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


  • eng

Conference Location

  • England