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Ataxia Telangiectasia Mutated Down-regulates Phospho-Extracellular Signal-Regulated Kinase 1/2 via Activation of MKP-1 in Response to Radiation

Departments of ¹ Radiation Oncology, ² Pathology, and ³ Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan and ⁴ Department of Radiation Medicine, Georgetown University Medical School, Washington, District of Columbia

Requests for reprints: Theodore S. Lawrence, Department of Radiation Oncology, University of Michigan Medical Center, UH-B2C490, Box 0010, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010. Phone: 734-647-9955; Fax: 734-763-7371; E-mail: tsl{at}med.umich.edu.

Ataxia telangiectasia mutated (ATM) kinase plays a crucial role in the cellular response to DNA damage and in radiation resistance. Although much effort has focused on the relationship between ATM and other nuclear signal transducers, little is known about interactions between ATM and mitogenic signaling pathways. In this study, we show a novel relationship between ATM kinase and extracellular signal-regulated kinase 1/2 (ERK1/2), a key mitogenic stimulator. Activation of ATM by radiation down-regulates phospho-ERK1/2 and its downstream signaling via increased expression of mitogen-activated protein kinase phosphatase MKP-1 in both cell culture and tumor models. This dephosphorylation of ERK1/2 is independent of epidermal growth factor receptor (EGFR) activity and is associated with radioresistance. These findings show a new function for ATM in the control of mitogenic pathways affecting cell signaling and emphasize the key role of ATM in coordinating the cellular response to DNA damage. (Cancer Res 2006; 66(24): 11554-9)

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