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- Publisher Website: 10.1128/MCB.00188-07
- Scopus: eid_2-s2.0-34547897630
- PMID: 17562856
- WOS: WOS:000248526100007
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Article: XIAP activity dictates Apaf-1 dependency for caspase 9 activation
Title | XIAP activity dictates Apaf-1 dependency for caspase 9 activation |
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Authors | |
Issue Date | 2007 |
Citation | Molecular and Cellular Biology, 2007, v. 27, n. 16, p. 5673-5685 How to Cite? |
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 procaspase 9 and Smac/Diablo-mediated sequestration of inhibitors of apoptosis proteins (IAPs). Here, we showed that either pathway can independently promote caspase 9 activation in response to apoptotic stimuli. In drug-treated Apaf-1-/- primary myoblasts, but not fibroblasts, Smac/Diablo accumulates in the cytosol and sequesters X-linked IAP (XIAP), which is expressed at lower levels in myoblasts than in fibroblasts. Consequently, caspase 9 activation proceeds in Apaf-1-/- myoblasts; concomitant ablation of Apaf-1 and Smac is required to prevent caspase 9 activation and the onset of apoptosis. Conversely, in stimulated Apaf-1 -/- fibroblasts, the ratio of XIAP to Smac/Diablo is high compared to that for myoblasts and procaspase 9 is not activated. Suppressing XIAP with exogenous Smac/Diablo or a pharmacological inhibitor can still induce caspase 9 in drug-treated Apaf-1-null fibroblasts. Thus, caspase 9 activation in response to intrinsic apoptotic stimuli can be uncoupled from Apaf-1 in vivo by XIAP antagonists. Copyright © 2007, American Society for Microbiology. All Rights Reserved. |
Persistent Identifier | http://hdl.handle.net/10722/292613 |
ISSN | 2023 Impact Factor: 3.2 2023 SCImago Journal Rankings: 1.452 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Ho, Andrew T. | - |
dc.contributor.author | Li, Qin H. | - |
dc.contributor.author | Okada, Hitoshi | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Zacksenhaus, Eldad | - |
dc.date.accessioned | 2020-11-17T14:56:51Z | - |
dc.date.available | 2020-11-17T14:56:51Z | - |
dc.date.issued | 2007 | - |
dc.identifier.citation | Molecular and Cellular Biology, 2007, v. 27, n. 16, p. 5673-5685 | - |
dc.identifier.issn | 0270-7306 | - |
dc.identifier.uri | http://hdl.handle.net/10722/292613 | - |
dc.description.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 procaspase 9 and Smac/Diablo-mediated sequestration of inhibitors of apoptosis proteins (IAPs). Here, we showed that either pathway can independently promote caspase 9 activation in response to apoptotic stimuli. In drug-treated Apaf-1-/- primary myoblasts, but not fibroblasts, Smac/Diablo accumulates in the cytosol and sequesters X-linked IAP (XIAP), which is expressed at lower levels in myoblasts than in fibroblasts. Consequently, caspase 9 activation proceeds in Apaf-1-/- myoblasts; concomitant ablation of Apaf-1 and Smac is required to prevent caspase 9 activation and the onset of apoptosis. Conversely, in stimulated Apaf-1 -/- fibroblasts, the ratio of XIAP to Smac/Diablo is high compared to that for myoblasts and procaspase 9 is not activated. Suppressing XIAP with exogenous Smac/Diablo or a pharmacological inhibitor can still induce caspase 9 in drug-treated Apaf-1-null fibroblasts. Thus, caspase 9 activation in response to intrinsic apoptotic stimuli can be uncoupled from Apaf-1 in vivo by XIAP antagonists. Copyright © 2007, American Society for Microbiology. All Rights Reserved. | - |
dc.language | eng | - |
dc.relation.ispartof | Molecular and Cellular Biology | - |
dc.title | XIAP activity dictates Apaf-1 dependency for caspase 9 activation | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1128/MCB.00188-07 | - |
dc.identifier.pmid | 17562856 | - |
dc.identifier.pmcid | PMC1952122 | - |
dc.identifier.scopus | eid_2-s2.0-34547897630 | - |
dc.identifier.volume | 27 | - |
dc.identifier.issue | 16 | - |
dc.identifier.spage | 5673 | - |
dc.identifier.epage | 5685 | - |
dc.identifier.isi | WOS:000248526100007 | - |
dc.identifier.issnl | 0270-7306 | - |