Abstract
Exposure of human cells to genotoxic agents induces various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation (IR) is associated with the human diseases ataxia-telangiectasia (A-T) and Nijmegen Breakage syndrome (NBS). Here, we show that IR efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. IR was found to enhance the expression of c-Jun and, in particular, ATF3, but, in contrast to various other stress stimuli, did not induce the expression of c-Fos. Using specific inhibitors, we found that the ATM- and Nibrin1-dependent activation of ATF3 does neither require p53 nor reactive oxygen species, but is dependent on the p38 and JNK MAPkinases. Via these kinases, IR activates ATF-2, one of the transcription factors acting on the atf3 promoter. The activation of ATF-2 by IR resembles ATF-2 activation by certain growth factors, since IR mainly induced the second step of ATF-2 phosphorylation via the stress-inducible MAPkinases, phosphorylation of Thr69. As IR does not enhance ATF-2 phosphorylation in ATM and Nibrin1-deficient cells, both ATF-2 and ATF3 seem to play an important role in the protective response of human cells to IR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Activating Transcription Factor 3
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Northern
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Blotting, Western
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / metabolism*
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DNA Damage
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DNA-Binding Proteins
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Fibroblasts / metabolism
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Fibroblasts / radiation effects
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Humans
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JNK Mitogen-Activated Protein Kinases
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Kinetics
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinases / metabolism
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Nuclear Proteins / metabolism
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Oxidative Stress
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Phosphorylation
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / metabolism
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Radiation, Ionizing*
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Signal Transduction*
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
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p38 Mitogen-Activated Protein Kinases
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Activating Transcription Factor 3
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Cell Cycle Proteins
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Cyclic AMP Response Element-Binding Protein
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DNA-Binding Proteins
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NBN protein, human
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Nuclear Proteins
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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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