p53 and pathways of apoptosis

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DESCRIPTION (provided by applicant): The p53 protein plays a critical role in tumor suppression, and represents a pivotal mediator of cellular responses to both intrinsic and extrinsic stress signals. As a nuclear transcription factor, p53 has the ability to activate, or repress, the expression a large number of genes. Accumulating evidence suggests that p53 also has a non-transcriptional function with a direct role at mitochondria in promoting apoptosis. The outcome of stress-mediated p53 activation generally is growth arrest or cell death (apoptosis). How this "decision" is made remains an unresolved question in the field, and is described in general terms as being determined by "cell context" or by the balance of prosurvival or proapoptotic factors. Thus, the goal of defining and characterizing key cellular determinants that control this important decision and mediate the diverse activities of p53 is of central importance in cancer biology. The focus of this research project centers on our very recent discovery of a functional link between a liver survival factor, insulin-like growth factor binding protein 1 (IGFBP1), and the p53 protein. While in many tissues, p53 activation leads to cell death, our data suggest that p53 in liver cells also has a cytoprotective role. Thus, a primary goal will be to investigate whether a p53/IGFBP1 feed-back circuit is part of a crucial pathway mediating the stress- response outcome of normal and neoplastic liver cells. These investigations center on important issues related to the ways p53 acts in response to stress, including: the contribution of mitochondrial p53 to apoptosis, the identification and characterization of critical modulators of p53 function, and the factors that determine whether stress-activated p53 will promote survival or apoptosis. In conjunction, they address the intracellular mechanism of action of the prosurvival/proregeneration protein, IGFBP1. The information obtained will provide an essential framework needed for development of greater insight into decisions that influence cell death signaling mechanisms in normal and neoplastic liver cells, an understanding that is needed for the rational design of effective therapeutic strategies in treating cancers and hepatic diseases that predispose to cancer.