title: Phosphorylation of XIAP by CDK1-cyclin-B1 controls mitotic cell death.
abstract: Regulation of cell death is crucial for the response of cancer cells to drug treatments that cause arrest in mitosis, and is likely to be important for protection against chromosome instability in normal cells. Prolonged mitotic arrest can result in cell death by activation of caspases and the induction of apoptosis. Here, we show that X-linked inhibitor of apoptosis (XIAP) plays a key role in the control of mitotic cell death. Ablation of XIAP expression sensitises cells to prolonged mitotic arrest caused by a microtubule poison. XIAP is stable during mitotic arrest, but its function is controlled through phosphorylation by the mitotic kinase CDK1-cyclin-B1 at S40. Mutation of S40 to a phosphomimetic residue (S40D) inhibits binding to activated effector caspases and abolishes the anti-apoptotic function of XIAP, whereas a non-phosphorylatable mutant (S40A) blocks apoptosis. By performing live-cell imaging, we show that phosphorylation of XIAP reduces the threshold for the onset of cell death in mitosis. This work illustrates that mitotic cell death is a form of apoptosis linked to the progression of mitosis through control by CDK1-cyclin-B1.
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, UK.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Allan
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, UK p.r.clarke@dundee.ac.uk.
authors.forename: Paul R
authors.identifier: 0000-0003-3525-2622
authors.initials: PR
authors.lastname: Clarke
mesh_terms: D017209:Apoptosis; D001224:Aspartic Acid / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D056744:Cyclin B1 / Q000378:metabolism*; D019610:Cytoprotection; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D056744:Cyclin B1; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D010768:Phosphoserine; D001224:Aspartic Acid; D016203:CDC2 Protein Kinase; D020169:Caspases
keywords: Apoptosis; Caspase; Cell death; Mitosis