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AssigneeYale University
InventorsTian Xu, Wufan Tao, Weiyi Wang, Sheng Zhang, Wan Yu
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The present invention relates to a tumor suppressor gene, termed large tumor suppressor (lats), and methods for identifying tumor suppressor genes. The method provides nucleotide sequences of lats genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the lats protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of lats which comprise one or more domains of a lats protein. Antibodies to lats, its derivatives and analogs, are additionally provided. Methods of production of the lats proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. The invention also relates to recombinant plants and animals and methods of increasing the growth of edible plants and animals. In specific examples, isolated lats genes, from Drosophila, mouse, and human, and the sequences thereof, are provided.
A purified protein that is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified protein encoded by a nucleic acid hybridizable under conditions of low stringency to the lats DNA sequence in plasmid pBS (KS)-h-lats as deposited with the ATCC and assigned accession number 69769, which protein is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide;
A purified protein encoded by a nucleic acid hybridizable under conditions of low stringency to the lats DNA sequence in plasmid pBS (KS)-h-lats as deposited with the ATCC and assigned accession number 69769, which protein (a) has kinase activity, and (b) is encoded by a first nucleic acid that is hybridizable under conditions of low stringency to a second nucleic acid consisting of a sequence complementary to a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA;
A purified protein that is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified protein encoded by a nucleic acid hybridizable under conditions of low stringency to a DNA consisting of a sequence complementary to the coding region of SEQ ID NO:3, which protein is capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, said low stringency conditions consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA;
A purified protein encoded by a nucleic acid hybridizable under conditions of low stringency to a DNA consisting of a sequence complementary to the coding region of SEQ ID NO:7, which protein is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA;
A purified fragment of a protein, which fragment lacks a kinase domain;
A purified first protein comprising an amino acid sequence that has at least 90% identity to a domain of a second protein, said second protein consisting of a sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, said domain being selected from the group consisting of a lats C-terminal domain 3 (LCD3), lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCD1), kinase domain, lats flanking domain (LFD), lats split domain 1 (LSD1), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain, in which the percentage identity is determined over an amino acid sequence of identical size to the domain.
A purified product of a process of producing a protein, said process comprising growing a recombinant cell containing a recombinant first nucleic acid comprising a nucleotide sequence encoding a protein such that the encoded protein is expressed by the cell;
A purified molecule, which molecule comprises 20 contiguous amino acids of a protein encoded by a first nucleic acid that is hybridizable under conditions of low stringency to a second nucleic acid consisting of a sequence complementary to a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA;
A purified protein that is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:2.
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:4.
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:6.
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:8.
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:4 with the exception that the serine residue at amino acid number 909 of SEQ ID NO:4, as depicted in FIG. 9, is a glutamate residue.
A purified protein which comprises the amino acid sequence as set forth in SEQ ID NO:2 with the exception that the serene residue at amino acid number 914 of SEQ ID NO:2, as depicted in FIG. 5, is a glutamate residue.
A purified human lats protein which is encoded by plasmid pBS(KS)-h-lats as deposited with the ATCC and assigned accession number 69769.
A purified fragment of a protein, which protein (a) is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified product of a process of producing a protein, said process comprising growing a recombinant cell containing a recombinant nucleic acid comprising a nucleotide sequence encoding a first protein such that the encoded first protein is expressed by the cell;
A purified product of a process of producing a fragment, said process comprising growing a recombinant cell containing a recombinant nucleic acid comprising a nucleotide sequence encoding a fragment of a protein such that the encoded fragment is expressed by the cell;
A purified fragment of a protein, which protein is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified molecule, which molecule comprises 20 contiguous amino acids of a protein encoded by a first nucleic acid that is hybridizable under conditions of low stringency to a second nucleic acid consisting of a sequence complementary to a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA;
A purified molecule comprising a fragment of a protein, which protein (a) is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified fragment of a protein, said fragment containing only sequences of the protein amino terminal to a kinase domain of the protein, said protein being (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A purified fragment of a protein, which protein consists of the amino acid sequence as set forth in SEQ ID NO:4, which fragment contains only sequences of the protein amino terminal to a kinase domain of the protein.
A purified fragment of a protein, said protein consisting of the sequence set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, wherein the fragment consists of at least 20 contiguous amino acids of the protein.
A purified fragment of a protein, said protein consisting of the sequence set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, wherein the fragment is capable of being bound to an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8.
A purified fragment of a protein, said protein consisting of the sequence set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, wherein the fragment comprises at least one domain of the protein, said domain being selected from the group consisting of a lats C-terminal domain 3 (LCD3), lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCD1), kinase domain, lats flanking domain (LFD), lats split domain 1 (LSD1), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain.
A purified fragment of a protein, said protein consisting of the sequence set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, wherein the fragment lacks at least one domain of the protein.
A purified protein comprising 20 contiguous amino acids of the amino acid sequence set forth in SEQ ID NO:4.
A purified fragment of a protein, which protein consists of the amino acid sequence as set forth in SEQ ID NO:4, said fragment comprising a domain of the protein selected from the group consisting of a lats C-terminal domain 3 (LCD3), lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCD1), kinase domain, lats flanking domain (LFD), lats split domain 1 (LSD1), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain.
A chimeric protein comprising a fragment of a first protein, said first protein being (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A chimeric protein comprising a fragment of a first protein, which first protein is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A composition comprising a pharmaceutically acceptable carrier;
A composition comprising a purified fragment of a protein, and a pharmaceutically acceptable carrier, in which said protein (a) is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A composition comprising a purified first protein, and a pharmaceutically acceptable carrier, in which said first protein comprises an amino acid sequence that has at least 90% identity to a domain of a second protein, said second protein consisting of a sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, and said domain being selected from the group consisting of a lats C-terminal domain 3 (LCD3), lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCD1), kinase domain, lats flanking domain (LFD), lats split domain 1 (LSD1), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain, in which the percentage identity is determined over an amino acid sequence of identical size to the domain.
A composition comprising a chimeric protein, and a pharmaceutically acceptable carrier, which chimeric protein comprises a fragment of a first protein, said first protein being (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A composition comprising a purified protein, and a pharmaceutically acceptable carrier, which protein is encoded by a nucleic acid hybridizable under conditions of low stringency to the lats DNA sequence in plasmid pBS (KS)-h-lats as deosited with the ATCC and assigned accession number 69769, which protein is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA, hybridization for 18-20 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mm EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 .mu.g/ml denatured salmon sperm DNA, and 10% (wt./vol.) dextran sulfate, and washing twice for 1.5 hours at 55.degree. C. in a solution containing 2.times.SSC, 25 mM Tris-HCl (pH7.4), 5 mM EDTA and 0.1% SDS.
A composition comprising a purified protein, which prot ein is encoded by plasmid PBS(KS)-h-lats as deposited with the ATCC and assigned accession number 69769;
A composition comprising a purified molecule;
A composition comprising a purified protein, which protein comprises the amino acid sequence as set forth in SEQ ID NO:4;
A composition comprising a purified protein, which protein comprises the amino acid sequence as set forth in SEQ ID NO:6;
A kit comprising in a container a purified molecule, which molecule comprises 20 contiguous amino acids of a protein encoded by a first nucleic acid that is hybridizable under conditions of low stringency to a second nucleic acid consisting of a sequence complementary to a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7, said conditions of low stringency consisting of pretreatment for 6 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 .mu.g/ml denatured salmon sperm DNA, hybridization for 18-20 hours at 40.degree. C. in a solution containing 35% formamide, 5.times.SSC, 50 mM Tris-HCl (pH 7.5) 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 .mu.g/ml denatured salmon sperm DNA, and 10% (wt./vol.) dextran sulfate;
A kit comprising in a container a purified fragment of protein, which protein (a) is able to be bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
A kit comprising in a container a purified first protein, said first protein comprising an amino acid sequence that has at least 90% identity to a domain of a second protein, said second protein consisting of a sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, or SEQ ID NO:8, said domain being selected from the group consisting of a lats C-terminal domain 3 (LCD3), lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCD1), kinase domain, lats flanking domain (LFD), lats split domain 1 (LSD1), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain, in which the percentage identity is determined over an amino acid sequence of identical size to the domain.
A kit comprising in a container a protein that is (a) capable of being bound by an antibody induced by immunization with at least an immunogenic fragment of a polypeptide, the sequence of which polypeptide consists of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8;
Dependencies are inferred from the claim text.