Journal Article

MEF immortalization to investigate the ins and outs of mutagenesis

Jochen vom Brocke, Heinz H. Schmeiser, Manuela Reinbold and Monica Hollstein

in Carcinogenesis

Volume 27, issue 11, pages 2141-2147
ISSN: 0143-3334
Published online June 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl101
MEF immortalization to investigate the ins and outs of mutagenesis

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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.

Journal Article.  3850 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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