p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest.
gamma-Irradiation of human diploid fibroblasts in the G1 interval caused arrest of the cell cycle prior to S phase. This cell cycle block was correlated with a lack of activation of both cyclin E-Cyclin-dependent kinase 2 (Cdk2) and cyclin A-Cdk2 kinases and depended on wild-type p53. Although the accumulation of cyclin A was strongly inhibited in gamma-irradiated cells, cyclin E accumulated and bound Cdk2 at normal levels but remained in an inactive state. We found that both whole-cell lysates and inactive cyclin E-Cdk2 complexes prepared from irradiated cells contained an activity capable of inactivating cyclin E-Cdk2 complexes. The protein responsible for this activity was shown to be p21CIP1/WAF1, recently described as a p53-inducible Cdk inhibitor. Our data suggest a model in which ionizing radiation confers G1 arrest via the p53-mediated induction of a Cdk inhibitor protein.
Dulić
V
V
Department of Molecular Biology MB-7, Scripps Research Institute, La Jolla, California 92037.
Kaufmann
W K
WK
Wilson
S J
SJ
Tlsty
T D
TD
Lees
E
E
Harper
J W
JW
Elledge
S J
SJ
Reed
S I
SI
D001483:Base Sequence; D002478:Cells, Cultured; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000528:radiation effects; D016193:G1 Phase / Q000502:physiology* / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D011494:Protein Kinases