Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest.
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.
Biomedical Research Institute, School of Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Margaret E
ME
Harley
Lindsey A
LA
Allan
Helen S
HS
Sanderson
Paul R
PR
Clarke
D000595:Amino Acid Sequence; D000818:Animals; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D017209:Apoptosis / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010748:Phosphopeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; C577366:CDC27 protein, human; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010748:Phosphopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C577488:CDC20 protein, human; D013912:Threonine; D012694:Serine; D016203:CDC2 Protein Kinase; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex