DNA damage-induced activation of p53 by the checkpoint kinase Chk2

Science. 2000 Mar 10;287(5459):1824-7. doi: 10.1126/science.287.5459.1824.

Abstract

Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2-/- embryonic stem cells failed to maintain gamma-irradiation-induced arrest in the G2 phase of the cell cycle. Chk2-/- thymocytes were resistant to DNA damage-induced apoptosis. Chk2-/- cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to gamma irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. This provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Checkpoint Kinase 2
  • DNA Damage*
  • DNA-Binding Proteins
  • G1 Phase
  • G2 Phase
  • Gamma Rays
  • Gene Expression Regulation
  • Gene Targeting
  • Genes, Tumor Suppressor
  • Genes, p53
  • Humans
  • Interphase*
  • Mice
  • Nuclear Proteins*
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Kinases*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • T-Lymphocytes / cytology
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Phosphoserine
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • CHEK2 protein, human
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases