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Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 1996 Aug; Vol. 16 (8), pp. 4445-55. - Publication Year :
- 1996
-
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.
- Subjects :
- Animals
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases antagonists & inhibitors
Cyclin-Dependent Kinases physiology
Cyclins physiology
Enzyme Inhibitors pharmacology
Mice
Microtubule-Associated Proteins physiology
Point Mutation
Protein Serine-Threonine Kinases physiology
Rats
Temperature
Cell Cycle
Cell Cycle Proteins
Cyclin-Dependent Kinases metabolism
Proto-Oncogene Proteins
Tumor Suppressor Protein p53 physiology
Tumor Suppressor Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 16
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 8754845
- Full Text :
- https://doi.org/10.1128/MCB.16.8.4445