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J. Biol. Chem., Vol. 281, Issue 7, 3876-3888, February 17, 2006

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Caspase-7 Is Directly Activated by the 700-kDa Apoptosome Complex and Is Released as a Stable XIAP-Caspase-7 200-kDa Complex^*

From the Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Rd., University of Leicester, Leicester LE1 9HN, United Kingdom

MCF-7 cells lack caspase-3 but undergo mitochondrial-dependent apoptosis via caspase-7 activation. It is assumed that the Apaf-1-caspase-9 apoptosome processes caspase-7 in an analogous manner to that described for caspase-3. However, this has not been validated experimentally, and we have now characterized the caspase-7 activating apoptosome complex in MCF-7 cell lysates activated with dATP/cytochrome c. Apaf-1 oligomerizes to produce 1.4-MDa and 700-kDa apoptosome complexes, and the latter complex directly cleaves/activates procaspase-7. This 700-kDa apoptosome complex, which is also formed in apoptotic MCF-7 cells, is assembled by rapid oligomerization of Apaf-1 and followed by a slower process of procaspase-9 recruitment and cleavage to form the p35/34 forms. However, procaspase-9 recruitment and processing are accelerated in lysates supplemented with caspase-3. In lysates containing very low levels of Smac and Omi/HtrA2, XIAP (X-linked inhibitor of apoptosis) binds tightly to caspase-9 in the apoptosome complex, and as a result caspase-7 processing is abrogated. In contrast, in MCF-7 lysates containing Smac and Omi/HtrA2, active caspase-7 is released from the apoptosome and forms a stable 200-kDa XIAP-caspase-7 complex, which apparently does not contain cIAP1 or cIAP2. Thus, in comparison to caspase-3-containing cells, XIAP appears to have a more significant antiapoptotic role in MCF-7 cells because it directly inhibits caspase-7 activation by the apoptosome and also forms a stable 200-kDa complex with active caspase-7.

Received for publication, July 8, 2005 , and in revised form, November 17, 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 44-116-252-5547; Fax: 44-116-252-5616; E-mail: kc5{at}le.ac.uk.

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