Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2.
Journal Article (Journal Article)
The apoptotic initiator caspase-2 has been implicated in oocyte death, in DNA damage- and heat shock-induced death, and in mitotic catastrophe. We show here that the mitosis-promoting kinase, cdk1-cyclin B1, suppresses apoptosis upstream of mitochondrial cytochrome c release by phosphorylating caspase-2 within an evolutionarily conserved sequence at Ser 340. Phosphorylation of this residue, situated in the caspase-2 interdomain, prevents caspase-2 activation. S340 was susceptible to phosphatase 1 dephosphorylation, and an interaction between phosphatase 1 and caspase-2 detected during interphase was lost in mitosis. Expression of S340A non-phosphorylatable caspase-2 abrogated mitotic suppression of caspase-2 and apoptosis in various settings, including oocytes induced to undergo cdk1-dependent maturation. Moreover, U2OS cells treated with nocodazole were found to undergo mitotic catastrophe more readily when endogenous caspase-2 was replaced with the S340A mutant to lift mitotic inhibition. These data demonstrate that for apoptotic stimuli transduced by caspase-2, cell death is prevented during mitosis through the inhibitory phosphorylation of caspase-2 and suggest that under conditions of mitotic arrest, cdk1-cyclin B1 activity must be overcome for apoptosis to occur.
Full Text
Duke Authors
Cited Authors
- Andersen, JL; Johnson, CE; Freel, CD; Parrish, AB; Day, JL; Buchakjian, MR; Nutt, LK; Thompson, JW; Moseley, MA; Kornbluth, S
Published Date
- October 21, 2009
Published In
Volume / Issue
- 28 / 20
Start / End Page
- 3216 - 3227
PubMed ID
- 19730412
Pubmed Central ID
- PMC2771089
Electronic International Standard Serial Number (EISSN)
- 1460-2075
Digital Object Identifier (DOI)
- 10.1038/emboj.2009.253
Language
- eng
Conference Location
- England