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

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.

Pubmed ID: 10710310

Authors

  • Hirao A
  • Kong YY
  • Matsuoka S
  • Wakeham A
  • Ruland J
  • Yoshida H
  • Liu D
  • Elledge SJ
  • Mak TW

Journal

Science (New York, N.Y.)

Publication Data

March 10, 2000

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM44664

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
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-mdm2
  • Stem Cells
  • T-Lymphocytes
  • Transcription, Genetic
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins