Chromosome 3p21.3 genes are tumor suppressors
OwnerLin Ji, John Dorrance Minna +2inventors
InventorsLin Ji, John Dorrance Minna, Jack Roth, Michael Lerman
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Abstract
Tumor suppressor genes play a major role in the pathogenesis of human lung cancer and other cancers. Cytogenetic and allelotyping studies of fresh tumor and tumor-derived cell lines showed that cytogenetic changes and allele loss on the short arm of chromosome 3 (3p) are most frequently involved in about 90% of small cell lung cancers and greater than 50% of non-small cell lung cancers. A group of recessive oncogenes, Fus1, 101F6, Gene 21 (NPRL2), Gene 26 (CACNA2D2), Luca 1 (HYAL1), Luca 2 (HYAL2), PL6, 123F2 (RaSSFI), SEM A3 and Beta* (BLU), as defined by homozygous deletions in lung cancers, have been located and isolated at 3p21.3.
Claims116
An isolated polynucleotide encoding a polypeptide comprising an amino acid sequence of SEQ ID NO:2.
An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:2.
A nucleic acid of 15 to about 100 base pairs comprising from 15 contiguous base pairs of SEQ ID NO:
- 1, or the complement thereof.
An isolated peptide having between 10 and about 50 consecutive residues of SEQ ID NO:2.
An expression cassette comprising a polynucleoticle encoding a polypeptide having the sequence of SEQ ID NO:2, wherein said polynucleotide is under the control of a promoter operable in eukaryotic cells.
A cell comprising an expression cassette comprising a polynucleotide encoding a polypeptide having the sequence of SEQ ID NO:2, wherein said polynucleotide is under the control of a promoter operable in eukaryotic cells, said promoter being heterologous to said polynucleotide.
A monoclonal antibody that binds immunologically to a polypeptide comprising SEQ ID NO:2, or an immunologic fragment thereof.
A hybridoma cell that produces a monoclonal antibody that binds immunologically to a polypeptide comprising SEQ ID NO:2, or an immunologic fragment thereof.
A polyclonal antisera, antibodies of which bind immunologically to a polypeptide comprising SEQ ID NO:2, or an immunologic fragment thereof.
A isolated and purified nucleic acid that hybridizes, under high stringency conditions, to a DNA segment comprising SEQ ID NO:
- 1, or the complement thereof.
A method for constructing a recombinant adenovirus comprising:
- (a) providing a shuttle vector, said shuttle vector comprising an adenoviral inverted terminal repeat (ITR) sequence, an expression cassette comprising a promoter and a poly-A sequence, a transgene under the control of said promoter, and unique restriction sites at the 5′- and 3′-ends of the ITR-promoter-transgene-poly-A segment;
- (b) cutting at said restriction enzyme sites;
- (c) ligating the released segment into an adenoviral vector lacking the entire E1 and E3 regions and transforming the resulting vector a bacterial host cell;
- (d) obtaining vector from said bacterial host cell and digesting the vector to release the E1/E3-deleted adenovirus genome;
- and
- (e) transfecting the adenovirus genome into E1-expressing host cells.
A method for constructing a recombinant adenovirus comprising:
- (a) providing a shuttle vector comprising an adenoviral inverted terminal repeat (ITR) sequence, an expression cassette comprising a promoter and poly-A signal sequence, a transgene under the control of said promoter, a tetracycline resistance-off responsive element, and unique restriction sites at the 5′ and 3′ ends of the IRT-promoter-transgene-poly-A segment;
- (b) cutting at said restriction enzyme sites;
- (c) ligating the released segment into an adenoviral vector comprising a tetracyclin resistant-off transactivator gene and lacking the entire E1 and E3 regions, and transforming the resulting vector a bacterial host cell;
- (d) obtaining vector from said bacterial host cell and digesting the vector to release the E1/E3-deleted adenovirus genome;
- and
- (e) transfecting the adenovirus genome into E1-expressing host cells.
A shuttle vector comprising an adenoviral inverted terminal repeat (ITR) sequence, an expression cassette comprising a promoter and. poly-A sequence, a TetR-Off responsive element, and unique restriction sites at the 5′- and 3′-ends of the ITR-promoter-poly-A segment.
An adenoviral vector comprising a tetracycline resistant-off transactivator gene and lacking the entire E1 and E3-regions.
A method of diagnosing cancer in a subject comprising the steps of:
- (i) obtaining a biological sample from said subject;
- and
- (ii) assessing the expression of a functional Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 product in sample.
A non-human transgenic animal lacking at least one functional Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 allele.
A non-human transgenic animal that overexpresses Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 as compared to a similar non-transgenic animal.
A non-human transgenic animal, the genome of which comprises an expression cassette comprising a Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 under the control of an inducible promoter.
A method for suppressing growth of a tumor cell comprising contacting said cell with an expression cassette comprising:
- (a) a nucleic acid encoding Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3;
- and
- (b) a promoter active in said tumor cell, under conditions permitting the uptake of said nuclcic acid by said tumor cell.
A method of altering the phenotype of a tumor cell comprising contacting said cell with an expression cassette comprising:
- (a) a nucleic acid encoding Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3;
- and
- (b) a promoter active in said tumor cell,
- under conditions permitting the uptake of said nucleic acid by said tumor cell.
A method of inhibiting cancer in a subject suffering therefrom comprising administering to said subject an expression cassette comprising:
- (a) a nucleic acid encoding Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 polypeptide;
- and
- (b) a promoter active in tumor cells of said subject,
- whereby expression of said polypeptide inhibits said cancer.
A method of treating a subject with cancer, comprising the step of administering to said subject a Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 polypeptide.
A method of screening a candidate substance for anti-tumor activity comprising the steps of:
- (i) providing a cell lacking a functional Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 polypeptide;
- (ii) contacting said cell with said candidate substance;
- and
- (iii) determining the effect of said candidate substance on said cell.
A method of screening a candidate substance for anti-tumor activity comprising the steps of:
- (i) providing a cell;
- (ii) contacting said cell with said candidate substance;
- and
- (iii) determining the effect of said candidate substance on expression of a Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3 polypeptide.
A method of producing a Beta* polypeptide in a host cell comprising:
- (a) providing an expression cassette comprising a nucleic acid encoding Beta* operably linked to an promoter active in said host cell;
- (b) transferring said expression cassette into said host cell;
- and
- (c) culturing said host cell under conditions permitting expression of said Beta* polypeptide.
A method of diagnosing cancer in a subject comprising the steps of:
- (i) obtaining a biological sample from said subject;
- and
- (ii) detecting hypermethylation of the promoter region of Gene 26 (CACNA2D2), PL6, Beta* (BLU), Luca-1 (HYAL1), Luca-2 (HYAL2), 123F2 (RASSF1), Fus1, 101F6, Gene 21 (NPRL2), or SEM A3.
Dependencies are inferred from the claim text.