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p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human

M L Agarwal1, A Agarwal, W R Taylor

  • 1Department of Molecular Biology, Cleveland Clinic Foundation, OH 44195, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 29, 1995
PubMed

Insights

Wild-type p53 (protein) induces cell cycle arrest in G1 and G2/M phases. Unlike DNA damage-induced arrest, p53-mediated arrest is reversible, suggesting alternative pathways for permanent cell cycle arrest.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Wild-type p53 protein is a tumor suppressor that regulates cell cycle arrest.
  • DNA damage typically induces p53 expression, leading to G1 cell cycle arrest via p21/WAF1.
  • The precise mechanisms and reversibility of p53-mediated cell cycle arrest require further investigation.

Purpose of the Study:

  • To investigate the effects of wild-type p53 on cell cycle progression independent of DNA damage.
  • To determine if p53 can induce cell cycle arrest at multiple stages, including G1 and G2/M.
  • To compare the reversibility of p53-induced cell cycle arrest with that induced by DNA damage.

Main Methods:

  • Utilized MDAH041 human fibroblasts lacking endogenous p53.
  • Employed tetracycline-inducible system to regulate wild-type p53 expression.
  • Assessed cell cycle distribution and arrest points using mimosine block and p53 level modulation.

Main Results:

  • Exogenous p53 expression induced cell cycle arrest in both G1 and G2/M phases.
  • p53-mediated arrest was confirmed at G2/M for cells released from an early S phase block.
  • p21/WAF1 was notably induced in p53-arrested cells.
  • Cells arrested by regulated p53 expression resumed growth upon p53 level reduction, contrasting with irreversible DNA damage-induced arrest.

Conclusions:

  • Wild-type p53 can independently mediate cell cycle arrest at both G1 and G2/M phases.
  • p53-induced cell cycle arrest, involving p21/WAF1, is reversible.
  • Irreversible cell cycle arrest likely involves additional pathways beyond p53-p21/WAF1 interactions with cyclin-dependent kinases.

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