Abstract
Cellular responses to DNA damage are mediated by an extensive network of signaling pathways. The ATM protein kinase is a master regulator of the response to double-strand breaks (DSBs), the most cytotoxic DNA lesion caused by ionizing radiation. ATM is the protein missing or inactive in patients with the pleiotropic genetic disorder ataxia-telangiectasia (A-T). A major response to DNA damage is altered expression of numerous genes. While studying gene expression in control and A-T cells following treatment with the radiomimetic chemical neocarzinostatin (NCS), we identified an expressed sequence tag that represented a gene that was induced by DSBs in an ATM-dependent manner. The corresponding cDNA encoded a dual specificity phosphatase of the MAP kinase phosphatase family, MKP-5. MKP-5 dephosphorylates and inactivates the stress-activated MAP kinases JNK and p38. The phosphorylation-dephosphorylation cycle of JNK and p38 by NCS was attenuated in A-T cells. Thus, ATM modulates this cycle in response to DSBs. These results further highlight ATM as a link between the DNA damage response and major signaling pathways involved in proliferative and apoptotic processes.
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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Ataxia Telangiectasia / genetics
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Ataxia Telangiectasia / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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Cell Line
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DNA Damage*
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DNA-Binding Proteins
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Dual-Specificity Phosphatases
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Enzyme Activation
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Gene Deletion
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Humans
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases
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Kinetics
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Mitogen-Activated Protein Kinase Phosphatases
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Mitogen-Activated Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Protein Tyrosine Phosphatases / biosynthesis*
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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RNA, Messenger / biosynthesis
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Radiation, Ionizing
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Transcriptional Activation*
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Tumor Suppressor Proteins
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Zinostatin / pharmacology*
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p38 Mitogen-Activated Protein Kinases
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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Tumor Suppressor Proteins
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Zinostatin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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DUSP10 protein, human
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Mitogen-Activated Protein Kinase Phosphatases
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Dual-Specificity Phosphatases
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Protein Tyrosine Phosphatases