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Generating chromosome instability through the simultaneous deletion of Mad2 and p53

Aurora A Burds1, Annegret Schulze Lutum, Peter K Sorger

  • 1Department of Biology, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 2, 2005
PubMed

Insights

Inactivating the spindle checkpoint and p53 pathways in mice creates chromosome instability (CIN) without causing cell death. This suggests the mitotic checkpoint isn't essential for viability but can drive CIN when disrupted.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Chromosome instability (CIN) is a hallmark of cancer cells.
  • The spindle assembly checkpoint (SAC) is crucial for accurate chromosome segregation.
  • Previous studies indicated that disrupting SAC genes leads to cell death, not CIN.

Purpose of the Study:

  • To investigate the role of the spindle checkpoint in establishing chromosome instability.
  • To determine if SAC inactivation is compatible with cell viability.
  • To explore the combined effect of SAC and p53 pathway inactivation on CIN.

Main Methods:

  • Generated mouse blastocysts and embryonic fibroblast cell lines with deletions in Mad2 and p53.
  • Assessed spindle checkpoint function.
  • Analyzed chromosome instability levels in the generated cell lines.

Main Results:

  • Cells lacking functional Mad2 and p53 exhibited premature anaphase.
  • These cells displayed an exceptionally high level of chromosome instability (CIN).
  • The absence of a functional spindle checkpoint did not impede cell viability.

Conclusions:

  • The mitotic spindle checkpoint is not essential for cell viability.
  • Inactivation of both Mad2- and p53-dependent pathways can establish a CIN phenotype.
  • This provides a model for studying CIN in the absence of cell death.

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