p53 Mutations in Benzo(a)Pyrene-Exposed Human p53 Knock-in Murine Fibroblasts Correlate with p53 Mutations in Human Lung Tumors
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- Zhipei Liu
- 1Genetic Alterations in Carcinogenesis and Departments of
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- Karl-Rudolf Muehlbauer
- 1Genetic Alterations in Carcinogenesis and Departments of
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- Heinz H. Schmeiser
- 2Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany
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- Manfred Hergenhahn
- 1Genetic Alterations in Carcinogenesis and Departments of
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- Djeda Belharazem
- 1Genetic Alterations in Carcinogenesis and Departments of
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- Monica C. Hollstein
- 1Genetic Alterations in Carcinogenesis and Departments of
書誌事項
- 公開日
- 2005-04-01
- DOI
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- 10.1158/0008-5472.can-04-3675
- 公開者
- American Association for Cancer Research (AACR)
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説明
<jats:title>Abstract</jats:title> <jats:p>Human p53 mutation spectra differ significantly from one cancer type to another. One possible reason is that carcinogenic risk factors differ, and these factors elicit distinct mutation patterns. There has been no mammalian assay, however, with which to generate mutation patterns in human p53 sequences experimentally, hampering interpretation of the human tumor spectra. We have designed a new mammalian cell assay using gene targeting technology that selects and scores human p53 gene sequence mutations in human-p53 knock-in (Hupki) murine embryonic fibroblasts (HUF) that have undergone immortalization. With the Hupki assay we examined here whether benzo(a)pyrene (BaP), a major tobacco smoke carcinogen could elicit p53 mutation patterns characterizing the human lung tumor p53 mutation spectrum. We found that, in contrast to unexposed HUFs or HUFs exposed to other carcinogenic agents, HUFs exposed to BaP acquire mutations that display major features of the human lung tumor p53 mutation spectrum: (a) predominance of G-to-T mutations, (b) unequivocal strand bias of the transversions, and (c) a mutation hotspot at codons 157 to 158. These data are consistent with the hypothesis that BaP has a direct role in causing smokers' lung tumor p53 mutations. The assay can be used to examine various hypotheses on the endogenous or exogenous factors responsible for the p53 mutations in human tumors arising in other tissues.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 65 (7), 2583-2587, 2005-04-01
American Association for Cancer Research (AACR)
