells become invasive and the cancer metastasizes. E-cadhedrine Transfection of a polynucleotide that expresses Cell morphology, restore cell-to-cell and cell-cell adhesion, By reducing the rate of cell growth and dramatically reducing the growth of anchorage-dependent cells, The changes associated with cancer were reversed. Thus, re-introducing E-cadhedrin expression Returns the carcinoma to a less advanced stage. Other cadherins are also used in other tissue It may have the same invasive inhibitory role in Ip-derived carcinomas. Soy sauce , A protein of the present invention having cadherin activity, and a gene encoding such a protein The bright polynucleotides can be used to treat cancer. Such protein or poly Introducing nucleotides into cancer cells may provide normal cadherin expression. Can reduce or eliminate the cancerous changes observed in these cells .   Cancer cells are also known to express cadherin in a different tissue type than originally intended. Therefore, these cancer cells can invade different tissues and metastasize. Mosquito The protein of the present invention having doherin activity, and the polynucleotide of the present invention encoding such a protein Nucleotide replaces cadherin, which is inappropriately expressed in these cells. Restores normal cell adhesion properties and reduces or eliminates cell propensity to metastasize sell.   Further, the protein of the present invention having cadherin activity, and encoding such a protein Antibodies that recognize and bind to cadherin using the polynucleotides of the present invention You can also get. Tumor cell cadherds inappropriately expressed using such antibodies Can block cell adhesion and prevent cells from forming tumors elsewhere. Wear. Such anti-cadhedrin antibodies can be used to evaluate cancer grade, pathological type, and prognosis. Can be used as a marker for In other words, when the cancer progresses, cadherin The expression is reduced and this cadherin expression can be Can be detected.   A fragment of the protein of the present invention having cadherin activity, preferably cadherin Of the present invention encoding such protein fragments Use polynucleotides to bind to cadherin, producing undesirable effects By blocking cadherin binding, it can also block cadherin function. Wear. Furthermore, a fragment of the protein of the present invention having cadherin activity, preferably Truncated soluble mosquitoes known to be stable in the circulatory system of cancer patients Dohedrin fragments and polynucs encoding such protein fragments Reotide can also be used to disrupt correct cell-cell attachment.   Assays for cadherin adhesion and entry inhibitory activity are described in Hortsch et al. J Bio l Chem 270 (32): 18809-18817, 1995; Miyaki et al. Oncogene 11: 2547-2552, 19 95; Ozawa et al. Cell 63: 1033-1038, 1990. Not limited to these.   Tumor inhibitory activity   In addition to the activities described above for the immunological treatment or prevention of tumors, the protein of the present invention Can exhibit antitumor activity. Certain proteins directly or indirectly affect tumor growth (eg, (Via ADCC). Certain proteins are found in tumor or tumor precursor tissue Act to inhibit the formation of tissue necessary to support tumor growth (eg, angiogenesis) Other factors, agents or cell types that inhibit tumor growth Factors, agents or agents that cause the production of Alternatively, a tumor inhibitory activity may be exhibited by removing or inhibiting a cell type.   Other activities   The proteins of the present invention may exhibit one or more of the following additional activities or effects: : Infections, including but not limited to bacteria, viruses, fungi and other parasites Sex factor killing; height, weight, hair color, eye color, skin or other tissue pigmentation Or the size or form of an organ or body part (eg, breast augmentation or vice versa) Effects on body characteristics (suppression or promotion), including: fat, protein or charcoal consumed Effects of hydrate on digestion; appetite, libido, stress, cognition (including cognitive disorders), depression Behavioral characteristics, including (but not limited to) depressive disorders and violent behavior Effects; providing analgesic or other pain relief; in non-hematopoietic lineages Promoting differentiation and proliferation of embryonic stem cells; hormonal or endocrine activity; Correct enzyme deficiency and treat related disorders; hyperproliferative disorders (eg, such as psoriasis) ) Treatment; immunoglobulin-like activity (eg, the ability to bind antibodies or complement); And such a protein or protein acting as an antigen in a vaccine composition. Ability to generate an immune response to other substances or entities that cross react with white.Administration and dose   The protein of the