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
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Apoptotic Protease-Activating Factor 1
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BH3 Interacting Domain Death Agonist Protein
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Bcl-2-Like Protein 11
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspases / genetics
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Caspases / metabolism
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Cell Line
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Cytochrome c Group / metabolism
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Enzyme Precursors / genetics
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Enzyme Precursors / metabolism
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Immunoblotting
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Membrane Proteins / metabolism
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Mitochondria / metabolism*
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Protein Structure, Tertiary
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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APAF1 protein, human
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Apoptosis Regulatory Proteins
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Apoptotic Protease-Activating Factor 1
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BCL2L11 protein, human
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BH3 Interacting Domain Death Agonist Protein
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Bcl-2-Like Protein 11
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Carrier Proteins
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Cytochrome c Group
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Enzyme Precursors
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Membrane Proteins
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PMAIP1 protein, human
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-Associated Death Protein
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bcl-X Protein
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Caspases