p53 is induced by telomere dysfunction, DMA damage, oncogene stress and severe hypoxia. These cellular stresses can result in p53 dependent growth arrest or apoptosis. We have identified a novel p53 pro-survival pathway involving up-regulation of genes encoding both growth factors and growth factor receptors, which can influence the balance between cell death and survival in a p53 dependent response. We hypothesize that this pro-survival pathway may function in normal tissue repair in response to cellular stresses such as those induced by genotoxic agents or hypoxia. Most known p53 induced genes function within extrinsic and/or intrinsic apoptotic pathways, and we have also identified novel p53-induced genes within these pathways.
Aim 1 of this proposal is directed at further elucidation of p53 prosurvival signaling effectors and pathways in vitro. We will also genetically dissect the roles of specific p53 prosurvival genes in normal tissue repair in response to genotoxic stress using appropriate gene knockout mouse models.
Aim 2 derives from our recent discovery of CDIP, a novel p53 direct target gene, which appears to act within the extrinsic apoptosis pathway. Investigations within this Aim are focused on elucidating CDIP functions in p53-mediated apoptosis. We plan to specifically investigate the role of CDIP in down-regulating survivin, an inhibitor of apoptosis (IAP) by a mechanism that may involve proteosome-mediated degradation as well as in identifying CDIP interacting proteins. Our preliminary evidence indicates that p53 proapoptotic and prosurvival functions may be differentially regulated in determining cell fate decisions in different reduced oxygen environments.
Aim 3 is directed at understanding p53 regulation and functions in hypoxic stress and, specifically, the roles of the novel p53 effectors identified by us in this response. Established collaborations with other investigators within the program should aid in these investigations, which have potentially important implications for cancer therapeutic intervention.
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