A polymorphism in the Mdm2 promoter enhances cancer risk

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DESCRIPTION (provided by applicant): One of the most commonly inactivated pathways in human cancers is the p53 tumor suppressor pathway. The p53 gene encodes a transcription factor required for the activation of numerous DNA-damage dependent checkpoint response and apoptotic genes.The gene encoding Mdm2, a p53 inhibitor, is amplified in over 30% of sarcomas and the protein is overexpressed by unknown mechanisms in many other tumors. Thus, the p53 pathway is inactivated in the vast majority of human cancers at multiple points within this pathway. We have recently identified a single nucleotide polymorphism (SNP) in the human Mdm2 (MDM2) promoter that creates a strong and stable Sp1 binding site that constitutively increases MDM2 transcription. This polymorphic change, a T to G, results in increased MDM2 mRNA and protein levels and consequently decreased p53 levels. This renders individuals with this polymorphism more susceptible to cancer. We believe that generating an Mdm2 SNP mouse model will allow us to follow and directly observe the stepwise natural progression of tumorigenesis in these mice and therefore have a better understanding of this complex process in humans.