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J. Biol. Chem., Vol. 280, Issue 46, 38271-38275, November 18, 2005

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Essential Roles of the Bcl-2 Family of Proteins in Caspase-2-induced Apoptosis^*

Zhonghua Gao, Yufang Shao, and Xuejun Jiang1

From the Cell Biology Program, Memorial Sloan-Kettering Cancer Center and the Cornell University Weill Graduate School of Medical Sciences, New York, New York 10021

Caspase-2 is an initiating caspase required for stress-induced apoptosis in various human cancer cells. Recent studies suggest that it can mediate the death function of tumor suppressor p53 and is activated by a multimeric protein complex, PIDDosome. However, it is not clear how caspase-2 exerts its apoptotic function in cells and whether its enzymatic activity is required for the apoptotic function. In this study, we used both in vitro mitochondrial cytochrome c release assays and cell culture apoptosis analyses to investigate the mechanism by which caspase-2 induces apoptosis. We show that active caspase-2, but neither a catalytically mutated caspase-2 nor active caspase-2 with its inhibitor, can cause cytochrome c release. Caspase-2 failed to induce cytochrome c release from mitochondria with Bid^–/– background, and the release could be restored by addition of the wild-type Bid protein, but not by Bid with the caspase-2 cleavage site mutated. Caspase-2 was not able to induce cytochrome c release from Bax^–/–Bak^–/– mitochondria either. In cultured cells, gene deletion of Bax/Bak or Bid abrogated apoptosis induced by overexpression of caspase-2. Collectively, these results indicate that proteolytic activation of Bid and the subsequent induction of the mitochondrial apoptotic pathway through Bax/Bak is essential for apoptosis triggered by caspase-2.

Received for publication, June 14, 2005 , and in revised form, August 22, 2005.

^* 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: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 522, NY, NY 10021. Tel.: 212-639-6814; Fax: 212-717-3298; E-mail: jiangx{at}mskcc.org.

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