Role of ATM in oxidative stress-mediated c-Jun phosphorylation in response to ionizing radiation and CdCl2.
Ionizing radiation-induced phosphorylation of the transcription factor c-Jun is impaired in cells derived from individuals with ataxia telangiectasia (AT), in which the ATM gene is mutated. We demonstrate here that ATM modulates c-Jun phosphorylation following exposure to ionizing radiation as well as treatment with CdCl(2), a potent pro-oxidant. Exposure of AT and control fibroblasts to CdCl(2) induced a biphasic increase in c-Jun phosphorylation on serine residues 63 and 73, with the extent of the second phase being markedly greater in AT cells than in control cells. Heme oxygenase-1, a marker of oxidative stress, was also significantly induced in AT fibroblasts. Expression of recombinant ATM in AT fibroblasts, however, reduced the extent of the effects of CdCl(2) on both c-Jun phosphorylation and heme oxygenase-1 induction. Our data suggest that ATM contributes to oxidative stress-mediated signaling that leads to c-Jun phosphorylation by acting as a sensor of ionizing radiation-induced oxidative stress and by modulating intracellular redox homeostasis.
Department of Radiation Medicine, Georgetown University Medical Center, Washington, D.C. 20007-2197, USA.
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Dritschilo
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D064007:Ataxia Telangiectasia Mutated Proteins; D019256:Cadmium Chloride / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019256:Cadmium Chloride