The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice.
The relative contribution to development of hepatocellular carcinoma of the mouse equivalent to the human p53ser249 mutation, found in human hepatocellular carcinoma associated with aflatoxin (AFB1) exposure, is compared with other major risk factors in a transgenic mouse model. Transgenic p53ser246 mice, expressing the mutant protein gene under the control of a truncated albumin promoter, were bred to mice lacking p53 (p53-/-) and to transgenic mice expressing hepatitis B surface antigen (HBsAg). AFB1 hepatocarcinogenesis was then determined in offspring with single or multiple risk factors by determination of the numbers of high-grade hepatic tumors at 13 months of age. In AFB1-treated male mice, expression of the p53ser246 mutation increases the incidence of high-grade tumors from 0% to 14% in HBsAg-negative, p53+/+ (wild-type homozygous) control mice; from 14% to 71% in HBsAg-negative, p53+/- (wild-type heterozygous) mice; and from 62% to 100% in HBsAg-positive, p53+/+ mice. Thus, whereas HBsAg expression and AFB1 together are strongly cocarcinogenic, the presence of the p53ser246 mutant not only significantly enhances this cocarcinogenic effect, it also increases tumorigenesis in AFB1-treated p53 heterozygous and homozygous mice not expressing HBsAg. The possibility that the p53ser246 mutant protein may act as a promoting agent for AFB1 hepatocarcinogenesis is discussed.
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Department of Pathology, Albany Medical College, NY 12208-3479, USA.
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D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D016604:Aflatoxin B1