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Phosphorylation of Mcl-1 by CDK1–cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest

Harley, Margaret E.; Allan, Lindsey A.; Sanderson, Helen S.; Clarke, Paul R.

Authors

Margaret E. Harley

Lindsey A. Allan

Paul R. Clarke



Abstract

The balance between cell cycle progression and apoptosis is important for both surveillance against genomic defects and responses to drugs that arrest the cell cycle. In this report, we show that the level of the human anti-apoptotic protein Mcl-1 is regulated during the cell cycle and peaks at mitosis. Mcl-1 is phosphorylated at two sites in mitosis, Ser64 and Thr92. Phosphorylation of Thr92 by cyclin-dependent kinase 1 (CDK1)-cyclin B1 initiates degradation of Mcl-1 in cells arrested in mitosis by microtubule poisons. Mcl-1 destruction during mitotic arrest requires proteasome activity and is dependent on Cdc20/Fizzy, which mediates recognition of mitotic substrates by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. Stabilisation of Mcl-1 during mitotic arrest by mutation of either Thr92 or a D-box destruction motif inhibits the induction of apoptosis by microtubule poisons. Thus, phosphorylation of Mcl-1 by CDK1-cyclin B1 and its APC/C Cdc20-mediated destruction initiates apoptosis if a cell fails to resolve mitosis. Regulation of apoptosis, therefore, is linked intrinsically to progression through mitosis and is governed by a temporal mechanism that distinguishes between normal mitosis and prolonged mitotic arrest. © 2010 European Molecular Biology Organization - All Rights Reserved.

Citation

Harley, M. E., Allan, L. A., Sanderson, H. S., & Clarke, P. R. (2010). Phosphorylation of Mcl-1 by CDK1–cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO Journal, 29(14), 2407-2420. https://doi.org/10.1038/emboj.2010.112

Journal Article Type Article
Online Publication Date Jun 4, 2010
Publication Date Jul 21, 2010
Deposit Date Jun 14, 2021
Journal The EMBO Journal
Print ISSN 0261-4189
Electronic ISSN 1460-2075
Publisher EMBO Press
Peer Reviewed Peer Reviewed
Volume 29
Issue 14
Pages 2407-2420
DOI https://doi.org/10.1038/emboj.2010.112
Public URL https://uwe-repository.worktribe.com/output/7470515