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Cell Death Differ. 2013 Oct;20(10):1393-403. doi: 10.1038/cdd.2013.93. Epub 2013 Aug 2.

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1.

Author information

1
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.

Abstract

Bcl-2-interacting mediator of cell death (Bim) is a pro-apoptotic B-cell lymphoma 2 family member implicated in numerous apoptotic stimuli. In particular, Bim is required for cell death mediated by antimitotic agents, however, mitotic regulation of Bim remains poorly understood. Here, we show that the major splice variant of Bim, BimEL, is regulated during mitosis by the Aurora A kinase and protein phosphatase 2A (PP2A). We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. These findings describe a novel mechanism by which the oncogenic kinase Aurora A promotes cell survival during mitosis by downregulating proapoptotic signals. Notably, we observed that knockdown of Bim significantly increased resistance of cells to the Aurora A inhibitor MLN8054. Inhibitors of Aurora A are currently under investigation as cancer chemotherapeutics and our findings suggest that efficacy of this class of drugs may function in part by enhancing apoptotic activity of BimEL.

PMID:
23912711
PMCID:
PMC3770328
DOI:
10.1038/cdd.2013.93
[Indexed for MEDLINE]
Free PMC Article

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