invention (from any source, recombinant and non-recombinant) Methods, including, but not limited to, those described above) with a pharmaceutically acceptable carrier. They may be used together in a pharmaceutical composition. Such compositions comprise (in addition to the protein and carrier, ), Diluents, fillers, salts, buffers, stabilizers, solubilizers, and the like. It may contain other substances well known in the above. The term "pharmaceutically acceptable" A non-toxic substance that does not interfere with the effectiveness of the biological activity of the active ingredient. Characteristics of carrier Sex depends on the route of administration. The pharmaceutical composition of the present invention comprises M-CSF, GM-CSF, T NF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL- 7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF , Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin Contain cytokines, lymphokines, or other hematopoietic factors, such as Good. The pharmaceutical composition further enhances the protein activity or its activity in therapy. Or it may contain other agents that supplement its usefulness. Such additional factors and Synergistic effect with the protein of the present invention by containing a pharmaceutical composition The results may be achieved or side effects may be minimized. Conversely, certain cytokines , Lymphokines, other hematopoietic factors, thrombolytic or antithrombotic factors, or anti-inflammatory Including the protein of the present invention in the formulation of the drug, cytokines, lymphokines, other hematopoietic factors May minimize the side effects of blood, thrombolytic or antithrombotic factors, or anti-inflammatory drugs. No.   The protein of the present invention may be a multimer (for example, a heterodimer or a homodimer) or It may be active by itself or in a complex with other proteins. As a result, The pharmaceutical composition comprises such a multimeric or complexed form of the protein of the present invention. You may.   The pharmaceutical composition of the present invention may be in the form of a complex of the protein of the present invention and a protein or peptide antigen. It may be in a state. Protein and / or peptide antigens can be It will deliver a stimulus signal to the lymphocytes. B lymphocytes have their surface immunity Will respond to antigen through globulin receptors. T lymphocytes are MHC proteins Will respond to the antigen through the T cell receptor (TCR). MHC and host cell class I and class II MHC genes Structurally related proteins, including those that have been loaded, are peptide-antigens against T lymphocytes. It will help to present the original. The antigen component was a purified MHC-peptide complex only. Or with co-stimulatory molecules that can send signals directly to T cells Can be done. Alternatively, surface immunoglobulins on B cells and T cells on T cells Antibodies that can bind CR and other molecules can also be mixed with the pharmaceutical compositions of the present invention. Wear.   The pharmaceutical composition of the present invention may be in the form of liposome, in which the protein of the present invention is contained. And other pharmaceutically acceptable carriers, amphipathic agents such as lipids (mice in aqueous solution). Agglomerate form, such as insoluble monolayer, liquid crystal or lamellar layer) Have been combined. Suitable lipids for liposome formulations are monoglycerides, diglycerides , Sulfatizide, lysolecithin, phospholipids, saponins, bile acids, etc. However, it is not limited to these. The preparation of such liposome formulations is within the level of ordinary skill in the art. And, for example, U.S. Pat. Nos. 4,235,871, 4501728, 4837028, And 4737323, all of which are described herein by reference. Also And the like).   As used herein, the term "therapeutically effective amount" refers to a significant patient benefit, e.g., Sufficient pharmaceutical composition or method to show improvement in symptoms of the condition, healing, increased rate of healing It means the total amount of each active ingredient. Used for individual active ingredients administered alone When used, the term refers only to that component. When used in combinations of active ingredients, The total amount of active ingredients that produces a therapeutic effect, regardless of whether U.   