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

Anat Bar-Shira, Sharon Rashi-Elkeles, Liat Zlochover, Lilach Moyal, Nechama I. Smorodinsky, Rony Seger, Yosef Shiloh

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)849-855
Number of pages7
Issue number5
StatePublished - 2002


FundersFunder number
National Institutes of Health
National Institute of Neurological Disorders and StrokeR01NS031763
Dr. Ralph and Marian Falk Medical Research Trust
Medical Research Foundation


    • ATM
    • Ataxia-telangiectasia
    • JNK
    • MAP kinase phosphatase
    • MAP kinases
    • p38


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