Journal Article

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

Ilona Silins, Niklas Finnberg, Annika Ståhl, Johan Högberg and Ulla Stenius

in Carcinogenesis

Volume 22, issue 12, pages 2023-2031
Published in print December 2001 | ISSN: 0143-3334
Published online December 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.12.2023
Reduced ATM kinase activity and an attenuated p53 response to DNA damage in carcinogen-induced preneoplastic hepatic lesions in the rat

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In previous studies we have demonstrated that the p53 response to DNA damage in preneoplastic liver lesions, referred to as enzyme-altered foci (EAF), is attenuated. In the present investigation comparative quantitative RT–PCR revealed no major difference in the p53 mRNA levels in EAF and non-EAF tissue. When CoCl2 was employed to induce hypoxia-inducible factor (HIF-1α), both non-EAF and EAF hepatocytes readily accumulated p53, whereas EAF hepatocytes did not accumulate p53 upon treatment with diethylnitrosamine (DEN). The p53 response was also induced in EAF hepatocytes by the inhibitor of nuclear export, leptomycin B. An inhibitor of DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM), wortmannin, blocked the DEN-induced p53 response in non-EAF hepatocytes. Assay of kinase activity in immunoprecipitated material from EAF and non-EAF tissue revealed attenuated ATM activity in EAF. Immunohistological and western blot analysis of the level of ATM protein was in agreement with the activity measurements and no phosphorylation of Ser15 in p53 was detected in EAF tissue 24 h after a challenging dose of DEN. Taken together with previously published data, these data indicate selective attenuation of the DNA damage pathway in EAF hepatocytes. Down-regulation of DNA damage-induced and ATM-mediated phosphorylation of p53 may confer a growth advantage on EAF hepatocytes.

Keywords: ATM, ataxia telangiectasia mutated;; ATR, ATM and Rad3-related; DEN, diethylnitrosamine; DNA-PK, DNA-dependent protein kinase; EAF, enzyme-altered foci; GST-P, glutathione S-transferase placental form; HIF-1α, hypoxia-inducible factor; LI, labelling index; LMB, leptomycin B; MDM2, murine double minute; PB, phenobarbital

Journal Article.  6669 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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