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PMID:14623868

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Citation

Potts, PR, Singh, S, Knezek, M, Thompson, CB and Deshmukh, M (2003) Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. J. Cell Biol. 163:789-99

Abstract

In sympathetic neurons, unlike most nonneuronal cells, growth factor withdrawal-induced apoptosis requires the development of competence in addition to cytochrome c release to activate caspases. Thus, although most nonneuronal cells die rapidly with cytosolic cytochrome c alone, sympathetic neurons are remarkably resistant unless they develop competence. We have identified endogenous X-linked inhibitor of apoptosis protein (XIAP) as the essential postcytochrome c regulator of caspase activation in these neurons. In contrast to wild-type neurons that are resistant to injection of cytochrome c, XIAP-deficient neurons died rapidly with cytosolic cytochrome c alone. Surprisingly, the release of endogenous Smac was not sufficient to overcome the XIAP resistance in sympathetic neurons. In contrast, the neuronal competence pathway permitted cytochrome c to activate caspases by inducing a marked reduction in XIAP levels in these neurons. Thus, the removal of XIAP inhibition appears both necessary and sufficient for cytochrome c to activate caspases in sympathetic neurons. These data identify a critical function of endogenous XIAP in regulating apoptosis in mammalian cells.

Links

PubMed PMC2173693 Online version:10.1083/jcb.200307130

Keywords

Animals; Animals, Newborn; Apoptosis/drug effects; Apoptosis/physiology; Caspases/drug effects; Caspases/metabolism; Cells, Cultured; Cytochromes c/metabolism; Cytochromes c/pharmacology; Drug Resistance/genetics; Enzyme Activation/physiology; Ganglia, Sympathetic/metabolism; Hydrogen Peroxide/pharmacology; Mice; Neurons/drug effects; Neurons/metabolism; Proteins/genetics; Proteins/metabolism; RNA, Messenger/drug effects; RNA, Messenger/metabolism; Recombinant Fusion Proteins/pharmacology; X-Linked Inhibitor of Apoptosis Protein

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