Cooperativity between the Preproinsulin mRNA Untranslated Regions Is Necessary for Glucose-stimulated Translation

Glucose regulates proinsulin biosynthesis via stimulation of the translation of the preproinsulin mRNA in pancreatic β-cells. However, the mechanism by which this occurs has remained unclear. Using recombinant adenoviruses that express the preproinsulin mRNA with defined alterations, the untranslated regions (UTRs) of the preproinsulin mRNA were examined for elements that specifically control translation of the mRNA in rat pancreatic islets. These studies revealed that the preproinsulin 5′-UTR was necessary for glucose stimulation of preproinsulin mRNA translation, whereas the 3′-UTR appeared to suppress translation. However, together the 5′- and 3′-UTRs acted cooperatively to markedly increase glucose-induced proinsulin biosynthesis. In primary hepatocytes the presence of the preproinsulin 3′-UTR led to reduced mRNA levels compared with the presence of the SV40 3′-UTR, consistent with the presence of mRNA stability determinants in the 3′-UTR that stabilize the preproinsulin mRNA in a pancreatic β-cell-specific manner. Translation of these mRNAs in primary hepatocytes was not stimulated by glucose, indicating that regulated translation of the preproinsulin mRNA occurs in a pancreatic β-cell-specific manner. Thus, the untranslated regions of the preproinsulin mRNA play crucial roles in regulating insulin production and therefore glucose homeostasis by regulating the translation and the stability of the preproinsulin mRNA. Glucose regulates proinsulin biosynthesis via stimulation of the translation of the preproinsulin mRNA in pancreatic β-cells. However, the mechanism by which this occurs has remained unclear. Using recombinant adenoviruses that express the preproinsulin mRNA with defined alterations, the untranslated regions (UTRs) of the preproinsulin mRNA were examined for elements that specifically control translation of the mRNA in rat pancreatic islets. These studies revealed that the preproinsulin 5′-UTR was necessary for glucose stimulation of preproinsulin mRNA translation, whereas the 3′-UTR appeared to suppress translation. However, together the 5′- and 3′-UTRs acted cooperatively to markedly increase glucose-induced proinsulin biosynthesis. In primary hepatocytes the presence of the preproinsulin 3′-UTR led to reduced mRNA levels compared with the presence of the SV40 3′-UTR, consistent with the presence of mRNA stability determinants in the 3′-UTR that stabilize the preproinsulin mRNA in a pancreatic β-cell-specific manner. Translation of these mRNAs in primary hepatocytes was not stimulated by glucose, indicating that regulated translation of the preproinsulin mRNA occurs in a pancreatic β-cell-specific manner. Thus, the untranslated regions of the preproinsulin mRNA play crucial roles in regulating insulin production and therefore glucose homeostasis by regulating the translation and the stability of the preproinsulin mRNA. signal recognition particle eukaryotic (translation) initiation factor untranslated regions 6 Histidine-tagged proinsulin cytomegalovirus glyceraldehyde 3-phosphate dehydrogenase prohormone convertase base pair(s) polymerase chain reaction N- 2-hydroxy-1,1-bis(hydroxymethyl)ethylglycine Pancreatic islet β-cells secrete insulin in response to increases in circulating nutrients, the most physiologically relevant of which is glucose (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar). To replenish secreted insulin and maintain optimal intracellular insulin stores there is a corresponding rapid and specific stimulation of proinsulin biosynthesis (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar, 2Dodson G. Steiner D. Curr. Opin. Struct. Biol. 1998; 8: 189-194Crossref PubMed Scopus (434) Google Scholar, 3Goodge K.A. Hutton J.C. Semin. Cell Dev. Biol. 2000; 11: 235-242Crossref PubMed Scopus (100) Google Scholar). Under normal circumstances this occurs by increasing translation of the existing preproinsulin mRNA and is mostly controlled at the initiation phase of the translational mechanism. Preproinsulin mRNA is mobilized from an inert intracellular storage pool (in which most of the mRNA is free) to membrane-bound polyribosomes, marking the entry of newly synthesized proinsulin into the β-cell secretory pathway (4Itoh N. Okamoto H. Nature. 