p53-dependent Inhibition of Cyclin-Dependent Kinase Activities in Human Fibroblasts During Radiation-Induced G1 Arrest

Cell. 1994 Mar 25;76(6):1013-23. doi: 10.1016/0092-8674(94)90379-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cells, Cultured
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Cyclins / physiology
  • Enzyme Activation
  • Fibroblasts / cytology*
  • Fibroblasts / enzymology
  • Fibroblasts / radiation effects
  • G1 Phase / physiology*
  • G1 Phase / radiation effects*
  • Gamma Rays
  • Humans
  • Male
  • Molecular Sequence Data
  • Oncogene Proteins / metabolism
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism*
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Protein Kinases