Molecular Cell
Volume 8, Issue 3, September 2001, Pages 705-711
Journal home page for Molecular Cell

Short article
BCL-2, BCL-XL Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis

https://doi.org/10.1016/S1097-2765(01)00320-3Get rights and content
Under an Elsevier user license
open archive

Abstract

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-XL 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.

Cited by (0)