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Caspase-independent mitotic death (CIMD)

Katsumi Kitagawa1, Yohei Niikura

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. katsumi.kitagawa@stjude.org

Cell Cycle (Georgetown, Tex.)
|April 17, 2008
PubMed

Insights

A novel cell death pathway, caspase-independent mitotic death (CIMD), prevents aneuploidy by eliminating cells with faulty spindle checkpoints. This discovery impacts cancer research and understanding of chromosome instability.

Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • The spindle checkpoint ensures accurate chromosome transmission, preventing aneuploidy which can lead to cancer.
  • The mechanism preventing aneuploidy due to spindle checkpoint failure remains largely unknown.

Purpose of the Study:

  • To identify the cell death mechanism that prevents aneuploidy caused by spindle checkpoint failure.
  • To characterize a novel form of cell death termed caspase-independent mitotic death (CIMD).

Main Methods:

  • Investigated BUB1-deficient and MAD2-deficient cells under spindle checkpoint-activating conditions (cold shock, nocodazole, paclitaxel, 17-AAG).
  • Assessed the roles of p73, p53, apoptosis-inducing factor (AIF), and endonuclease G (Endo G) in CIMD.
  • Examined the consequences of complete BUB1 depletion on chromosome segregation and cell death.

Main Results:

  • Identified CIMD, a novel caspase-independent cell death, induced in BUB1-deficient cells under spindle checkpoint activation.
  • CIMD requires p73, AIF, and Endo G, but not p53.
  • Complete BUB1 depletion leads to aneuploidy instead of CIMD, suggesting CIMD prevents chromosome missegregation.
  • Mitotic index monitoring may be misleading for evaluating spindle checkpoint activity in mutant or cancer cells.

Conclusions:

  • CIMD acts as a protective mechanism against aneuploidy by eliminating cells with defective spindle checkpoints and high risk of chromosome missegregation.
  • Findings challenge previous methods of assessing spindle checkpoint function and have implications for cancer biology.

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