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MAD2DeltaC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells

K W To-Ho1, H W Cheung, M-T Ling

  • 1Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

Oncogene
|July 11, 2007
PubMed

Insights

A defective mitotic checkpoint, caused by a mutated MAD2 protein, leads to chromosomal instability and promotes cancer development in human cells. This highlights MAD2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The mitotic checkpoint ensures accurate chromosome segregation during cell division.
  • Mitotic arrest deficient 2 (MAD2) protein is crucial for mitotic checkpoint function by inhibiting the anaphase-promoting complex/cyclosome (APC/C).
  • The biological significance of MAD2 mutations in human cells remains largely unexplored.

Purpose of the Study:

  • To investigate the biological significance of a C-terminal-deleted MAD2 mutant (MAD2DeltaC) in human prostate epithelial cells.
  • To assess the effects of MAD2DeltaC on chromosomal instability, cell proliferation, mitotic checkpoint control, and anchorage-independent growth.
  • To explore the role of a defective mitotic checkpoint in carcinogen-induced malignant transformation.

Main Methods:

  • Stable transfection of MAD2DeltaC into human prostate epithelial Hpr-1 cells.
  • Analysis of chromosomal instability, cell proliferation, and mitotic checkpoint control.
  • Soft agar colony-forming assays with and without 7,12-dimethylbenz[A]anthracene (DMBA) challenge.
  • Assessment of p53 response and MAPK pathway activation.

Main Results:

  • MAD2DeltaC induced aneuploidy and chromosomal duplication due to impaired mitotic checkpoint and cytokinesis.
  • MAD2DeltaC-transfected cells exhibited anchorage-independent growth after DMBA treatment, indicating a cancer-promoting effect.
  • DMBA-induced transformation in MAD2DeltaC cells showed a complete loss of DNA damage-induced p53 response and MAPK pathway activation.

Conclusions:

  • A functional MAD2-mediated mitotic checkpoint is critical for maintaining chromosome stability in human cells.
  • A defective mitotic checkpoint predisposes cells to carcinogen-induced malignant transformation, but is not a direct cause of tumorigenesis.
  • Inactivation of MAD2 is linked to the malignant transformation of epithelial cells.

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