Abstract
A central issue in the regulation of apoptosis by the Bcl-2 family is whether its BH3-only members initiate apoptosis by directly binding to the essential cell-death mediators Bax and Bak, or whether they can act indirectly, by engaging their pro-survival Bcl-2-like relatives. Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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BH3 Interacting Domain Death Agonist Protein / chemistry
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BH3 Interacting Domain Death Agonist Protein / genetics
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BH3 Interacting Domain Death Agonist Protein / metabolism*
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Bcl-2-Like Protein 11
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Cell Line
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Cells, Cultured
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Humans
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Ligands
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Models, Biological
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Mutation
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Protein Structure, Tertiary
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Proteins / metabolism
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Proto-Oncogene Proteins / chemistry
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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 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / chemistry
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bcl-2-Associated X Protein / metabolism*
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bcl-Associated Death Protein / metabolism
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bcl-X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAD protein, human
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BAK1 protein, human
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BCL2L11 protein, human
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BH3 Interacting Domain Death Agonist Protein
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Bad protein, mouse
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Bak1 protein, mouse
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Bcl-2-Like Protein 11
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Bcl2l1 protein, mouse
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Bcl2l11 protein, mouse
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Bcl2l2 protein, mouse
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Ligands
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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PUMA protein, mouse
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Pmaip1 protein, mouse
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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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Tumor Suppressor 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