Role of the INK4a locus in tumor suppression and cell mortality.
The cell cycle inhibitor p16INK4a is inactivated in many human tumors and in families with hereditary melanoma and pancreatic cancer. Tumor-associated alterations in the INK4a locus may also affect the overlapping gene encoding p19ARF and the adjacent gene encoding p15I1NK4b, both negative regulators of cell proliferation. We report the phenotype of mice carrying a targeted deletion of the INK4a locus that eliminates both p16INK4a and p19ARF. The mice are viable but develop spontaneous tumors at an early age and are highly sensitive to carcinogenic treatments. INK4a-deficient primary fibroblasts proliferate rapidly and have a high colony-formation efficiency. In contrast with normal cells, the introduction of activated Ha-ras into INK4a-deficient fibroblasts can result in neoplastic transformation. These findings directly demonstrate that the INK4a locus functions to suppress neoplastic growth.
Serrano
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Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, 11724 USA.
Lee
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Chin
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Cordon-Cardo
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Beach
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DePinho
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D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D005347:Fibroblasts / Q000737:chemistry / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF