Abstract
The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19Arf and MDM2 physically interact and that p19Rrf blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19Arf functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Biotin
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Cell Line / chemistry
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Cell Line / cytology
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Cell Line / physiology
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DNA Fragmentation
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Deoxyuracil Nucleotides
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Genes, p16 / physiology*
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Lens, Crystalline / cytology
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins*
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Osteoblasts / chemistry
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Osteoblasts / cytology
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Osteoblasts / physiology
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Proteins / metabolism*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Retinoblastoma Protein / metabolism
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Staining and Labeling
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Transformation, Genetic
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Deoxyuracil Nucleotides
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Neoplasm Proteins
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Nuclear Proteins
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Proteins
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Biotin
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2