BCL-2, BCL-X(L) Sequester BH3 Domain-Only Molecules Preventing BAX- And BAK-mediated Mitochondrial Apoptosis

Mol Cell. 2001 Sep;8(3):705-11. doi: 10.1016/s1097-2765(01)00320-3.

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-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Apoptotic Protease-Activating Factor 1
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line
  • Cytochrome c Group / metabolism
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Immunoblotting
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism*
  • Protein Structure, Tertiary
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • APAF1 protein, human
  • Apoptosis Regulatory Proteins
  • Apoptotic Protease-Activating Factor 1
  • BCL2L11 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Carrier Proteins
  • Cytochrome c Group
  • Enzyme Precursors
  • Membrane Proteins
  • PMAIP1 protein, human
  • 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
  • Caspases