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A model for p53-induced apoptosis

K Polyak1, Y Xia, J L Zweier

  • 1The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Nature
|September 26, 1997
PubMed

Insights

The p53 tumor suppressor protein triggers apoptosis through a novel three-step process involving oxidative stress. This discovery sheds light on p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Mechanisms

Background:

  • The p53 tumor suppressor gene is frequently inactivated in human cancers, prompting research into its functions.
  • p53 expression can induce cell cycle arrest or apoptosis, but the mechanisms of p53-dependent apoptosis are not fully understood.
  • While p53-induced growth arrest in colorectal cancer involves p21WAF1/CIP1, the apoptotic pathway remains largely uncharacterized.

Purpose of the Study:

  • To investigate the transcriptional targets of p53 that precede apoptosis.
  • To elucidate the molecular mechanisms underlying p53-mediated programmed cell death.

Main Methods:

  • Gene expression profiling was used to identify transcripts upregulated by p53 expression.
  • Analysis of 7,202 transcripts in p53-expressing versus control cells.
  • Biochemical and pharmacological experiments were conducted to validate findings.

Main Results:

  • Only 14 (0.19%) of 7,202 transcripts were significantly increased upon p53 expression.
  • Many upregulated genes were predicted to be involved in oxidative stress responses.
  • A novel three-step apoptotic pathway induced by p53 was proposed: redox gene induction, reactive oxygen species generation, and mitochondrial damage.

Conclusions:

  • p53-induced apoptosis is mediated by the transcriptional upregulation of redox-related genes.
  • Reactive oxygen species formation and subsequent oxidative degradation of mitochondria are key events in p53-dependent cell death.
  • This study reveals a novel mechanism for p53-driven apoptosis involving oxidative stress.

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