Carcinogenesis Advance Access first published online on May 25, 2005
This version published online on June 1, 2005
Carcinogenesis, doi:10.1093/carcin/bgi142
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1 Institute of Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany
* To whom correspondence should be addressed. Mouse models are important tools in toxicologic research. Differences between species in pathways contributing to tumor development, however, raise the question in how far mouse models are valid for human risk assessment. One striking difference relates to the frequency of spontaneous liver cancer which is high in certain mouse strains but rather low in humans. Likewise, mutation frequencies in cancer genes are characteristically different, i.e. P53 mutations are frequent in human but very rare in murine liver tumors, whereas Ras genes are often mutated in mouse liver tumors but hardly ever in human liver cancers. Since P53 has been shown to control oncogenic RAS in human cells, we hypothesized that this function of the tumor suppressor could differ in mouse hepatocytes. To test this hypothesis, we used hupki mice (human p53 knock in) which carry a partly humanized P53 sequence (P53KI). Here we report the results of the first hepatocarcinogenesis experiment with this strain of mice. Mice of the genotypes P53KI/KI, P53WT/KI, and P53WT/WT were treated with N-nitrosodiethylamine at two weeks of age and sacrificed 35 weeks later. The frequency of liver tumors and glucose-6-phosphatase-altered liver lesions was almost identical in all three P53 genotypes and about 40-50% of liver tumors showed activating mutations in codon 61 of the Ha-Ras gene independent of genotype. Moreover, only very few P53-positive lesions were observed but without nuclear localisation of the protein, suggesting absence of P53 mutations. These data suggest that the humanized P53 knock-in allele behaves like its murine ortholog in mouse hepatocarcinogenesis.
Received April 8, 2005
Revised May 20, 2005
Accepted May 22, 2005
CARCINOGENESIS
Human p53 knock-in (HUPKI) mice do not differ in liver tumor response from their counterparts with murine p53
2 Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center, P.O. Box 101949, 69009 Heidelberg, Germany
3 Central Unit Biostatistics, German Cancer Research Center, P.O. Box 101949, 69009 Heidelberg, Germany
Michael Schwarz, E-mail: michael.schwarz{at}uni-tuebingen.de
Abstract
The originally published version of this paper was incorrect. Two sections of text were underlined.
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