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Mol. Cell. Biol. doi:10.1128/MCB.00188-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

XIAP Activity Dictates Apaf-1 Dependency for Caspase9 Activation

Division of Cell & Molecular Biology, Toronto General Research Institute - University Health Network, 67 College Street, Toronto, Ontario, Canada M5G 2M1, Departments of Medical Biophysics, Laboratory Medicine & Pathobiology, Medicine and; Immunology, University of Toronto, The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, 620 University Ave Toronto, Ontario, Canada M5G 2C1

^* To whom correspondence should be addressed. Email: eldad.zacksenhaus{at}utoronto.ca.

	Abstract

The current model for the intrinsic apoptotic pathway holds that mitochondrial activation of caspases in response to cytotoxic drugs requires both Apaf-1 induced dimerization of pro-caspase9 and Smac/Diablo-mediated sequestration of Inhibitors of Apoptosis Proteins (IAPs). Here we show that either pathway can independently promote caspase9 activation in response to apoptotic stimuli. In drug treated Apaf1^-/- primary myoblasts but not fibroblasts, Smac/Diablo accumulates in the cytosol and sequesters XIAP, which is expressed at lower levels in myoblasts relative to fibroblasts. Consequently, caspase9 activation proceeds in Apaf1^-/- myoblasts; concomitant ablation of Apaf1 and Smac is required to prevent caspase9 activation and the onset of apoptosis. Conversely, in stimulated Apaf1^-/- fibroblasts, the ratio of XIAP to Smac/Diablo is high compared to myoblasts, and pro-caspase9 is not activated. Suppressing XIAP with exogenous Smac/Diablo or a pharmacological inhibitor can still induce Caspase9 in drug-treated Apaf1 null fibroblasts. Thus, caspase9 activation in response to intrinsic apoptotic stimuli can be uncoupled from Apaf-1 in vivo by XIAP antagonists.