Abstract
Caspase-8 is the initiator caspase of the extrinsic apoptosis pathway and also has a role in non-apoptotic physiologies. Identifying endogenous substrates for caspase-8 by using integrated bioinformatics and biological approaches is required to delineate the diverse roles of this caspase. We describe a number of novel putative caspase-8 substrates using the Prediction of Protease Specificity (PoPS) program, one of which is histone deacetylase 7 (HDAC7). HDAC7 is cleaved faster than any other caspase-8 substrate described to date. It is also cleaved in primary CD4+CD8+ thymocytes undergoing extrinsic apoptosis. By using naturally occurring caspase inhibitors that have evolved exquisite specificity at concentrations found within the cell, we could unequivocally assign the cleavage activity to caspase-8. Importantly, cleavage of HDAC7 alters its subcellular localization and abrogates its Nur77 repressor function. Thus we demonstrate a direct role for initiator caspase-mediated proteolysis in promoting gene transcription.
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 / physiology
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COS Cells
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Caspase 8 / chemistry
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Caspase 8 / genetics
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Caspase 8 / metabolism*
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Caspase Inhibitors
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Chlorocebus aethiops
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Histone Deacetylases / chemistry
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Mice
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Protease Inhibitors / chemistry
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Protease Inhibitors / metabolism
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Software*
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Substrate Specificity / physiology
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Transcription, Genetic / physiology*
Substances
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Caspase Inhibitors
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DNA-Binding Proteins
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NR4A1 protein, human
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Protease Inhibitors
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Receptors, Steroid
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Repressor Proteins
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Caspase 8
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HDAC7 protein, human
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Hdac7 protein, mouse
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Histone Deacetylases