Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis.
Published
Journal Article
Many pro-apoptotic signals trigger mitochondrial cytochrome c release, leading to caspase activation and ultimate cellular breakdown. Cell survival pathways, including the mitogen-activated protein kinase (MAPK) cascade, promote cell viability by impeding mitochondrial cytochrome c release and by inhibiting subsequent caspase activation. Here, we describe a mechanism for the inhibition of cytochrome c-induced caspase activation by MAPK signalling, identifying a novel mode of apoptotic regulation exerted through Apaf-1 phosphorylation by the 90-kDa ribosomal S6 kinase (Rsk). Recruitment of 14-3-3ɛ to phosphorylated Ser268 impedes the ability of cytochrome c to nucleate apoptosome formation and activate downstream caspases. High endogenous levels of Rsk in PC3 prostate cancer cells or Rsk activation in other cell types promoted 14-3-3ɛ binding to Apaf-1 and rendered the cells insensitive to cytochrome c, suggesting a potential role for Rsk signalling in apoptotic resistance of prostate cancers and other cancers with elevated Rsk activity. Collectively, these results identify a novel locus of apoptosomal regulation wherein MAPK signalling promotes Rsk-catalysed Apaf-1 phosphorylation and consequent binding of 14-3-3ɛ, resulting in decreased cellular responsiveness to cytochrome c.
Full Text
Duke Authors
Cited Authors
- Kim, J; Parrish, AB; Kurokawa, M; Matsuura, K; Freel, CD; Andersen, JL; Johnson, CE; Kornbluth, S
Published Date
- March 2012
Published In
Volume / Issue
- 31 / 5
Start / End Page
- 1279 - 1292
PubMed ID
- 22246185
Pubmed Central ID
- 22246185
Electronic International Standard Serial Number (EISSN)
- 1460-2075
International Standard Serial Number (ISSN)
- 0261-4189
Digital Object Identifier (DOI)
- 10.1038/emboj.2011.491
Language
- eng