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Induction of p53 renders ATM-deficient mice refractory to hepatocarcinogenesis

Narci Teoh1, Pawan Pyakurel, Yock Young Dan

  • 1Australian National University Medical School at The Canberra Hospital, Canberra, Australia.

Gastroenterology
|November 19, 2009
PubMed
Abstract

Insights

Mice lacking ATM kinase are protected from liver cancer induced by diethylnitrosamine (DEN). This refractoriness is linked to increased p53 and apoptosis, preventing malignant transformation in hepatocytes.

Area of Science:

  • Hepatology
  • Cancer Biology
  • DNA Damage Response

Background:

  • p53 mutations are frequent in human hepatocellular carcinoma (HCC).
  • Ataxia Telangiectasia Mutated (ATM) kinase detects DNA breaks and activates p53.
  • The role of ATM in DEN-induced hepatocarcinogenesis is unknown.

Purpose of the Study:

  • To investigate if ATM deficiency impacts DEN-induced liver cancer.
  • To assess the effect of ATM deficiency on p53 activation and hepatocyte response to DEN.

Main Methods:

  • Mice with varying ATM gene status (ATM(-/-), ATM(+/-), WT) were injected with DEN.
  • Liver tissues were analyzed for p53, cell cycle markers, apoptosis, and tumor development up to 12 months.

Main Results:

  • ATM-deficient mice showed no HCC development after DEN exposure, unlike WT and heterozygote mice.
  • ATM(-/-) livers exhibited elevated p53, p19ARF, ATR, Chk1, and apoptosis markers.
  • Senescence markers were present, alongside telomerase upregulation, suggesting potential immortalization of DEN-treated ATM(-/-) hepatocytes.

Conclusions:

  • ATM deficiency abrogates DEN-induced hepatocarcinogenesis.
  • ATR/Chk1/p53 pathway activation and subsequent apoptosis/cell cycle arrest protect ATM(-/-) hepatocytes from malignant transformation.
  • Sustained p53 induction with senescence features does not necessarily lead to organ failure.

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