Abstract
Regulation of cell death is critical 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 Ser40. Mutation of Ser40 to a phospho-mimetic residue (S40D) inhibits binding to activated effector caspases and abolishes the anti-apoptotic function of XIAP, whereas a non-phosphorylated mutant (S40A) blocks apoptosis. By 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 B.
mitosis. This work illustrates that mitotic cell death is a form of apoptosis linked to the progression of mitosis through control by CDK1-cyclin B.
Original language | English |
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Pages (from-to) | 502-511 |
Number of pages | 38 |
Journal | Journal of Cell Science |
Volume | 130 |
Issue number | 2 |
Early online date | 7 Dec 2016 |
DOIs | |
Publication status | Published - 15 Jan 2017 |
Keywords
- Mitosis
- apoptosis
- cell death
- caspase