The overall goal of the project is to elucidate the mechanisms by which the PI 3-kinase/Akt signaling pathway acts to prevent programmed cell death. The regulation of programmed cell death by growth factors that suppress apoptosis is critical to normal development and maintenance of adult tissues, and mutations in many of the genes that control apoptosis play important roles in human cancers. Although PI 3-kinase/Akt signaling is the major pathway by which growth factors suppress apoptosis in mammalian cells, the critical targets of Akt remain to be fully understood. Akt phosphorylates a variety of substrates, including Bad, several transcription factors, and the protein kinase GSK-3beta. Initially identified as a metabolic regulator, it is now recognized that GSK-3beta plays an important role in apoptosis, as well as in metabolism and development. Recent studies have further demonstrated that translation initiation factor 2B (elF2B) is a critical target of GSK-3beta in regulation of cell survival, linking global regulation of protein synthesis to programmed cell death. We plan to continue these studies with the goal of identifying the targets of translational regulation that control apoptosis downstream of PI 3-kinase/Akt/GSK-3beta signaling. In addition, we will investigate the role of metabolic control and transcriptional regulation by the PI 3-kinase/Akt/GSK-3beta signaling pathway in cell survival. These experiments will proceed according to the following specific aims. 1. Identification of targets for translational regulation downstream of GSK-3beta signaling. We will test the hypothesis that decreases in the levels of rapidly degraded anti-apoptotic proteins, including Bcl-2 family members, contribute to programmed cell death resulting from global inhibition of translation. Investigation of the role of regulation of glucose metabolism in control of programmed cell death by GSK-3beta. We will determine whether effects of GSK-3beta on glycogen synthase or glucose uptake contribute to regulation of apoptosis. 3. Analysis of transcriptional alterations resulting from PI 3-kinase/Akt/GSK-3beta signaling. Changes in global transcription profiles will be analyzed using DNA arrays and small molecule inhibitors to identify genes that are regulated by PI 3-kinase and may be involved in programmed cell death. Candidate genes will be characterized with respect to both their functions in apoptosis and their regulation.
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