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The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate

M V Chernov1, G R Stark

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

Oncogene
|May 29, 1997
PubMed

Insights

Adriamycin or U.V.C. treatment triggers p53-dependent gene transcription in mouse cells, leading to transient cell cycle arrest and eventual apoptosis. Salicylate inhibits this p53 response by blocking DNA binding, revealing long-lived p53-activating signals.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • DNA damage response pathways are crucial for maintaining genomic stability.
  • The p53 tumor suppressor protein plays a central role in orchestrating cellular responses to stress.
  • p53-dependent transcription regulates genes involved in cell cycle arrest, DNA repair, and apoptosis.

Purpose of the Study:

  • To investigate the role of p53-dependent transcription in cellular responses to DNA damage.
  • To elucidate the mechanisms underlying p53 activation and its downstream effects.
  • To examine the impact of salicylate on p53-mediated gene expression and apoptosis.

Main Methods:

  • Treatment of mouse 121/CA cells with adriamycin or U.V.C. irradiation.
  • Measurement of beta-galactosidase reporter gene and endogenous p21/Waf1/Cip1 gene expression.
  • In situ analysis of beta-galactosidase activity.
  • Inhibition studies using salicylate to block protein kinase and transcription factor activation.

Main Results:

  • Adriamycin or U.V.C. induced p53-dependent transcription of reporter and p21/Waf1/Cip1 genes.
  • Cells exhibited transient G1/G2 arrest, followed by growth resumption and apoptosis.
  • Higher p53-dependent transcription levels were observed in apoptotic cells compared to arrested cells.
  • Salicylate inhibited p53-dependent transcription and apoptosis by impairing p53 DNA binding.
  • p53-activating signals persisted for at least 60 hours post-damage.
  • Resumption of transcription occurred upon salicylate removal without further p53 protein accumulation.

Conclusions:

  • p53-dependent transcription is a key component of the cellular response to DNA damage.
  • The p53 activation pathway initiated by DNA damage is long-lived and regulated independently of p53 protein levels.
  • Salicylate effectively inhibits p53-mediated transcription and apoptosis by targeting p53 DNA binding.

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