Abstract
Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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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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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 9
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Caspases / metabolism*
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Cell Line
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Dimerization
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Enzyme Activation
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Humans
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Membrane Proteins*
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Mice
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Molecular Sequence Data
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Mutation
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Protein Binding
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Protein Structure, Quaternary
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Proteins / chemistry
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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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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Tissue Distribution
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Transfection
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bcl-X Protein
Substances
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APAF1 protein, human
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AVEN protein, human
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Adaptor Proteins, Signal Transducing
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Apaf1 protein, mouse
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Apoptosis Regulatory Proteins
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Apoptotic Protease-Activating Factor 1
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Carrier Proteins
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Membrane Proteins
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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bcl-X Protein
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CASP9 protein, human
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Casp9 protein, mouse
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Caspase 9
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Caspases