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PMID: 14623868 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis.

The Journal of cell biology ·Vol. 163 ·No. 4 ·2003-11-24 ·Pages 789-99

Potts PR, Singh S, Knezek M, Thompson CB, Deshmukh M

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.

MeSH Terms
Animals Animals, Newborn Apoptosis/drug effects,physiology Caspases/drug effects,metabolism Cells, Cultured Cytochromes c/metabolism,pharmacology Drug Resistance/genetics Enzyme Activation/physiology Ganglia, Sympathetic/metabolism Hydrogen Peroxide/pharmacology Mice Neurons/drug effects,metabolism Proteins/genetics,metabolism RNA, Messenger/drug effects,metabolism Recombinant Fusion Proteins/pharmacology X-Linked Inhibitor of Apoptosis Protein
Chemicals
Proteins RNA, Messenger Recombinant Fusion Proteins X-Linked Inhibitor of Apoptosis Protein Cytochromes c Hydrogen Peroxide Caspases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Potts Patrick Ryan
Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Singh Shweta
Knezek Malia
Thompson Craig B
Deshmukh Mohanish
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200307130
Published
2003-11-24
Epub
2003-00-17
Pages
789-99
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2173693
Subset
IM
Grants
NINDS NIH HHS · R01 NS042197 · United States
NINDS NIH HHS · NS42197 · United States
External Links
PubMed source DOI: 10.1083/jcb.200307130 PMC Full Text View journal details
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