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Reduced ATM kinase activity and an attenuated p53 response to DNA damage in carcinogen-induced preneoplastic hepatic

I Silins1, N Finnberg, A Ståhl

  • 1Occupational Toxicology Group, Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.

Carcinogenesis
|December 26, 2001
PubMed

Insights

The p53 response to DNA damage is weakened in preneoplastic liver lesions (EAF). This attenuation, particularly of ATM-mediated phosphorylation, may promote EAF cell growth.

Area of Science:

  • Molecular Biology
  • Hepatocarcinogenesis
  • DNA Damage Response

Background:

  • Previous studies indicated an attenuated p53 response to DNA damage in enzyme-altered foci (EAF).
  • The p53 protein is a critical tumor suppressor involved in DNA damage response.
  • EAFs are preneoplastic lesions in the liver that can progress to cancer.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the attenuated p53 response in EAF.
  • To compare p53 mRNA levels and its activation pathways in EAF versus non-EAF liver tissue.
  • To determine if the DNA damage response pathway, specifically ATM kinase, is altered in EAF.

Main Methods:

  • Comparative quantitative RT-PCR to measure p53 mRNA levels.
  • Treatment with CoCl2 to induce hypoxia-inducible factor (HIF-1alpha).
  • Treatment with diethylnitrosamine (DEN) to induce DNA damage.
  • Treatment with leptomycin B (nuclear export inhibitor) and wortmannin (DNA-PK/ATM inhibitor).
  • Assay of kinase activity, immunohistological analysis, and Western blotting for ATM and p53 phosphorylation.

Main Results:

  • No significant difference in p53 mRNA levels between EAF and non-EAF tissue.
  • EAF hepatocytes failed to accumulate p53 upon DEN treatment, unlike non-EAF cells.
  • Attenuated ATM kinase activity and lack of Ser15 p53 phosphorylation were observed in EAF tissue after DEN challenge.
  • Wortmannin blocked DEN-induced p53 response in non-EAF cells, highlighting the role of ATM/DNA-PK.

Conclusions:

  • Selective attenuation of the DNA damage response pathway, particularly ATM-mediated p53 phosphorylation, occurs in EAF hepatocytes.
  • This down-regulation of DNA damage signaling may provide a growth advantage to EAF cells, contributing to hepatocarcinogenesis.
  • The findings elucidate a key mechanism in early liver lesion development and potential therapeutic targets.

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