1980; 283: 100-102Crossref PubMed Scopus (227) Google Scholar, 5Welsh M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar). Translation of the preproinsulin mRNA is targeted to the endoplasmic reticulum through an interaction between its signal peptide and the signal recognition particle (SRP).1 It has been reported that SRP-mediated translocation of secretory pathway mRNAs to the endoplasmic reticulum is glucose-regulated in pancreatic β-cells (6Welsh N. Oberg C. Welsh M. Biochem. J. 1991; 275: 23-28Crossref PubMed Scopus (6) Google Scholar,7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar).Glucose stimulates general protein synthesis in the β-cell approximately 2-fold (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar, 8Grimaldi K.A. Siddle K. Hutton J.C. Biochem. J. 1991; 245: 567-573Crossref Scopus (22) Google Scholar, 9Alarcon C. Lincoln B. Rhodes C.J. J. Biol. Chem. 1993; 268: 4276-4280Abstract Full Text PDF PubMed Google Scholar). This occurs through an increase in the activity of the general translation machinery, largely through protein phosphorylation regulation of eukaryotic initiation factor (eIF) activity (10Rhoads R.E. J. Biol. Chem. 1999; 274: 30337-30340Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). In β-cells, glucose stimulation of general translation has been shown to occur through the regulation of the activity of two basal translation factors, eIF-2B and PHAS-1/eIF-4E-BP (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Xu G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). However, glucose-stimulated proinsulin biosynthesis can increase in a specific control mechanism the general of glucose protein in this that specific translational regulation of preproinsulin mRNA the translational regulation of mRNAs can elements untranslated regions the translation of the mRNA is regulated by intracellular levels through an in the 5′-UTR T.A. N. of an response that a This mRNA translation in response to through an interaction with a response elements in chain mRNAs from the preproinsulin mRNA has of the rat preproinsulin mRNA the presence of a in the 5′-UTR that to in the 5′-UTR of preproinsulin mRNAs Docherty K. J. 8: Scholar, C. Rhodes C.J. and in and R. G. Scholar). of preproinsulin mRNA the presence of a the 3′-UTR that between the signal and the the 3′-UTR of mRNAs been shown to necessary for the regulation of mRNA translation, and stability C.J. R. Curr. Opin. Cell Biol. PubMed Scopus Google Scholar). These consistent with a for the untranslated regions of the preproinsulin mRNA in regulating its specific translation in response to glucose, which has been in this mRNA was of the mRNAs to specifically regulated at the translational (4Itoh N. Okamoto H. Nature. 1980; 283: 100-102Crossref PubMed Scopus (227) Google Scholar). However, the the mechanism of this regulation has remained of glucose protein synthesis in pancreatic islet β-cells, which in a of increasing proinsulin Glucose stimulates increases in general protein synthesis in pancreatic islet β-cells, most by the phosphorylation of general translation initiation (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Xu G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). there is an general control mechanism to newly synthesized for the β-cell secretory via the signal most through the signal interaction and of SRP-mediated of translation M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, C. Steiner D.F. A. 2000; PubMed Scopus (144) Google Scholar). of these general to the of proinsulin synthesis and not for the specific of glucose-induced preproinsulin mRNA this a recombinant of a proinsulin in rat revealed that the specific translational regulation of proinsulin biosynthesis by glucose was largely elements that in the untranslated regions of preproinsulin mRNA. 5′-UTR of preproinsulin mRNA an most in a Docherty K. J. 8: Scholar, C. Rhodes C.J. and in and R. G. that was necessary for the specific stimulation of proinsulin biosynthesis translation in response to 3′-UTR of preproinsulin mRNA an most the that a to suppress glucose-induced proinsulin biosynthesis to stabilize the preproinsulin mRNA in a pancreatic islet β-cell-specific manner. the 5′- and 3′-UTRs of preproinsulin mRNA acted to markedly the proinsulin biosynthesis translation in a of the proinsulin of a between the 5′- and 3′-UTRs of preproinsulin mRNA for translational control of proinsulin biosynthesis with the basal translational that an interaction between the and the A. N. of Scholar). the in this a for the translation of the preproinsulin in there two is an of glucose the β-cell translational machinery, mostly at the initiation phase (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google in an increase in protein is at a signal interaction M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, N. Oberg C. Welsh M. Biochem. J. 1991; 275: 23-28Crossref PubMed Scopus (6) Google Scholar, P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google which is to an in biosynthesis of for the pancreatic β-cell secretory of which proinsulin is However, the specific translational control of proinsulin biosynthesis by glucose is via the of preproinsulin mRNA. the glucose glucose, the 5′-UTR a increase in translation of preproinsulin and there is an of preproinsulin mRNA translation at the 3′-UTR, via an interaction with the in the 3′-UTR specifically increase preproinsulin mRNA stability in β-cells, which proinsulin biosynthesis at the translational by the of preproinsulin