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|Title:||The role and regulation of elF2[alpha] phosphorylation in pancreatic [beta]-cells|
|Authors:||Powell, Michael L|
|Presented at:||University of Leicester|
|Abstract:||Incubation of pancreatic beta-cells or islets with glucose leads to acute increases in the rate of total protein synthesis, which are almost entirely regulated at the post-transcriptional level. However, the metabolic signals and the molecular mechanisms by which glucose stimulates increases in the rate of protein synthesis are poorly understood. In this thesis, I demonstrate that the mitochondrial metabolism of glucose is likely sufficient for glucose-stimulated protein synthesis. However, these increases are not regulated through changes in intracellular ATP content, an autocrine effect of secreted insulin, or by regulation of the activity of AMPK. I also demonstrated that glucose-stimulated protein synthesis in pancreatic beta-cells parallels the dephosphorylation of eIF2alpha and increases in the availability of the translational ternary complex (eIF2.GTP:Met-tRNAi). As with glucose-stimulated protein synthesis, the mitochondrial metabolism of glucose is sufficient for the regulation of eIF2alpha phosphorylation in response to glucose. However, these changes in eIF2alpha phosphorylation do not regulate glucose-stimulated protein synthesis in pancreatic beta-cells, but importantly are required for pancreatic beta-cell survival. I demonstrate that glucose-regulated eIF2alpha phosphorylation is dependent on the eIF2alpha kinase, PERK. Importantly, I show that the activity of PERK and increases in eIF2alpha phosphorylation closely parallel intracellular ATP content, and that ATP depletion activates PERK and stimulates the phosphorylation of eIF2alpha. Therefore, PERK is likely to act as an intracellular ATP sensor in pancreatic beta-cells, regulating the phosphorylation of eIF2alpha in response to changing glucose concentrations.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Biochemistry|
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