DNA damage-induced activation of p53 by the checkpoint kinase Chk2.
Journal:
Science 2000 MarAuthors:
Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW
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. Reintrodu
...[more]ction 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.[less]
Mesh Headings:
Animals, Apoptosis, Cell Cycle Proteins, 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