Bcr-Abl-Mediated Protection from Apoptosis Downstream of Mitochondrial Cytochrome c Release
Open Access
- 1 December 2004
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 24 (23), 10289-10299
- https://doi.org/10.1128/mcb.24.23.10289-10299.2004
Abstract
Bcr-Abl, activated in chronic myelogenous leukemias, is a potent cell death inhibitor. Previous reports have shown that Bcr-Abl prevents apoptosis through inhibition of mitochondrial cytochrome c release. We report here that Bcr-Abl also inhibits caspase activation after the release of cytochrome c. Bcr-Abl inhibited caspase activation by cytochrome c added to cell-free lysates and prevented apoptosis when cytochrome c was microinjected into intact cells. Bcr-Abl acted posttranslationally to prevent the cytochrome c-induced binding of Apaf-1 to procaspase 9. Although Bcr-Abl prevented interaction of endogenous Apaf-1 with the recombinant prodomain of caspase 9, it did not affect the association of endogenous caspase 9 with the isolated Apaf-1 caspase recruitment domain (CARD) or Apaf-1 lacking WD-40 repeats. These data suggest that Apaf-1 recruitment of caspase 9 is faulty in the presence of Bcr-Abl and that cytochrome c/dATP-induced exposure of the Apaf-1 CARD is likely defective. These data provide a novel locus of Bcr-Abl antiapoptotic action and suggest a distinct mechanism of apoptosomal inhibition.Keywords
This publication has 67 references indexed in Scilit:
- Differentiation-dependent Sensitivity to Apoptogenic Factors in PC12 CellsJournal of Biological Chemistry, 2004
- Cell DeathCell, 2004
- Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPKNature, 2003
- Role of Smac in human leukaemic cell apoptosis and proliferationOncogene, 2003
- IAP proteins: blocking the road to death's doorNature Reviews Molecular Cell Biology, 2002
- Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5–Dependent Expression of Bcl-XLThe Journal of Experimental Medicine, 2000
- Caspase Phosphorylation, Cell Death, and Species VariabilityScience, 2000
- The Hallmarks of CancerCell, 2000
- Apoptosis induced by microinjection of cytochrome c is caspase-dependent and is inhibited by Bcl-2Cell Death & Differentiation, 1998
- Crk is required for apoptosis in Xenopus egg extractsThe EMBO Journal, 1997