Applications of the human p53 knock‐in ( <i>Hupki</i> ) mouse model for human carcinogen testing

<jats:title>ABSTRACT</jats:title> <jats:p> Tumor‐driving mutations in the <jats:italic>TP53</jats:italic> gene occur frequently in human cancers. These inactivating mutations arise predominantly from a singlepoint mutation in the DNA‐binding domain of this tumor suppressor gene ( <jats:italic>i.e</jats:italic> ., exons 4–9). The human p53 <jats:italic>k</jats:italic> nock <jats:italic>‐i</jats:italic> n ( <jats:italic>Hupki</jats:italic> ) mouse model was constructed using gene‐targeting technology to create a mouse strain that harbors human wild‐type <jats:italic>TP53</jats:italic> DNA sequences in both copies of the mouse <jats:italic>TP53</jats:italic> gene. Replacement of exons 4–9 of the endogenous mouse <jats:italic>TP53</jats:italic> alleles in the <jats:italic>Hupki</jats:italic> mouse with the homologous normal human <jats:italic>TP53</jats:italic> gene sequences has offered a humanized replica of the <jats:italic>TP53</jats:italic> gene in a murine genetic environment. The <jats:italic>Hupki</jats:italic> mouse model system has proven to be an invaluable research tool for studying the underlying mechanisms of human <jats:italic>TP53</jats:italic> mutagenesis. The utility of the <jats:italic>Hupki</jats:italic> mouse model system for exploring carcinogen‐induced <jats:italic>TP53</jats:italic> mutagenesis has been demonstrated in both <jats:italic>in vivo</jats:italic> animal experiments and <jats:italic>in vitro</jats:italic> cell culture experiments. Here, we highlight applications of the <jats:italic>Hupki</jats:italic> mouse model system for investigating mutagenesis induced by a variety of environmental carcinogens, including sunlight ultraviolet radiation, benzo [ <jats:italic>a</jats:italic> ] pyrene (a tobacco smoke‐derived carcinogen), 3‐nitrobenzanthrone (an urban air pollutant), aristolochic acid (a component of Chinese herbal medicine), and aflatoxin B1 (a food contaminant). We summarize the salient findings of the respective studies and discuss their relevance to human cancer etiology.—Besaratinia, A., Pfeifer, G. P. Applications of the human p53 knock‐in ( <jats:italic>Hupki</jats:italic> ) mouse model for human carcinogen testing. <jats:italic>FASEB J</jats:italic> . 24, 2612–2619 (2010). <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://www.fasebj.org">www.fasebj.org</jats:ext-link> </jats:p>