Abstract
MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by direct interaction with caspases, the effector proteases of apoptosis. DIABLO is a mammalian protein that can bind to IAPs and antagonize their antiapoptotic effect, a function analogous to that of the proapoptotic Drosophila molecules, Grim, Reaper, and HID. Here, we show that after UV radiation, MIHA prevented apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA functioned after release of cytochrome c and DIABLO from the mitochondria and was able to bind to both processed caspase 9 and processed caspase 3 to prevent feedback activation of their zymogen forms. Once released into the cytosol, DIABLO bound to MIHA and disrupted its association with processed caspase 9, thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins
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Apoptosis* / drug effects
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Apoptosis* / radiation effects
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Apoptotic Protease-Activating Factor 1
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Blotting, Western
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Carrier Proteins / metabolism*
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Caspase 3
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Caspase 9
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Caspases / metabolism*
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Cell Line
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Culture Media, Serum-Free
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Enzyme Activation
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Enzyme Inhibitors / pharmacology*
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Flow Cytometry
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Humans
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins*
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Precipitin Tests
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Protein Precursors / metabolism
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Proteins / metabolism
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Proteins / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Transfection
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Ultraviolet Rays
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X-Linked Inhibitor of Apoptosis 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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Carrier Proteins
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Culture Media, Serum-Free
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DIABLO protein, human
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Protein Precursors
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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CASP3 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 9
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Caspases