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Gain of function properties of mutant p53 proteins at the mitotic spindle cell cycle checkpoint

M L Hixon1, A Flores, M Wagner

  • 1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.

Histology and Histopathology
|May 16, 2000
PubMed

Insights

Mutant p53 proteins disrupt cell division by interfering with cell cycle checkpoints, leading to chromosomal instability. This gain-of-function at mitosis causes cells to lose control over cell division progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Mutations in the p53 tumor suppressor gene are linked to chromosomal instability.
  • p53 mutations can affect mitotic spindle and postmitotic cell cycle checkpoints.

Purpose of the Study:

  • To investigate the role of mutant p53 in chromosomal instability.
  • To elucidate the mechanisms by which mutant p53 interferes with cell cycle control.

Main Methods:

  • Analysis of p53 mutant protein function in cell cycle checkpoints.
  • Investigation of p53's effect on mitotic spindle and postmitotic checkpoints.
  • Examination of p53's role in regulating the anaphase promoting complex (APC).

Main Results:

  • Wild type p53 is essential for postmitotic checkpoint activity but not mitotic spindle checkpoint.
  • Dominant p53 mutants exhibit gain-of-function at the mitotic spindle checkpoint and dominant-negative effects at the postmitotic checkpoint.
  • Mutant p53 up-regulates CKs1 expression, interfering with APC inactivation and mitotic arrest.

Conclusions:

  • Mutant p53 gain-of-function at mitosis contributes significantly to chromosomal instability.
  • Interference with cell cycle checkpoints by mutant p53 promotes uncontrolled cell division.

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