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Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice

Ya-Hui Chi1, Jerrold M Ward, Lily I Cheng

  • 1Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

International Journal of Cancer
|December 10, 2008
PubMed

Insights

Loss of spindle assembly checkpoint (SAC) genes Mad1/Mad2 and p53 function cooperatively promotes tumor development and aneuploidy in mice. This highlights SAC

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • The spindle assembly checkpoint (SAC) is crucial for preventing chromosomal missegregation during cell division.
  • Tumorigenesis is often associated with genetic instability and aneuploidy.
  • The p53 tumor suppressor gene plays a vital role in maintaining genomic integrity.

Purpose of the Study:

  • To investigate the role of SAC genes (Mad1, Mad2) in tumor development in conjunction with p53.
  • To determine if loss of SAC function contributes to tumorigenesis in a p53-deficient context.

Main Methods:

  • Mice with heterozygous knockout of Mad1 and/or Mad2 genes were crossed with p53 heterozygous knockout mice.
  • Tumor frequencies and types were monitored in the resulting offspring.
  • Chromosome content analysis was performed on cells from these mice.

Main Results:

  • Mice lacking Mad2 and p53 function (Mad2(+/-)p53(+/-)) exhibited significantly increased tumor frequencies (88.2%) compared to p53(+/-) mice (66.7%).
  • Combined loss of Mad1, Mad2, and p53 function (Mad1(+/-)Mad2(+/-)p53(+/-)) led to even higher tumor incidence (95.0%).
  • A notable increase in lymphomas was observed in Mad2(+/-)p53(+/-) mice (53%) versus p53(+/-) mice (11%), with increased aneuploidy in Mad2(+/-)p53(+/-) cells.

Conclusions:

  • Loss of SAC function, specifically Mad1/Mad2, cooperates with p53 deficiency to drive tumorigenesis.
  • The combined genetic defects lead to increased aneuploidy and tumor development, underscoring the importance of SAC and p53 in preventing cancer.

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