Carcinogenesis Advance Access published online on June 15, 2006
Carcinogenesis, doi:10.1093/carcin/bgl101
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1 Department of Molecular Toxicology, German Cancer Research Center (DKFZ, Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280, D69120 Heidelberg, Germany
* To whom correspondence should be addressed. 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 (ROS), 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 a driving event 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 murine embryonic fibroblasts harboring human p53 sequences (Hupki, human p53 knock-in) have p53 mutations that match p53 mutations in human tumors.
Received March 3, 2006
Revised May 23, 2006
Accepted May 24, 2006
CARCINOGENESIS
MEF immortalization to investigate the ins and outs of mutagenesis
Jochen vom Brocke 1,
Heinz H. Schmeiser 1,
Manuela Reinbold 2,
and
Monica Hollstein 2 *
2 Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center (DKFZ, Deutsches Krebsforschungszentrum), Im Neuenheimer Feld 280, D69120 Heidelberg, Germany
Monica Hollstein, E-mail: m.hollstein{at}dkfz-heidelberg.de
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