In practicing the treatment method of the present invention, a disease to be treated with a therapeutically effective amount of the protein of the present invention. Administered to a mammal having a morphology. According to the method of the present invention, alone or with a cytokine The protein of the invention together with other therapeutic agents such as lymphokines or other hematopoietic factors. It may be administered. One or more cytokines, lymphokines or other When co-administered with hematopoietic factors, the protein of the present invention may be administered with cytokines, lymphokines, and other It may be administered simultaneously or sequentially with blood, thrombolytic or antithrombotic factors. Gradually When administering the next dose, the attending physician will ask for cytokines, lymphokines, other hematopoietic factors, blood Appropriate administration of thrombolytic factor or antithrombotic factor in combination with the protein of the present invention Will determine the order.   The administration of the protein of the present invention in the pharmaceutical composition of the present invention or used in the practice of the present invention can be carried out by various conventional methods. Administration methods, e.g., oral feeding, inhalation, or intradermal, subcutaneous, or intravenous injection. I can. Intravenous injection into a patient is preferred.   When a therapeutically effective amount of the protein of the present invention is orally administered, the protein of the present invention may contain , Powder, solution or elixir form. When administered in tablet form, The pharmaceutical composition may further comprise a solid carrier such as gelatin or an adjuvant. It may be. Tablets, capsules, and powders contain about 5 to 95% of a protein of the present invention, It preferably contains about 25-90% of the protein of the invention. Place to administer in liquid form Oil, water, petroleum, oils of animal or vegetable origin, such as peanut oil, mineral oil , Soybean oil, sesame oil, or synthetic fats and oils may be added. Pharmaceutical group in liquid form The composition can be a saline solution, dextrose or other saccharide solution, or glycol (Eg, ethylene glycol, propylene glycol or polyethylene glycol) Ricoh ) May further be contained. When administered in liquid form, the pharmaceutical composition comprises 0.5 to 90% by weight of the protein of the present invention, preferably about 1 to 50% of the protein of the present invention. Contains white.   When a therapeutically effective amount of the protein of the present invention is administered by intravenous, intradermal or subcutaneous injection, The protein of the present invention may be in the form of a pyrogen-free, parenterally acceptable aqueous solution . Of such a parenterally acceptable protein solution having the appropriate pH, isotonicity, and stability. Preparation is within the skill of the art. Preferred medicament for intravenous, intradermal or subcutaneous injection The composition comprises, in addition to the protein of the present invention, sodium chloride for injection, Ringer's solution, Dextrose, dextrose and sodium chloride solution for injection, lactic acid for injection Should contain Ringer's solution, or other carriers known in the art . The pharmaceutical composition of the present invention may comprise a stabilizer, a preservative, a buffer, an antioxidant, Other additives known to the consumer.   The amount of the protein of the invention in the pharmaceutical composition of the invention depends on the nature and severity of the condition to be treated, As well as the nature of the treatment the patient has already received. Ultimately, your doctor Each patient will determine the amount of the protein of the invention to be treated. First, the doctor in charge Administer an amount of the protein of the invention and observe the patient's response. Until optimal therapeutic effects are obtained Higher doses of the protein of the present invention may be administered and may be used once optimal therapeutic effect is obtained. Do not increase the volume further. Various pharmaceutical compositions for performing the methods of the present invention include About 0.01 μg to about 100 mg of the protein of the present invention (preferably, About 0.1 μg to about 10 mg / kg body weight, more preferably 1 kg / kg body weight 0.1 to about 1 mg of the protein of the present invention.   The duration of treatment by intravenous administration using the composition of the present invention depends on the severity of the disease to be treated. And will vary depending on the condition and response of each patient. Each of the proteins of the present invention The duration of application will range from 12 to 24 hours for continuous intravenous administration . Ultimately, the attending physician will determine the stage of treatment by intravenous administration using the pharmaceutical composition of the present invention. Will decide between.   