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    Biological Roles and Regulation of Phosphatidylinositol 3-Kinase (PI3K) Isoforms

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    Chattopadhyay_grad.sunysb_0771E_10109.pdf (2.267Mb)
    Date
    1-May-10
    Author
    Chattopadhyay, Mohar
    Publisher
    The Graduate School, Stony Brook University: Stony Brook, NY.
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    Abstract
    Class IA PI3Ks are signaling molecules that control cell survival, growth, proliferation and metabolism. Dysregulated PI3K signaling is found in patients with diseases such as diabetes and cancer. The two aims of my thesis research were (1) to determine the distinct roles of the PI3K isoforms p110&#913; and p110&#914; in regulating hepatic lipid and glucose metabolism and (2) to investigate the regulation of p110&#913; and p110&#914; by the heterotrimeric G protein G&#913;<sub>q</sub>. For aim 1, mice with liver-specific gene deletion of p110&#913; or p110&#914; were generated. My studies found that mice lacking hepatic p110&#913; were largely protected from high-fat diet-induced liver steatosis, whereas p110&#914; ablation did not attenuate triglyceride accumulation in the liver. The protective effect of p110&#913; ablation is probably due to decreased liver uptake of long chain fatty acids. High-fat diet-induced increases in mRNA and protein levels of liver fatty acid binding protein were blunted in the p110&#913;-null liver. On the other hand, mice lacking hepatic p110&#914; developed glucose intolerance and hyperinsulinemia. Higher cAMP levels and increased expression of adenylyl cyclase 5 correlated with increased gluconeogenesis and glycogenolysis in p110&#914;<super>-/-</super> hepatocytes. Mice with p110&#913;-null liver did not exhibit glucose intolerance or hyperinsulinemia. Furthermore, ablation of p110&#913; decreased insulin signaling in the liver, whereas deletion of p110&#914; had relatively minor effects on this signaling pathway. Aim 2 of my thesis research investigated the mechanism by which G&#913;<sub>q</sub> inhibits PI3Ks. My studies used purified recombinant proteins and fluorescence spectroscopy to demonstrate that G&#913;<sub>q</sub> directly binds to p110&#913; and blocks Ras binding to p110&#913;. In addition, in vitro PI3K activity assays revealed that G&#913;<sub>q</sub> inhibits the four PI3K enzyme complexes p110&#913;/p85&#913;, p110&#913;/p85&#914;, p110&#914;/p85&#913; and p110&#914;/p85&#914;. It was determined that G&#913;<sub>q</sub> binds to the p85-binding domain of p110&#913; and does not appear to directly interact with the catalytic domain. Further, I found that G&#913;<sub>q</sub> can bind to free p85 in the iSH2 region independently of p110 binding. In summary, findings from my thesis research indicate that p110&#913; and p110&#914; have differential effects on hepatic lipid and glucose metabolism and that activated G&#913;<sub>q</sub> can directly bind and inhibit PI3K complexes.
    URI
    http://hdl.handle.net/1951/55384
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    • Stony Brook Theses & Dissertations [SBU] [1955]

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