Induction of p53 renders ATM-deficient mice refractory to hepatocarcinogenesis

Gastroenterology. 2010 Mar;138(3):1155-65.e1-2. doi: 10.1053/j.gastro.2009.11.008. Epub 2009 Nov 14.

Abstract

Background & aims: p53 Mutations are very common in human hepatocellular carcinoma, and induction of hepatic p53 expression causes lysis of implanted hepatoblastoma cells in a chimeric mouse. Ataxia Telangiectasia Mutated (ATM) kinase senses DNA strand breaks and induces p53. Our aims were to establish whether ATM deficiency alters the carcinogenic response of hepatocytes to diethylnitrosamine (DEN).

Methods: Male ATM-deficient (ATM(-/-)), heterozygote (ATM(+/-)), and wild-type (WT) mice were injected with DEN at age 15 days, and animals were killed up to 12 months to assess p53, cell cycle, apoptosis, and liver tumor development.

Results: Whereas >80% of WT and ATM(+/-) mice developed hepatocellular carcinoma (HCC), at 9-12 months, ATM(-/-) mice remained refractory to DEN-induced HCC up to 15 months. At 6 and 9 months, and compared with WT mice, p53 and p19(ARF) expression were greatly enhanced in ATM(-/-) liver associated with up-regulation of ATR and Chk1; cleaved caspase-3 immunohistochemistry and caspase-3 activity were also significantly increased. Whereas livers of DEN-treated ATM(-/-) mice showed markers of senescence (beta-galactosidase, Cxcl-1), up-regulation of telomerase occurred concurrently. The possibility that such balanced senescence could result in immortalization was demonstrated in hepatocytes prepared at 9 months from DEN-treated ATM(-/-) liver.

Conclusions: Hepatocarcinogenesis is abrogated in ATM-deficient mice in association with induction of ATR, Chk1, p53, and p19(ARF). Resultant cell cycle arrest and apoptosis of DNA-damaged cells are possible mechanisms that underlie this unique "refractoriness" to malignant transformation in DEN-initiated ATM(-/-) hepatocytes. The findings also show that prolonged up-regulation of p53 associated with some features of senescence does not inevitably cause organ failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control*
  • Caspase 3 / metabolism
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence
  • Checkpoint Kinase 1
  • Chromosome Aberrations
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Diethylnitrosamine
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Heterozygote
  • Karyotyping
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control*
  • Male
  • Mice
  • Mice, Knockout
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Telomerase / metabolism
  • Time Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics
  • Up-Regulation

Substances

  • Cdkn2a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Diethylnitrosamine
  • Protein Kinases
  • Atr protein, mouse
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Telomerase
  • Casp3 protein, mouse
  • Caspase 3