Immunizing an animal with the protein of the present invention to specifically react with the protein of the present invention; And monoclonal antibodies may be obtained. Whole protein or its fragment G May be used as an immunogen to obtain such antibodies. Peptide immunogen is carboxy powder It may further contain a cysteine residue at the end, and can be Binds to haptens such as anine (KLH). Method for synthesizing such a peptide Are known in the art, for example, R.P.Merrifield, J.Amer.Chem.Soc. 8 5, 2149-2154 (1963); J.L. Krstenansky, et. al., FEBS Lett. 211, 10 (1987) There is a thing as described in. The monoclonal antibody that binds to the protein of the present invention It may be a useful diagnostic agent for immunodetection of the light protein. Neutralizing antibodies that bind to the protein of the present invention Can be useful as therapeutics for conditions related to the protein of the present invention. Certain tumors in the treatment of some forms of cancer involving aberrant protein expression May be useful in the treatment of In the case of cancer cells or white blood cells, the protein of the present invention Neutralizing monoclonal antibodies against cancer cell metastasis can be mediated by the protein of the invention It may be useful for detecting and preventing infestations.   For compositions of the invention useful for the regeneration of bone, cartilage, keys or ligaments, the method of treatment comprises: The composition can be administered locally, systemically, or locally as an implant or device. Administration. When administered, the therapeutic composition used in the present invention comprises Of course, it is a pyrogen-free, physiologically acceptable form. In addition, Alternatively, the composition may be encapsulated or injected as a viscous form to provide bone, cartilage or May be delivered to the site of tissue damage. Local administration is suitable for wound healing and tissue repair I do. Therapeutically useful action other than the protein of the present invention which may be contained in the above composition The agent is, alternatively or additionally, administered simultaneously or sequentially with the composition in the method of the present invention. May be. Preferably, for bone and / or cartilage formation, the composition comprises Delivering the white-containing composition to the site of bone and / or cartilage damage, and developing the bone and cartilage; Provides a structure for living, and optimally contains a matrix that can be absorbed into the body Will have. Such matrices are currently used for other implanted medical devices It may be made from the materials that have been used.   The choice of matrix material depends on its biocompatibility, biodegradability, mechanical properties, cosmetic Based on appearance and interface properties. The appropriate formulation will be determined by the particular application of the composition. U. Possible matrices for the composition are biodegradable, chemically known sulfuric acid Lucium, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglyco It may be oleic acid and polyanhydride. Other available materials are biodegradable, Well-known in nature, for example, bone or skin collagen. further The matrix may contain pure proteins or extracellular matrix components. Other possible matrices include sintered hydroxyapatite, bioglass, aluminum Not biodegradable, such as silicates or other ceramics, It is. The matrix is a combination of materials of the above type, for example polylactic acid and Including hydroxyapatite or collagen and tricalcium phosphate It may be. The bioceramics are added to the composition, for example, calcium-alumina. It may be altered in the to-phosphate and processed to produce pore size, particle size, The particle shape and biodegradability may be varied.   Lactic acid in the form of porous particles having a diameter in the range of 150 to 800 microns and A 50:50 (molar weight) copolymer of biglycolic acid is presently preferred. . In some applications, carboxymethylcellulose or autologous Prevent the dissociation of the protein composition from the matrix using a sequestering agent such as a clot And would be useful.   Preferred families of sequestrants are methylcellulose, ethylcellulose, Roxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl Alkyl cells containing methylcellulose and carboxymethylcellulose Cellulosic materials such as loin (including hydroxyalkylcellulose) Most preferred is a cationic salt of carboxymethylcellulose (CMC). Other preferred sequestering agents are hyaluronic acid, sodium alginate, poly (ethylene Glycol), polyoxyethylene oxide, carboxyvinyl polymer and Poly (vinyl alcohol). The amount of sequestrant useful in the present invention depends on the total formulation weight. 0.5 to 20% by weight, preferably 1 to 10% by weight, based on the amount, Prevents protein desorption from the polymer matrix and allows for proper handling of the composition The amount of progenitor cells that infiltrate the matrix To give the protein a chance to promote the osteogenic activity of cells, not much Not to be.   