This is a proposal to examine in detail the mechanisms underlying the translational regulation of proinsulin biosynthesis in the islet beta cells. Previous studies have established that proinsulin and several other proteins of the beta cell are translationally up-regulated by glucose by a rapidly- acting activating mechanism that does not require increased synthesis of mRNA. Translational control by glucose is selective and effects principally proinsulin and other proteins such as the convertases PC3, and possibly PC2, that are involved in processing proinsulin, as well as other unidentified lower-abundance proteins. Previous studies have indicated that translational stimulation is accompanied by increased mobilization of insulin RNA to the membrane-bound form on the rough endoplasm reticulum (RER), indicating that the rate of translational initiation is enhanced by glucose. Other studies have indicated that the rate of translational elongation may also be stimulated and that glucose does in fact result in minor degrees of enhancement of total islet protein biosynthesis, while proinsulin biosynthesis is increased by factors of 10-20 fold. Thus far efforts to determine how the selective turn-on of insulin messenger translation is effected have only been partially successful. It has been suggested that it may be due to enhanced SRP/SRP receptor interaction but there are strong indications that this may not be a sufficiently specific mechanism. The applicant proposes a new approach to this problem through investigation of potential regulatory protein binding stem-loop structures in the 5' upstream region of the insulin mRNA and those of other glucose-stimulated or non-stimulated proteins to examine the possibility that stimulation results from specific protein-RNA interactions similar to these involved in the control of ferritin biosynthesis by iron in the liver. Other studies will be directed toward examination of the role of protein phosphorylation/dephosphorylation mediated by PKA and PKC in regulating initiation of protein translation. The ultimate goal will be to elucidate the role of glucose metabolism, protein kinases and related factors in the rapid regulation of proinsulin biosynthesis in the beta cell and/or a model transformed beta cell line - the MIN6 line.
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| Boland, Brandon B; Rhodes, Christopher J; Grimsby, Joseph S (2017) The dynamic plasticity of insulin production in ?-cells. Mol Metab 6:958-973 |
| Wasserfall, Clive; Nick, Harry S; Campbell-Thompson, Martha et al. (2017) Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata. Cell Metab 26:568-575.e3 |
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| Boland, Brandon B; Alarcón, Cristina; Ali, Almas et al. (2015) Monomethylated-adenines potentiate glucose-induced insulin production and secretion via inhibition of phosphodiesterase activity in rat pancreatic islets. Islets 7:e1073435 |
| Rhodes, Christopher J; White, Morris F; Leahy, John L et al. (2013) Direct autocrine action of insulin on ?-cells: does it make physiological sense? Diabetes 62:2157-63 |
| Diaferia, Giuseppe R; Jimenez-Caliani, Antonio J; Ranjitkar, Prerana et al. (2013) ?1 integrin is a crucial regulator of pancreatic ?-cell expansion. Development 140:3360-72 |
| Guan, H; Chow, K M; Shah, R et al. (2012) Degradation of islet amyloid polypeptide by neprilysin. Diabetologia 55:2989-98 |
| Arvan, Peter; Pietropaolo, Massimo; Ostrov, David et al. (2012) Islet autoantigens: structure, function, localization, and regulation. Cold Spring Harb Perspect Med 2: |
| Alarcon, Cristina; Verchere, C Bruce; Rhodes, Christopher J (2012) Translational control of glucose-induced islet amyloid polypeptide production in pancreatic islets. Endocrinology 153:2082-7 |
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