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Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2

Oncogene volume 22, pages 4235–4242 (2003)Cite this article

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.

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Acknowledgements

We thank Corina van der Burgt and Kim Janssen for their contributions to some of the experiments and Drs DM Ouwens and AG Jochemsen for critically reading the manuscript. This work was supported by grants from the Netherlands Organisation for Scientific Research (NWO), the Dutch Cancer Society (KWF) and the Radiation Protection, Biomed and TMR Programs of the European Community.

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Authors and Affiliations

  1. Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Centre, Wassenaarseweg 72, Leiden, 2333AL, The Netherlands

    Jaap Kool, Paulien Cornelissen-Steijger, Alex J van der Eb & Carrol Terleth

  2. Department of Molecular Cell Biology, Centre for Biomedical Genetics, Section Gene Regulation, Leiden University Medical Centre, Wassenaarseweg 72, Leiden, 2333AL, The Netherlands

    Mohamed Hamdi & Hans van Dam

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  1. Jaap Kool
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Correspondence to Hans van Dam.

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Kool, J., Hamdi, M., Cornelissen-Steijger, P. et al. Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2. Oncogene 22, 4235–4242 (2003). https://doi.org/10.1038/sj.onc.1206611

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