In a further composition, the protein of the present invention comprises a bone and / or cartilage defect, wound, Alternatively, it may be mixed with other agents that are beneficial in treating the tissue. These agents are , Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transformed growth factor (TGF-α and TGF-β) and insulin-like growth factor (IGF) Include.   At present, the therapeutic compositions are also valuable for veterinary use. For details, In addition to humans, livestock and thoroughbred horses are treated with the protein of the present invention. Is a desirable patient.   Rules of administration of protein-containing pharmaceutical compositions used for tissue regeneration alter the effect of proteins Factors, such as tissue weight, damage site, and damage desired to be formed. The condition of the tissue received, the size of the wound, the type of tissue required (eg, bone), the patient's year Consider age, gender and diet, severity of infection, duration of administration, and other clinical factors And your doctor will decide. The dose depends on the type of matrix used for reconstitution. And depending on the content of other proteins in the pharmaceutical composition. For example, IGF   Addition of other known growth factors, such as I (insulin-like growth factor I) to the final composition Addition can also affect dosage. Tissue / bone growth and / or repair, By regular assessment by morphological survey and tetracycline labeling The progress can be monitored.   The polynucleotide of the present invention can also be used for gene therapy. Such polynuks Leotide is introduced into cells in vivo or ex vivo and expressed in a mammalian subject. Can be made. Other known methods for introducing nucleic acids into cells or organisms The polynucleotide of the present invention may be administered more (in a viral vector, Or in the form of naked DNA, but is not limited thereto).   Culturing and growing the cells ex vivo in the presence of the protein of the invention, or Produce the desired effect on such cells or produce the desired activity in such cells. May be. The treated cells are then introduced in vivo for therapeutic purposes. can do.   The patents and publications cited herein are hereby incorporated by reference in their entirety. It is assumed that

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/08 A61P 29/00 21/00 35/04 29/00 37/02 35/04 C07K 14/47 37/02 C12P 21/02 C C07K 14/47 C12N 15/00 ZNAA C12N 5/10 5/00 B C12P 21/02 A61K 37/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU , ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Roverie, Edward R. United States 01451 Larry, Lisa Ai, 113 Anne Lee Road, Harvard, Massachusetts, United States 01720 School Street 124, Acton, Massachusetts, United States Inventor Tracy, Maurice United States Country 02167 Chesnut Hill, Mass., Walcott Road 93 (72) Inventor Spalding, Vicky United States 01821 Billerica, Mass., Meadowbank Road 11 (72) Inventor Augustino, Michael Jay United States 01810 Massachusetts Dover, Walcott Ave. 26 (72) Inventor Howes, Stephen H. United States 02144 Massachusetts, USA 44, Chester Street, Apartment 2 (72) Inventor Fechtel, Kim United States 02174 Arlington, Mass., 46 Marion Road 46

Claims (1)

[Claims]   1. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1;   (B) nucleotides from nucleotide 12 to nucleotide 800 of SEQ ID NO: 1 A polynucleotide comprising an otide sequence;   (C) the nucleotide sequence from nucleotide 78 to nucleotide 800 of SEQ ID NO: 1 A polynucleotide comprising an otide sequence;   (D) the nucleotide from nucleotide 1 to nucleotide 547 of SEQ ID NO: 1 A polynucleotide comprising a nucleotide sequence;   (E) clone bh389_1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of one full length protein coding sequence;   (F) clone bh389_1 deposited under accession number ATCC 98451 Polynucleic acid encoding full length protein encoded by one cDNA insert Leotide;   (G) Clone bh389_1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of one mature protein coding sequence;   (H) clone bh389_1 deposited under accession number ATCC 98451 Polynucleic acid encoding mature protein encoded by one cDNA insert Leotide;   (I) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 2 Tide;   (J) including a fragment of the amino acid sequence of SEQ ID NO: 2 having biological activity (The fragment is SEQ ID NO: 2-8) Contiguous amino acids);   (K) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (h) above Nucleotides;   (L) A polynucleotide encoding a species homolog of the protein of (i) or (j) above Otide; and   (M) any one of the polynucleotides (a) to (j) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   2. 