Induction of p53 renders ATM-deficient mice refractory to hepatocarcinogenesis

Gastroenterology
Narci C TeohGeoffrey Farrell

Abstract

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). 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. 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 ...Continue Reading

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Citations

Jun 19, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jae Uk ShinJong Chul Rhee
Sep 27, 2015·Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract·Dimitrios KaraviasVasiliki Bravou
Sep 21, 2010·Seminars in Cancer Biology·Polina IakovaNikolai A Timchenko
Jan 26, 2011·Journal of Gastroenterology and Hepatology·Narci C Teoh
Apr 12, 2013·Journal of Gastroenterology and Hepatology·Sharon PokNarci C Teoh
Feb 24, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Lingling ZhangZhenyu Ju
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Mar 30, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Nuno Paula SantosPaula Alexandra Oliveira
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Dec 6, 2018·International Journal of Molecular Sciences·Tetsuo NakajimaMitsuru Nenoi
Nov 18, 2015·Journal of Gastroenterology and Hepatology·Sharon PokNarci C Teoh
Sep 29, 2019·World Journal of Gastroenterology : WJG·Nazmul HudaXiao-Ming Yin
Sep 6, 2018·Cancer Research·Chadia L RobertsonDevanand Sarkar
Jan 24, 2021·Cellular and Molecular Gastroenterology and Hepatology·Laura Elisa Buitrago-MolinaArndt Vogel
Jul 6, 2020·Mechanisms of Ageing and Development·Avadh KumarDan Ehninger
Feb 18, 2014·Genes & Development·Ramon RosetJohn H J Petrini

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