Abstract
Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
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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Cell Cycle Proteins*
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Cell Cycle*
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism*
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Cyclin-Dependent Kinases / physiology
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Cyclins / physiology
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Enzyme Inhibitors / pharmacology
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Mice
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Microtubule-Associated Proteins / physiology
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Point Mutation
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins*
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Rats
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Temperature
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Tumor Suppressor Protein p53 / physiology*
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Tumor Suppressor Proteins*
Substances
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Cdkn1a protein, mouse
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Cdkn1a protein, rat
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Cdkn1b protein, mouse
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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Cdk4 protein, mouse
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Cdk4 protein, rat
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Cdk6 protein, mouse
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Cdk6 protein, rat
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases