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ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage

Oncogene volume 21, pages 849–855 (2002)Cite this article

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.

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Acknowledgements

This work was supported by research grants from the A-T Children's Project, the A-T Medical Research Foundation, The Thomas Appeal (A-T Medical Research Trust), and the National Institutes of Health (RO1 NS31763).

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Author notes

  1. Anat Bar-Shira

    Present address: Research and Development Laboratory, The Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, The David and Inez Myers Laboratory for Genetic Research, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Anat Bar-Shira, Sharon Rashi-Elkeles, Liat Zlochover, Lilach Moyal & Yosef Shiloh

  2. Hybridoma Unit, The George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel

    Nechama I Smorodinsky

  3. Department of Biological Regulation, The Weizmann Institute of Science, 76100, Rehovot, Israel

    Rony Seger

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Correspondence to Yosef Shiloh.

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Bar-Shira, A., Rashi-Elkeles, S., Zlochover, L. et al. ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage. Oncogene 21, 849–855 (2002). https://doi.org/10.1038/sj.onc.1205127

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