NDLI: Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O 6- methylguanine-DNA methyltransferase

Content Provider	PubMed Central
Author	Zhou, Zi-qiang Manguino, Diwi Kristen, Kewitt Intano, Gabriel W. Mcmahan, C. Alex Herbert, Damon C. Hanes, Martha Reddick, Robert Ikeno, Yuji Walter, Christi A.
Copyright Year	2001
Abstract	O 6-methylguanine (O 6mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O 6mG through a direct reversal mechanism by a protein termed O 6-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O 6mG 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 indicate that spontaneous O 6mG lesions induced hepatocellular carcinogenesis in C3HeB/FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis.
Related Links	http://dx.doi.org/10.1073/pnas.221232998
Ending Page	12571
Page Count	6
Starting Page	12566
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	22
Volume Number	98
Language	English
Publisher	The National Academy of Sciences
Publisher Date	2001-10-23
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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