Transgenic murine models of human cancer: bridging the gap from mouse to man

摘要

The use of gene targeting technology to develop new mouse models of human cancer has allowed genetic and biochemical data to be put to the test for their biological consequences in vivo, Mice with specifically modified p53 rumor suppressor genes provide an interesting demonstration of this approach. Strains in which p53 is absent are cancer prone, confirming the importance of this protein in inhibiting tumor development [Nature 356 (1992) 215], The tumor igenicity of murine cells with a mutant p53 transcriptional transactivation domain has clarified the importance of p53-regulated gene expression in the mechanism of cancer suppression by p53 [Nat. Genet. 26 (2000) 37]. Genetically engineered mice also promise to provide new insights into the p53 point mutations found in human tumors. A key question in cancer research has been the relative contributions of various environmental exposures on the one hand, and endogenous biological processes on the other, in the induction of cancer gene mutations in humantumors, Since a mutation spectrum can provide important information on the nature of the mutagenic agents that gave rise to the mutations, internet-accessible mutation databases are being scrutinized for clues to environmental etiological agents, or for confirmation of a role for putative endogenous pro-mutagenic risk factors in contributing to the human cancer burden. To facilitate decoding of human mutation patterns, we have generated a knock-in mouse with human p53 gene sequences. This mouse model (hupki, for human p53 fcnock-m) can be applied to some of the puzzles that the human p53 tumor mutation database presents.