Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis.
Despite the potential of the inhibitor of apoptosis proteins (IAPs) to block cytochrome c-dependent caspase activation, the critical function of IAPs in regulating mammalian apoptosis remains unclear. We report that the ability of endogenous IAPs to effectively regulate caspase activation depends on the differentiation state of the cell. Despite being expressed at equivalent levels, endogenous IAPs afforded no protection against cytochrome c-induced apoptosis in naive pheochromocytoma (PC12) cells, but were remarkably effective in doing so in neuronally differentiated cells. Neuronal differentiation was also accompanied with a marked reduction in Apaf-1, resulting in a significant decrease in apoptosome activity. Importantly, this decrease in Apaf-1 protein was directly linked to the increased ability of IAPs to stringently regulate apoptosis in neuronally differentiated PC12 and primary cells. These data illustrate specifically how the apoptotic pathway acquires increased regulation with cellular differentiation, and are the first to show that IAP function and apoptosome activity are coupled in cells.
Wright
Kevin M
KM
Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599, USA.
Linhoff
Michael W
MW
Potts
Patrick Ryan
PR
Deshmukh
Mohanish
M
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013997:Time Factors
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D045304:Cytochromes c; D020169:Caspases