Phosphorylation of XIAP by CDK1-cyclin B controls mitotic cell death

Yingping Hou; Lindsey A. Allan; Paul R. Clarke

doi:10.1242/jcs.192310

Phosphorylation of XIAP by CDK1-cyclin B controls mitotic cell death

Yingping Hou
, Lindsey A. Allan
, Paul R. Clarke (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

247 Downloads (Pure)

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.

Original language	English
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	https://doi.org/10.1242/jcs.192310
Publication status	Published - 15 Jan 2017

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SDG 3 Good Health and Well-being

Keywords

Mitosis
apoptosis
cell death
caspase

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10.1242/jcs.192310Licence: CC BY

Final Published Version
© 2016. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Final published version, 2.86 MBLicence: CC BY

Cite this

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title = "Phosphorylation of XIAP by CDK1-cyclin B controls mitotic cell death",

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. ",

keywords = "Mitosis, apoptosis, cell death, caspase",

author = "Yingping Hou and Allan, \{Lindsey A.\} and Clarke, \{Paul R.\}",

note = "The work was supported by a Cancer Research UK grant (C275/A13424).",

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AU - Hou, Yingping

AU - Allan, Lindsey A.

AU - Clarke, Paul R.

N1 - The work was supported by a Cancer Research UK grant (C275/A13424).

PY - 2017/1/15

Y1 - 2017/1/15

N2 - 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.

AB - 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.

KW - Mitosis

KW - apoptosis

KW - cell death

KW - caspase

UR - http://jcs.biologists.org/content/early/2016/12/07/jcs.192310

U2 - 10.1242/jcs.192310

DO - 10.1242/jcs.192310

M3 - Article

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SN - 0021-9533

VL - 130

SP - 502

EP - 511

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 2

ER -

Phosphorylation of XIAP by CDK1-cyclin B controls mitotic cell death

Abstract

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