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J. Biol. Chem., Vol. 282, Issue 19, 14132-14139, May 11, 2007

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Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis^*

Ali Masud¹, Alexander Mohapatra¹, Saquib A. Lakhani^¶, Anthony Ferrandino, Razqallah Hakem^||, and Richard A. Flavell²

From the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, ^¶Shady Grove Adventist Hospital for Children, Rockville, Maryland 20850, and ^||Division of Cellular and Molecular Biology, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Ontario M5G 2C1, Canada

Members of the caspase family are essential for many apoptotic programs. We studied mouse embryonic fibroblasts (MEFs) deficient in caspases 3 and 7 and in caspase 9 to determine the role of these proteases in endoplasmic reticulum (ER) stress-induced apoptosis. Both caspase 3^–/–/caspase 7^–/– and caspase 9^–/– MEFs were resistant to cytotoxicity induced via ER stress and failed to exhibit apoptotic morphology. Specifically, apoptosis induced by increased intracellular calcium was shown to depend only on caspases 3 and 9, whereas apoptosis induced by disruption of ER function depended additionally on caspase 7. Caspase 3^–/–/caspase 7^–/– and caspase 9^–/– MEFs also exhibited decreased loss of mitochondrial membrane potential, which correlated with altered caspase 9 processing, increased induction of procaspase 11, and decreased processing of caspase 12 in caspase 3^–/–/caspase 7^–/– cells. Furthermore, disruption of ER function was sufficient to induce accumulation of cleaved caspase 3 and 7 in a heavy membrane compartment, suggesting a potential mechanism for caspase 12 processing and its role as an amplifier in the death pathway. Caspase 8^–/– MEFs were not resistant to ER stress-induced cytotoxicity, and processing of caspase 8 was not observed upon induction of ER stress. This study thus demonstrates a requirement for caspases 3 and 9 and a key role for the intrinsic pathway in ER stress-induced apoptosis.

Received for publication, January 3, 2007 , and in revised form, March 15, 2007.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Howard Hughes Medical Institute, Yale University School of Medicine, Dept. of Immunobiology, 300 Cedar St., TAC S-569A, New Haven, CT 06519–1612. Tel.: 203-737-2216; Fax: 203-737-2958; E-mail: richard.flavell{at}yale.edu.

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