BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.
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.
Pubmed ID: 11583631 RIS Download
Animals | Apoptosis | Apoptosis Regulatory Proteins | Apoptotic Protease-Activating Factor 1 | BH3 Interacting Domain Death Agonist Protein | Carrier Proteins | Caspases | Cell Line | Cytochrome c Group | Enzyme Precursors | Immunoblotting | Membrane Proteins | Mitochondria | Protein Structure, Tertiary | Proteins | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-bcl-2 | Recombinant Proteins | bcl-2 Homologous Antagonist-Killer Protein | bcl-2-Associated X Protein | bcl-Associated Death Protein | bcl-X Protein