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

Science (New York, N.Y.) | Mar 10, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10710310

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 RIS Download

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

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM44664

OMIM (Data, Gene Annotation)

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