Abstract
Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family "BH3-only" proteins have dual functions. Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-x(L) and/or Mcl-1 proteins, some displaying a specificity for either Bcl-x(L) or Mcl-1. Besides having this derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Apoptosis Regulatory Proteins
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Apoptosis*
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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 / metabolism
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Cytochromes c / metabolism
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HeLa Cells
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Humans
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Intracellular Membranes / metabolism*
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Membrane Proteins / metabolism
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Mitochondria / metabolism*
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Mitochondrial Proteins / metabolism
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Molecular Sequence Data
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Peptide Fragments / metabolism*
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Permeability
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sequence Homology, Amino Acid
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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BCL2L1 protein, human
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BCL2L11 protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Bax protein (53-86)
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Bcl-2-Like Protein 11
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Carrier Proteins
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Membrane Proteins
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Mitochondrial Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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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-Associated X Protein
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bcl-X Protein
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Cytochromes c