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Mechanisms of G2 arrest in response to overexpression of p53

W R Taylor1, S E DePrimo, A Agarwal

  • 1Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

Molecular Biology of the Cell
|November 17, 1999
PubMed

Insights

Overexpression of the p53 tumor suppressor induces G2 cell cycle arrest by suppressing cdc2 and cyclin B1 transcription. This arrest is likely due to multiple distinct pathways, including nuclear accumulation interference.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Biology

Background:

  • The p53 protein is a critical tumor suppressor involved in cell cycle control.
  • G2 arrest is a key checkpoint preventing entry into mitosis with damaged DNA.
  • CDC2 (also known as CDK1) and cyclin B1 are essential regulators of the G2/M transition.

Purpose of the Study:

  • To investigate the molecular mechanisms by which p53 overexpression induces G2 arrest.
  • To identify the specific promoter regions of cdc2 and cyclin B1 involved in p53-mediated suppression.
  • To determine the role of CDC2 activity and nuclear accumulation in p53-induced G2 arrest.

Main Methods:

  • Utilized reporter constructs to analyze the transcriptional activity of the cdc2 and cyclin B1 promoters.
  • Induced p53 expression to study its effects on cell cycle progression.
  • Employed constitutively active CDC2 and cyclin B1 variants to assess their impact on p53-dependent G2 arrest.

Main Results:

  • p53 overexpression suppressed the transcription of both cdc2 and cyclin B1.
  • Specific promoter regions (-287 to -123 for cyclin B1 and -104 to -74 for cdc2) were identified as critical for p53-mediated suppression.
  • p53-dependent G2 arrest was not reversed by constitutive cyclin B1 expression or active CDC2 alone, but was overcome by nuclear targeting of cyclin B1 with active CDC2.

Conclusions:

  • p53 induces G2 arrest primarily through transcriptional suppression of cdc2 and cyclin B1.
  • Interference with the nuclear accumulation of CDC2/cyclin B1 complexes is a significant contributor to p53-mediated G2 arrest.
  • Multiple distinct pathways likely converge to mediate the p53-dependent G2 arrest.

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