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

Margaret E. Harley, Lindsey A. Allan, Helen S. Sanderson, Paul R. Clarke (Lead / Corresponding author)

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    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. The EMBO Journal (2010) 29, 2407-2420. doi:10.1038/emboj.2010.112; Published online 4 June 2010

    Original languageEnglish
    Pages (from-to)2407-2420
    Number of pages14
    JournalEMBO Journal
    Volume29
    Issue number14
    DOIs
    Publication statusPublished - 21 Jul 2010

    Keywords

    • apoptosis
    • Cdc20
    • cyclin-dependent kinase
    • Mcl-1
    • mitosis
    • SPINDLE-ASSEMBLY CHECKPOINT
    • ANAPHASE-PROMOTING COMPLEX/CYCLOSOME
    • CELL-CYCLE
    • CANCER-CELLS
    • ANTIMITOTIC DRUGS
    • UBIQUITIN LIGASE
    • PROTEIN-KINASE
    • CASPASE 9
    • APOPTOSIS
    • SURVIVAL

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