2. The method of claim 1, wherein the polypeptide is operably linked to at least one expression control sequence. Renucleotide.   3. A host cell transformed with the polynucleotide of claim 2.   4. 4. The host cell of claim 3, wherein said cell is a mammalian cell.   5. (A) growing the culture of the host cell of claim 3 in a suitable medium;   (B) Purifying the protein from the culture A method for producing a protein encoded by the polynucleotide of claim 2, comprising:   6. A protein produced by the method of claim 5.   7. (A) the amino acid sequence of SEQ ID NO: 2;   (B) the amino acid sequence of amino acid 1 to amino acid 178 of SEQ ID NO: 2;   (C) the amino acid of SEQ ID NO: 2, comprising eight consecutive amino acids of SEQ ID NO: 2 Fragments of an acid sequence; and   (D) clone bh389_1 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert 1 A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   8. The protein of claim 7, comprising the amino acid sequence of SEQ ID NO: 2.   9. Includes amino acid sequence from amino acid 1 to amino acid 178 of SEQ ID NO: 2 The protein of claim 7.   10. A composition comprising the protein of claim 7 and a pharmaceutically acceptable carrier.   11. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 1.   12. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 3;   (B) including nucleotides 100 to 882 of SEQ ID NO: 3 A polynucleotide;   (C) including nucleotides 635 to 867 of SEQ ID NO: 3 A polynucleotide;   (D) clone bk1121 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of 5 of the full-length protein coding sequence;   (E) clone bk1121 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert 5 Tide;   (F) clone bk1121 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of 5;   (G) clone bk1121 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert 5 Tide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 4 ;   (I) including a fragment of the amino acid sequence of SEQ ID NO: 4 having biological activity A polynucleotide encoding the protein (the fragment comprises the eight Contiguous amino acid sequences);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above C; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   13. (A) the amino acid sequence of SEQ ID NO: 4;   (B) amino acid sequence from amino acid 200 to amino acid 256 of SEQ ID NO: 4 ;   (C) the amino acid of SEQ ID NO: 4, comprising eight consecutive amino acids of SEQ ID NO: 4 Fragments of an acid sequence; and   (D) clone bk1121 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert 5 A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   14． An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 3.   15. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 5;   (B) the nucleotide sequence from nucleotide 245 to nucleotide 520 of SEQ ID NO: 5 A polynucleotide comprising a reotide sequence;   (C) the nucleotide sequence from nucleotide 181 to nucleotide 527 of SEQ ID NO: 5 A polynucleotide comprising a reotide sequence;   (D) clone bk200 1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of 3 full length protein coding sequences;   (E) clone bk200 1 deposited under accession number ATCC 98451 Polynucleic acid encoding full length protein encoded by cDNA insert 3 Leotide;   (F) clone bk200 1 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of 3;   (G) clone bk200 1 deposited under accession number ATCC 98451 Polynucleic acid encoding mature protein encoded by cDNA insert of No. 3 Leotide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 6 Tide;   (I) including a fragment of the amino acid sequence of SEQ ID NO: 6 having biological activity (The fragment is SEQ ID NO: 6 8 Contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   16. (A) the amino acid sequence of SEQ ID NO: 6;   (B) the amino acid of SEQ ID NO: 6, comprising eight consecutive amino acids of SEQ ID NO: 6 Fragments of an acid sequence; and   (C) clone bk200 1 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert 3 A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   17． An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 5.   18. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 7;   (B) the nucleotide sequence from nucleotide 365 to nucleotide 784 of SEQ ID NO: 7 A polynucleotide comprising a reotide sequence;   (C) the nucleotide sequence from nucleotide 518 to nucleotide 784 of SEQ ID NO: 7 A polynucleotide comprising a reotide sequence;   (D) clone di386_3 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone di386_3 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone di386_3 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) Clone di386_3 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 8 Tide;   (I) including a fragment of the amino acid sequence of SEQ ID NO: 8 having biological activity (The fragment is SEQ ID NO: 8-8) Contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   19. (A) the amino acid sequence of SEQ ID NO: 8;   (B) an amino acid sequence from amino acid 1 to amino acid 140 of SEQ ID NO: 8;   (C) the amino acid of SEQ ID NO: 8, comprising eight consecutive amino acids of SEQ ID NO: 8 Fragments of an acid sequence; and   (D) clone di386_3 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   20. Isolated genes corresponding to the cDNA sequences of SEQ ID NO: 7 and SEQ ID NO: 9 .   21. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 10;   (B) nucleotides from nucleotide 191 to nucleotide 781 of SEQ ID NO: 10 A polynucleotide comprising a nucleotide sequence;   (C) the nucleotide sequence from nucleotide 56 to nucleotide 492 of SEQ ID NO: 10 A polynucleotide comprising a reotide sequence;   (D) Clone em3972 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone em3972 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone em3972 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) Clone em3972 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 11 Otide;   (I) a fragment of the amino acid sequence of SEQ ID NO: 11 having biological activity A polynucleotide encoding the protein comprising the fragment (SEQ ID NO: 11 Of 8 amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   22. (A) the amino acid sequence of SEQ ID NO: 11;   (B) the amino acid sequence of amino acid 1 to amino acid 101 of SEQ ID NO: 11;   (C) an amino acid sequence of SEQ ID NO: 11 comprising eight consecutive amino acids of SEQ ID NO: 11 A fragment of the amino acid sequence; and   (D) Clone em3972 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   23. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 10.   24. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 12;   (B) nucleotides from nucleotide 65 to nucleotide 1636 of SEQ ID NO: 12 A polynucleotide comprising a nucleotide sequence;   (C) the sequence from nucleotide 482 to nucleotide 1636 of SEQ ID NO: 12 A polynucleotide comprising a nucleotide sequence;   (D) SEQ ID NO: 12 from nucleotide 487 to nucleotide 1006 A polynucleotide comprising a nucleotide sequence;   (E) Clone fh170 7 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (F) Clone fh170 7 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (G) Clone fh170 7 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (H) clone fh170 7 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (I) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 13 Otide;   (J) a fragment of the amino acid sequence of SEQ ID NO: 13 having biological activity A polynucleotide encoding the protein comprising the fragment (the fragment is SEQ ID NO: 13 8 contiguous amino acids);   (K) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (h) above Nucleotides;   (L) A polynucleotide encoding a species homolog of the protein of (i) or (j) above Otide; and   (M) any one of the polynucleotides (a) to (j) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   25. (A) the amino acid sequence of SEQ ID NO: 13;   (B) amino acid sequence from amino acid 142 to amino acid 314 of SEQ ID NO: 13 Column;   (C) an amino acid sequence of SEQ ID NO: 13 comprising eight consecutive amino acids of SEQ ID NO: 13 A fragment of the amino acid sequence; and   (D) clone fh170 7 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   26. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 12.   27. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 15;   (B) the nucleotide sequence from nucleotide 41 to nucleotide 550 of SEQ ID NO: 15 A polynucleotide comprising a reotide sequence;   (C) of clone fn534 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence;   (D) of clone fn534 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert Tide;   (E) of clone fn534 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence;   (F) of clone fn534 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert Tide;   (G) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 16 Otide;   (H) a fragment of the amino acid sequence of SEQ ID NO: 16 having biological activity A polynucleotide encoding the protein comprising the fragment (SEQ ID NO: 16 8 contiguous amino acids);   (I) a polynucleotide that is an allelic variant of the polynucleotide of (a) to (f) above Nucleotides;   (J) A polynucleotide encoding a species homolog of the protein of (g) or (h) above. Otide; and   (K) any one of the polynucleotides (a) to (h) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   28. (A) the amino acid sequence of SEQ ID NO: 16;   (B) the amino acid sequence of SEQ ID NO: 16 from amino acid 40 to amino acid 170 ;   (C) SEQ ID NO: 16 comprising eight consecutive amino acids of SEQ ID NO: 16 A fragment of the amino acid sequence; and   (D) of clone fn534 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   29. CDNA sequences of SEQ ID NO: 15, SEQ ID NO: 14 and SEQ ID NO: 17 Isolated gene corresponding to   30. