Abstract
Bcl-2 family proteins regulate a critical step in apoptosis referred to as mitochondrial outer membrane permeabilization (MOMP). Members of a subgroup of the Bcl-2 family, known as the BH3-only proteins, activate pro-apoptotic effectors (Bax and Bak) to initiate MOMP. They do so by neutralizing pro-survival Bcl-2 proteins and/or directly activating Bax/Bak. Bim and Bid are reported to be direct activators; however, here we show that BH3 peptides other than Bim and Bid exhibited various degrees of direct activation of the effector Bax or Bak, including Bmf and Noxa BH3s. In the absence of potent direct activators, such as Bim and Bid, we unmasked novel direct activator BH3 ligands capable of inducing effector-mediated cytochrome c release and liposome permeabilization, even when both Bcl-xL- and Mcl-1-type anti-apoptotic proteins were inhibited. The ability of these weaker direct activator BH3 peptides to cause MOMP correlated with that of the corresponding full-length proteins to induce apoptosis in the absence of Bim and Bid. We propose that, in certain contexts, direct activation by BH3-only proteins other than Bim and Bid may significantly contribute to MOMP and apoptosis.
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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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / metabolism*
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BH3 Interacting Domain Death Agonist Protein / chemistry
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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 Membrane / metabolism
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Cell Membrane Permeability
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Cytochromes c / metabolism
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HEK293 Cells
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Humans
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Liposomes / metabolism
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism*
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Mice
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Molecular Sequence Data
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Peptide Fragments / metabolism
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Protein Multimerization
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Protein Structure, Quaternary
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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bcl-2 Homologous Antagonist-Killer Protein / chemistry
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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-X Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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BCL2L11 protein, human
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BH3 Interacting Domain Death Agonist Protein
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BMF protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Liposomes
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Membrane Proteins
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PMAIP1 protein, human
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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bcl-X Protein
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Cytochromes c