The central importance of the p53 tumor suppressor gene to human cancer research is best epitomized by the following facts: 1) p53 is the most frequently mutated gene in human cancer;2) p53 is a central signaling molecule in DNA damage-mediated apoptosis;3) tumors with mutations in p53 have universally poor prognosis. Much is currently known regarding the molecular basis for p53's tumor suppressor function;tumor suppression by this protein is mediated by its ability to induce growth arrest, senescence and apoptosis. p53 is best characterized as a sequence-specific transcription factor, and it elicits growth arrest primarily through transactivation of the cyclin-dependent kinase inhibitor p21/waf1. In order to induce death p53 transactivates pro-apoptotic target genes such as the BH3-only proteins PUMA and NOXA;p53 also has a direct apoptogenic role at the mitochondria. While a great deal is understood about how p53 functions as a tumor suppressor, remarkably little is known about how coding region polymorphisms in p53 impact these functions. There are three polymorphic variants of p53. A common polymorphism exists at codon 72, encoding either arginine (R72) or proline (P72). Work from our group and others has shown that the R72 form of p53 has markedly increased apoptotic function, due to increased ability to localize to mitochondria and transactivate the p53 target gene PERP. At codon 47, p53 encodes proline (wild type) or serine (S47). We have found the S47 variant has decreased phosphorylation on serine 46, and up to three-fold decreased apoptotic function due to impaired ability to transactivate PUMA. Therefore, in terms of apoptosis, R72 >P72 >S47. The long-term objective of proposed research is to use mouse models for p53 polymorphic variants in order to dissect the different mitochondrial and transcriptional functions of these variants in the context of a living organism. An added goal is to use our P72, R72 and S47 mice in order to more accurately assess the impact of these variants on cancer progression and the efficacy of cancer therapy in mouse models of lymphoma and colorectal cancer. The lesser-apoptotic P72 and S47 variants are significantly more common in African Americans. Therefore these studies will be important for understanding (and eventually eliminating) disparities in cancer risk and prognosis in underserved populations, which is one goal of the NIH roadmap.
Published data from our group and others indicate that there are three coding region variants of the p53 protein in human populations, and further that these three variants all have significant differences in p53 function. Whereas a great deal is known about how p53 functions to suppress cancer, to date very little is known about how these polymorphic variants of p53 influence cancer risk or the efficacy of therapy;the proposed research will directly address this question. Because the two lesser-functioning variants (S47 and P72) are both more common in African Americans, data generated from this study has direct relevance to understanding the differences in cancer risk and prognosis in this population.
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