View the Current Issue

Article

  • The EMBO Journal (2009) 28, 3216 - 3227
  • doi:10.1038/emboj.2009.253

Published online: 3 September 2009

Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2

Joshua L Andersen1, Carrie E Johnson1, Christopher D Freel1, Amanda B Parrish1, Jennifer L Day1, Marisa R Buchakjian1, Leta K Nutt2, J Will Thompson3, M Arthur Moseley3 and Sally Kornbluth1

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
  2. Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN, USA
  3. Proteomics Core Facility, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC, USA

Correspondence to:

Sally Kornbluth, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Research Dr, LSRC C370A, Box 3813, Durham, NC 27710, USA. Tel.: +1 919 613 8624; Fax: +1 919 681 1005; E-mail: kornb001@mc.duke.edu

Received 16 April 2009; Accepted 29 July 2009

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.

  • Keywords:

    • apoptosis,
    • caspase-2,
    • cdk1,
    • mitosis