Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O6- methylguanine-DNA methyltransferase

Proceedings of the National Academy of Sciences of the United States of America
Z Q ZhouC A Walter

Abstract

O(6)-methylguanine (O(6)mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O(6)mG through a direct reversal mechanism by a protein termed O(6)-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O(6)mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB/FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB/FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacI transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacI. Tumors that arose in C3HeB/FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicat...Continue Reading

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Citations

Oct 2, 2002·Current Oncology Reports·Kathryn Z Guyton, Thomas W Kensler
Apr 16, 2004·DNA Repair·Christi A WalterRonald B Walter
Nov 6, 2003·Toxicology·Markus ChristmannBernd Kaina
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May 2, 2003·Annals of the New York Academy of Sciences·Mukesh Verma
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Jul 15, 2016·BioMed Research International·Michael A McilhattonJoanna Groden
Apr 2, 2004·Nature Reviews. Cancer·Stanton L Gerson

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