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J. Biol. Chem., Vol. 281, Issue 26, 17689-17698, June 30, 2006

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Ubiquitous Calpains Promote Both Apoptosis and Survival Signals in Response to Different Cell Death Stimuli^*

Yinfei Tan, Chao Wu, Teresa De Veyra, and Peter A. Greer¹

From the Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute and Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L-3N6, Canada

The µ- and m-calpain proteases have been implicated in both pro- or anti-apoptotic functions. Here we compared cell death responses and apoptotic or survival signaling pathways in primary mouse embryonic fibroblasts (MEFs) derived from wild type or capn4 knock-out mice which lack both µ- and m-calpain activities. Capn4^–/– MEFs displayed resistance to puromycin, camptothecin, etoposide, hydrogen peroxide, ultraviolet light, and serum starvation, which was consistent with pro-apoptotic roles for calpain. In contrast, capn4^–/– MEFs were more susceptible to staurosporine (STS) and tumor necrosis factor -induced cell death, which provided evidence for anti-apoptotic signaling roles for calpain. Bax activation, release of cytochrome c, and activation of caspase-9 and caspase-3 all correlated with the observed cell death responses of wild type or capn4^–/– MEFs to the various challenges, suggesting that calpain might play distinct roles in transducing different death signals to the mitochondria. There was no evidence that calpain cleaved Bcl-2 family member proteins that regulate mitochondrial membrane permeability including Bcl-2, Bcl-xl, Bad, Bak, Bid, or Bim. However, activation of the phosphatidylinositol 3 (PI3)-kinase/Akt survival signaling pathway was compromised in capn4^–/– MEFs under all challenges regardless of the cell death outcome, and blocking Akt activation using the PI3-kinase inhibitor LY294002 abolished the protective effect of calpain to STS challenge. We conclude that the anti-apoptotic function of calpain in tumor necrosis factor - and STS-challenged cells relates to a novel role in activating the PI3-kinase/Akt survival pathway.

Received for publication, March 1, 2006 , and in revised form, April 20, 2006.

^* This work was supported by an operating grant from the Canadian Institutes of Health Research. 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.

¹ To whom correspondence should be addressed: Queen's University Cancer Research Institute, Botterell Hall, Rm. A309, Kingston, Ontario, K7L-3N6, Canada. Tel.: 613-533-8213; Fax: 613-533-6830; E-mail: greerp{at}post.queensu.ca.

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