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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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Checkpoint Kinase 2
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DNA Damage*
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DNA-Binding Proteins
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G1 Phase
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G2 Phase
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Gamma Rays
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Gene Expression Regulation
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Gene Targeting
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Genes, Tumor Suppressor
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Genes, p53
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Humans
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Interphase*
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Mice
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Nuclear Proteins*
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Phosphorylation
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Phosphoserine / metabolism
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Protein Kinases*
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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Stem Cells / cytology
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Stem Cells / metabolism
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T-Lymphocytes / cytology
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Transcription, Genetic
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Phosphoserine
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Protein Kinases
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK2 protein, human
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases