This application is in response to NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Different individuals exposed to the same environmental agent often respond differently due to additional factors such as genetics. Therefore, understanding how human sequence variations (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. The p53 tumor suppressor plays a critical role in the response to many cellular stresses, including exposure to genotoxic chemicals and radiation. MDM2 is a critical regulator of p53 through its ability to respond to increased p53 activity and target p53 for inactivation and degradation. Both the p53 and MDM2 genes contain common single nucleotide polymorphisms (SNPs) that are associated with increased risk for some human cancers. In the case of p53, a non-synonymous SNP results in either an arginine (R) or proline (P) residue at position 72 of the p53 protein. Laboratory studies demonstrate that the two p53 variants have different biological properties, particularly in their abilities to induce apoptosis. In the case of MDM2, the SNP lies within intron 1 regulatory sequences (G or T at position 309) and affects the expression levels of MDM2. The presence of G at SNP309 results in increased expression of MDM2 and decreased p53 responsiveness compared to the T allele of SNP309.The original application (R01 ES015587) was based on the use of novel mouse models for the p53 R72P polymorphism to study the role of this SNP in modulating the response to environmental and oncogenic stresses in squamous cell carcinoma development. In this competitive revision, we propose to expand our studies to include novel mouse models for the MDM2 SNP309 polymorphism. These mouse models are the first to mimic naturally occurring human polymorphisms and will allow us to examine at the molecular level the role of these SNPs in modulating the response to stress and cancer development in a highly physiological setting. Moreover, by including the MDM2 SNP309 mouse models into these studies, gene-gene interactions between the p53 and MDM2 variants can be studied. To validate the usefulness of our mouse models in mimicking human disease we will also perform molecular epidemiological studies to confirm that similar gene-gene interactions also modulate cancer development in humans.
Genetic differences among individuals play a major role in determining the response to environmental exposures and risk for developing disease. The goal of this project is to use novel mouse models to study how two common human gene variants interact with each other to modulate the development of squamous cell carcinoma of the skin and head &neck.
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