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J. Biol. Chem., Vol. 278, Issue 28, 26031-26038, July 11, 2003

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Calpains Mediate p53 Activation and Neuronal Death Evoked by DNA Damage^*

Mary Sedarous , Elizabeth Keramaris , Michael O'Hare , Edon Melloni , Ruth S. Slack , John S. Elce ¶, Peter A. Greer || and David S. Park, Recipient of the Glaxo Wellcome Award in Stroke, and a Canadian Institutes of Health Research Scholar  **

From the Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the Department of Experimental Medicine, University of Genoa, Viale Benedetto XV, Genoa, Italy, and the Departments of ^¶Biochemistry and ^||Pathology, Queen's University, Kingston, Ontario K7L 3N6, Canada

DNA damage is an initiator of neuronal death implicated in neuropathological conditions such as stroke. Previous evidence has shown that apoptotic death of embryonic cortical neurons treated with the DNA damaging agent camptothecin is dependent upon the tumor suppressor p53, an upstream death mediator, and more distal death effectors such as caspases. We show here that the calcium-regulated cysteine proteases, calpains, are activated during DNA damage induced by camptothecin treatment. Moreover, calpain deficiency, calpastatin expression, or pharmacological calpain inhibitors prevent the death of embryonic cortical neurons, indicating the important role of calpain in DNA damage-induced death. Calpain inhibition also significantly reduced and delayed the induction of p53. Consistent with the actions of calpains upstream of p53 and the proximal nature of p53 death signaling, calpain inhibition inhibited cytochrome c release and DEVD-AFC cleavage activity. Taken together, our results indicate that calpains are a key mediator of p53 induction and consequent caspase-dependent neuronal death due to DNA damage.

Received for publication, March 19, 2003 , and in revised form, April 28, 2003.

^* This work was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and the Canadian Stroke Network (to D. S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 613-562-5800 (ext. 8816); Fax: 613-562-5403; E-mail: dpark{at}uottawa.ca.

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