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Carcinogenesis Advance Access originally published online on June 15, 2006
Carcinogenesis 2006 27(11):2141-2147; doi:10.1093/carcin/bgl101
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MEF immortalization to investigate the ins and outs of mutagenesis

Jochen vom Brocke, Heinz H. Schmeiser, Manuela Reinbold1 and Monica Hollstein1,*

Department of Molecular Toxicology, German Cancer Research Center (DKFZ, Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280 D69120 Heidelberg, Germany
1 Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center (DKFZ, Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280 D69120 Heidelberg, Germany

*To whom correspondence should be addressed. Email: m.hollstein{at}dkfz-heidelberg.de

The importance of tumor suppressor/oncogene mutations in tumor development is clear, but the causes of the DNA sequence changes in human cancers are not. Although elegant experiments with transgenic mice harboring lacZ or cII target sequences show that exposure to mutagenic human carcinogens can cause base substitutions in vivo, it does not follow from this that the mutations found in human cancers have to be the direct result of damage by external mutagens. They could be due to endogenously generated reactive oxygen species, or polymerase infidelity, for example. Specific patterns of mutations in the defined sequence of a test system set up to address this question can provide information on the molecular events leading to DNA sequence changes in humans if the experimentally induced mutations and patient tumor mutations are compared in the same gene. Fortuitously, inactivating point mutations in the p53 gene are driving events in the immortalization of murine embryonic fibroblasts (MEFs) in vitro. This discovery offers a natural biological strategy for selecting p53 mutants. Immortalized cell lines arising from primary MEFs harboring human p53 sequences (Hupki, human p53 knock-in) have p53 mutations that match p53 mutations in human tumors.


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