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Originally published In Press as doi:10.1074/jbc.M601299200 on April 5, 2006

J. Biol. Chem., Vol. 281, Issue 23, 16016-16024, June 9, 2006
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Ubiquitous Calpains Promote Caspase-12 and JNK Activation during Endoplasmic Reticulum Stress-induced Apoptosis*Formula

Yinfei Tan{ddagger}, Nathalie Dourdin§, Chao Wu{ddagger}, Teresa De Veyra{ddagger}, John S. Elce§, and Peter A. Greer{ddagger}§1

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

Ubiquitously expressed µ- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of µ- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation.


Received for publication, February 9, 2006 , and in revised form, March 29, 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.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

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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