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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Phosphorylation of XIAP by CDK1-cyclin-B1 controls mitotic cell death

Ying Hou1, Lindsey A Allan1, Paul R Clarke2

  • 1Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, UK.

Journal of Cell Science
|December 9, 2016
PubMed

Insights

X-linked inhibitor of apoptosis (XIAP) controls mitotic cell death. Its phosphorylation by CDK1-cyclin-B1 regulates apoptosis onset, impacting cancer cell drug response and genomic stability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Regulation of cell death is critical for cancer treatment efficacy and preventing genomic instability.
  • Prolonged mitotic arrest can trigger apoptosis via caspase activation.

Purpose of the Study:

  • To investigate the role of X-linked inhibitor of apoptosis (XIAP) in regulating mitotic cell death.
  • To elucidate the mechanism by which XIAP controls apoptosis during mitotic arrest.

Main Methods:

  • Ablation of XIAP expression in cells.
  • Utilizing microtubule poisons to induce mitotic arrest.
  • Site-directed mutagenesis of XIAP phosphorylation site (S40).
  • Live-cell imaging to observe cell death dynamics.

Main Results:

  • XIAP deficiency sensitizes cells to mitotic arrest-induced death.
  • XIAP phosphorylation by CDK1-cyclin-B1 at S40 is crucial for its anti-apoptotic function.
  • Phosphomimetic mutation (S40D) impairs XIAP's ability to bind caspases.
  • Non-phosphorylatable mutation (S40A) blocks apoptosis, indicating XIAP's role in promoting cell death.
  • XIAP phosphorylation lowers the threshold for initiating cell death during mitosis.

Conclusions:

  • XIAP is a key regulator of apoptosis during mitotic arrest.
  • CDK1-cyclin-B1-mediated phosphorylation of XIAP at S40 is a critical control point for mitotic cell death.
  • Mitotic cell death is a form of apoptosis controlled by cell cycle progression.
Keywords:
ApoptosisCaspaseCell deathMitosis

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