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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing
Ahmad Besaratinia1, Gerd P Pfeifer
1Department of Cancer Biology, Beckman Research Institute of the City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. ania@coh.org
Abstract:
Tumor-driving mutations in the TP53 gene occur frequently in human cancers. These inactivating mutations arise predominantly from a single-point mutation in the DNA-binding domain of this tumor suppressor gene (i.e., exons 4-9). The human p53 knock-in (Hupki) mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human wild-type TP53 DNA sequences in both copies of the mouse TP53 gene. Replacement of exons 4-9 of the endogenous mouse TP53 alleles in the Hupki mouse with the homologous normal human TP53 gene sequences has offered a humanized replica of the TP53 gene in a murine genetic environment. The Hupki mouse model system has proven to be an invaluable research tool for studying the underlying mechanisms of human TP53 mutagenesis. The utility of the Hupki mouse model system for exploring carcinogen-induced TP53 mutagenesis has been demonstrated in both in vivo animal experiments and in vitro cell culture experiments. Here, we highlight applications of the Hupki mouse model system for investigating mutagenesis induced by a variety of environmental carcinogens, including sunlight ultraviolet radiation, benzo[a]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.
Insights
The human p53 knock-in (Hupki) mouse model accurately mimics human TP53 mutagenesis. This model is crucial for studying how environmental carcinogens induce TP53 mutations, advancing cancer etiology research.
Area of Science:
- Genetics
- Cancer Biology
- Toxicology
Background:
- TP53 gene mutations are frequent drivers of human cancers, primarily occurring in its DNA-binding domain.
- The TP53 tumor suppressor gene is critical for maintaining genomic stability.
- Understanding TP53 mutagenesis is key to deciphering cancer development.
Purpose of the Study:
- To introduce the human p53 knock-in (Hupki) mouse model for studying TP53 gene mutations.
- To evaluate the utility of the Hupki mouse model in investigating carcinogen-induced mutagenesis.
- To explore the relevance of these findings to human cancer etiology.
Main Methods:
- Gene-targeting technology was used to create the Hupki mouse model, replacing mouse TP53 exons 4-9 with human wild-type TP53 sequences.
- The Hupki mouse model was utilized in both in vivo and in vitro experiments.
- Studies involved exposure to various environmental carcinogens including UV radiation, benzo[a]pyrene, 3-nitrobenzanthrone, aristolochic acid, and aflatoxin B1.
Main Results:
- The Hupki mouse model successfully replicated human TP53 mutagenesis patterns.
- The model demonstrated efficacy in studying mutagenesis induced by diverse environmental carcinogens.
- Specific carcinogens were shown to induce distinct TP53 mutation profiles in the Hupki model.
Conclusions:
- The Hupki mouse model is an invaluable tool for studying the mechanisms of human TP53 mutagenesis.
- This model provides critical insights into how environmental factors contribute to cancer development.
- Findings from Hupki mouse studies are relevant for understanding human cancer etiology and prevention strategies.
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