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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


  • Cheng EH
  • Wei MC
  • Weiler S
  • Flavell RA
  • Mak TW
  • Lindsten T
  • Korsmeyer SJ


Molecular cell

Publication Data

September 3, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: R01CA50239

Mesh Terms

  • 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