Cellular hypoxia is a physiologically relevant cellular stress that triggers a host of cellular responses involved in tissue repair, angiogenesis, and tumorigenesis. A major cellular component of this phenomena is the tumor suppressor p53, which is stabilized by hypoxic stress. In contrast to transactivation phenomena observed during DNA damaging stress, hypoxia appears to have a distinctly different mechanism of transcriptional regulation, even though many of the downstream cellular effects are similar. This implies that p53 can mediate a number of its tumor suppressive functions through several non-intersecting pathways. The objective of this proposal is to determine how p53 suppresses tumor progression during hypoxic stress. To achieve this goal we will use a series of hypoxia regulated p53 constructs to identify genes that are specifically downregulated during hypoxia. We will use a combination of expression microarray technology and chromatin immunoprecipitation to identify direct targets of p53 repression in a cell culture model. Complementary mouse tumor studies will be used to verify the importance of general and specific gene repression on tumor cell apoptosis in the hypoxic regions of tumors. These studies will be essential for future experiments defining the functional consequences of transcriptional repression by p53. The low oxygen concentrations (hypoxia) that occur in tumors often lead to the formation of more aggressive tumors. The tumor suppressor gene p53 is frequently mutated in hypoxic tumors, aiding in the progression of tumor growth. Understanding how p53 regulates gene expression in hypoxic tumors will lead to the identification of new pathways to target for cancer therapies. ? ? ?
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