Journal
MOLECULAR CELL
Volume 8, Issue 3, Pages 705-711Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(01)00320-3
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Funding
- NCI NIH HHS [R01CA50239] Funding Source: Medline
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Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from BH3 domain-only molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking multidomain BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X-L indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.
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