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 18;   (B) the nucleotide sequence from nucleotide 84 to nucleotide 404 of SEQ ID NO: 18 A polynucleotide comprising a reotide sequence;   (C) the nucleotide sequence from nucleotide 78 to nucleotide 493 of SEQ ID NO: 18 A polynucleotide comprising a reotide sequence;   (D) clone fq505 4 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) clone fq505 4 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) clone fq505 4 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) clone fq5054 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 19 Otide;   (I) a fragment of the amino acid sequence of SEQ ID NO: 19 having biological activity A polynucleotide encoding the protein (including the fragment of SEQ ID NO: 19) 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   31. (A) the amino acid sequence of SEQ ID NO: 19;   (B) amino acid sequence from amino acid 23 to amino acid 107 of SEQ ID NO: 19 ;   (C) an amino acid sequence of SEQ ID NO: 19 comprising eight consecutive amino acids of SEQ ID NO: 19; A fragment of the amino acid sequence; and   (D) clone fq505 4 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   32. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 18.   33. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 20;   (B) from nucleotide 1439 to nucleotide 1744 of SEQ ID NO: 20 A polynucleotide comprising the nucleotide sequence of   (C) from nucleotide 1241 to nucleotide 1754 of SEQ ID NO: 20 A polynucleotide comprising the nucleotide sequence of   (D) of clone fw139 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence;   (E) of clone fw139 deposited under accession number ATCC 98451 Polynucleotide encoding full-length protein encoded by cDNA insert Tide;   (F) of clone fw139 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence;   (G) of clone fw139 deposited under accession number ATCC 98451 Polynucleotide encoding mature protein encoded by cDNA insert Tide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 21 Otide;   (I) a fragment of the amino acid sequence of SEQ ID NO: 21 having biological activity A polynucleotide encoding a protein comprising the fragment (SEQ ID NO: 21 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   34. (A) the amino acid sequence of SEQ ID NO: 21;   (B) an amino acid sequence from amino acid 1 to amino acid 57 of SEQ ID NO: 21;   (C) an amino acid sequence of SEQ ID NO: 21 comprising eight consecutive amino acids of SEQ ID NO: 21 A fragment of the amino acid sequence; and   (D) of clone fw139 deposited under accession number ATCC 98451 Amino acid sequence encoded by cDNA insert A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   35. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 20.   36. (A) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 22;   (B) the nucleotide sequence from nucleotide 47 to nucleotide 919 of SEQ ID NO: 22 A polynucleotide comprising a reotide sequence;   (C) nucleotides from nucleotide 124 to nucleotide 452 of SEQ ID NO: 22 A polynucleotide comprising a nucleotide sequence;   (D) clone gg6192 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of   (E) Clone gg6192 deposited under accession number ATCC 98451 Polynucleotide encoding the full-length protein encoded by the cDNA insert of Otide;   (F) Clone gg6192 deposited under accession number ATCC 98451 A polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of   (G) clone gg6192 deposited under accession number ATCC 98451 Encoding a mature protein encoded by a cDNA insert Otide;   (H) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 23 Otide;   (I) a fragment of the amino acid sequence of SEQ ID NO: 23 having biological activity A polynucleotide encoding the protein containing the fragment (the fragment is SEQ ID NO: 23 8 contiguous amino acids);   (J) Polynucleic acid which is an allelic variant of the polynucleotide of (a) to (g) above Nucleotides;   (K) a polynucleotide encoding a species homolog of the protein of (h) or (i) above Otide; and   (L) any one of the polynucleotides (a) to (i) under strict conditions Polynucleotide that can hybridize to An isolated polynucleotide selected from the group consisting of:   37. (A) the amino acid sequence of SEQ ID NO: 23;   (B) amino acid sequence from amino acid 27 to amino acid 135 of SEQ ID NO: 23 ;   (C) an amino acid sequence of SEQ ID NO: 23 comprising eight consecutive amino acids of SEQ ID NO: 23; A fragment of the amino acid sequence; and   (D) clone gg6192 deposited under accession number ATCC 98451 Amino acid sequence encoded by the cDNA insert of A protein comprising an amino acid sequence selected from the group consisting of: A protein substantially free of.   38. An isolated gene corresponding to the cDNA sequence of SEQ ID NO: 22.