The development of tumor cells from normal cells requires the sequential acquisition of mutations to several genes. These genes fall into two major categories, the first can be referred to as oncogenes, genes that normally act to promote cell division and a second category that includes genes that function to arrest cell division, commonly referred to as tumor suppressor genes. Cancer can therefore arise from activation of oncogenes and/or inactivation of tumor suppression genes. The p53 tumor suppressor protein is unique in that it has the ability to detect the presence of damaged DNA wherein it blocks cell cycle progression to allow for the damaged DNA to be repaired (thus ensuring that mutations aren't propagated) but it also has the ability to activate the cellular suicide program such that cells having un-repairable DNA are eliminated from the organism. This unique role of p53 as the """"""""Guardian of the genome"""""""" is exemplified by the fact that 60% of all tumors carry a mutation in the p53 gene and that inherited mutations in p53 strongly predispose individuals to cancer. The goal of this project is to develop a strategy wherein the activation of p53 in response to DNA damaging events (i.e. carcinogenesis) can be non-invasively imaged. The strategy is based on the fact that p53 is expressed in all normal cells but is rapidly degraded. In response to a DNA damaging event, degradation of p53 is blocked thus resulting in accumulation of p53. We hypothesize that fusion of an in-vivo reporter gene (such as luciferase) to p53 would result in degradation of the reporter with p53 however upon DNA damage, inhibition of degradation of the fusion would result in accumulation of the reporter (as well as p53) which could then be imaged as increased reporter activity (e.g. bioluminescense). This will enable rapid, non-invasive imaging of p53 levels within a tissue, which is a direct measure of the mutagenic potential of a specific environmental condition. In addition, this imaging strategy could also be used to evaluate chemopreventative agents as well as the efficacy of sunscreens. In addition, since the majority of tumor-associated, p53 inactivating mutations also result in p53 accumulation, constitutive elevation of p53 levels (and therefore bioluminescence) will be used as a reliable measure of p53 inactivation (whereas transiently increased p53 levels, and therefore bioluminescence, would reflect a recent genotoxic stress).
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