Abstract:
:Proliferating metazoan cells respond to damage that has the potential to cause genomic instability by restricting the cell division cycle or by initiating apoptosis. The molecular mechanisms determining the balance between these responses are not well understood. Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, Thr125. This site is phosphorylated by CDK1/cyclin B1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. Using an RNA interference strategy, we show that induction of apoptosis from mitosis in response to these drugs is caspase-9 dependent and is greatly increased when endogenous caspase-9 is replaced by a nonphosphorylatable mutant. Thus, phosphorylation of caspase-9 at Thr125 sets the threshold for activation of the intrinsic apoptotic pathway during the cell cycle, restrains apoptosis during mitosis, and determines sensitivity to antimitotic drugs.
journal_name
Mol Celljournal_title
Molecular cellauthors
Allan LA,Clarke PRdoi
10.1016/j.molcel.2007.03.019subject
Has Abstractpub_date
2007-04-27 00:00:00pages
301-10issue
2eissn
1097-2765issn
1097-4164pii
S1097-2765(07)00189-Xjournal_volume
26pub_type
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