Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2.
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.
Andersen
Joshua L
JL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Johnson
Carrie E
CE
Freel
Christopher D
CD
Parrish
Amanda B
AB
Day
Jennifer L
JL
Buchakjian
Marisa R
MR
Nutt
Leta K
LK
Thompson
J Will
JW
Moseley
M Arthur
MA
Kornbluth
Sally
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D004591:Electrophoresis, Polyacrylamide Gel; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D009865:Oocytes; D010766:Phosphorylation; D034741:RNA, Small Interfering; D012694:Serine / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014981:Xenopus
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D034741:RNA, Small Interfering; D012694:Serine; D016203:CDC2 Protein Kinase; D053143:Caspase 2; D015739:Nocodazole