mRNA Thus, there for specific regulation of preproinsulin mRNA translation for the control of proinsulin biosynthesis by glucose in pancreatic islet β-cells. It is that elements the 5′- and 3′-UTRs of preproinsulin mRNA with factors, to in glucose-regulated proinsulin biosynthesis translation preproinsulin mRNA factors, to specific to the pancreatic the preproinsulin mRNA not specific glucose-regulated translation of the preproinsulin mRNA in glucose is for glucose-induced proinsulin biosynthesis (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google that with the elements in the 5′- and 3′-UTRs of the preproinsulin mRNA in a that to that from glucose and that these preproinsulin mRNA translation. to β-cell-specific preproinsulin for the translational regulation of the preproinsulin mRNA in response to Translation of the preproinsulin mRNA is regulated by glucose through general translational and secretory and by specific that in the 5′- and to the the signal peptide by the preproinsulin untranslated regions of preproinsulin mRNAs that necessary for the regulation of proinsulin translation. studies shown that the translation of in β-cells is stimulated in response to glucose (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). a in the 5′-UTR of the mRNA two of these the prohormone and revealed a to that to in the 5′-UTR of the preproinsulin mRNA. It is that this is in glucose-induced translational regulation of and biosynthesis in β-cells to that of proinsulin C. Lincoln B. Rhodes C.J. J. Biol. Chem. 1993; 268: 4276-4280Abstract Full Text PDF PubMed Google Scholar, H. Rhodes C.J. 1996; PubMed Google Scholar, R. M. Steiner D.F. PubMed Scopus Google Scholar). However, and mRNAs the in the 3′-UTR that translational response to glucose C. Rhodes C.J. and in and R. G. a mRNA to preproinsulin mRNA Rhodes C.J. Biochem. J. Scopus Google Scholar). is that of the mechanism for glucose-induced translation control of proinsulin biosynthesis in this to the biosynthesis of for the insulin secretory that proinsulin and regulated (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). the that translational regulation of proinsulin biosynthesis to crucial in of β-cell and this is the control of insulin production in normal (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar, 2Dodson G. Steiner D. Curr. Opin. Struct. Biol. 1998; 8: 189-194Crossref PubMed Scopus (434) Google Scholar, 3Goodge K.A. Hutton J.C. Semin. Cell Dev. Biol. 2000; 11: 235-242Crossref PubMed Scopus (100) Google Scholar, K. A. J. 8: PubMed Scopus Google Scholar). there is of proinsulin biosynthesis in an of which to β-cell and of insulin C. Rhodes C.J. J. PubMed Scopus Google Scholar). is that the translational control mechanism for glucose-stimulated proinsulin biosynthesis in pancreatic β-cells a for regulating production of the in that a primary and in secretory that by of the in response to an regulation of mRNA of a by the a to and replenish intracellular stores by and maintain at optimal secretory of the Pancreatic islet β-cells secrete insulin in response to increases in circulating nutrients, the most physiologically relevant of which is glucose (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar). To replenish secreted insulin and maintain optimal intracellular insulin stores there is a corresponding rapid and specific stimulation of proinsulin biosynthesis (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar, 2Dodson G. Steiner D. Curr. Opin. Struct. Biol. 1998; 8: 189-194Crossref PubMed Scopus (434) Google Scholar, 3Goodge K.A. Hutton J.C. Semin. Cell Dev. Biol. 2000; 11: 235-242Crossref PubMed Scopus (100) Google Scholar). Under normal circumstances this occurs by increasing translation of the existing preproinsulin mRNA and is mostly controlled at the initiation phase of the translational mechanism. Preproinsulin mRNA is mobilized from an inert intracellular storage pool (in which most of the mRNA is free) to membrane-bound polyribosomes, marking the entry of newly synthesized proinsulin into the β-cell secretory pathway (4Itoh N. Okamoto H. Nature. 1980; 283: 100-102Crossref PubMed Scopus (227) Google Scholar, 5Welsh M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar). Translation of the preproinsulin mRNA is targeted to the endoplasmic reticulum through an interaction between its signal peptide and the signal recognition particle (SRP).1 It has been reported that SRP-mediated translocation of secretory pathway mRNAs to the endoplasmic reticulum is glucose-regulated in pancreatic β-cells (6Welsh N. Oberg C. Welsh M. Biochem. J. 1991; 275: 23-28Crossref PubMed Scopus (6) Google Scholar,7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). Glucose stimulates general protein synthesis in the β-cell approximately 2-fold (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar, 8Grimaldi K.A. Siddle K. Hutton J.C. Biochem. J. 1991; 245: 567-573Crossref Scopus (22) Google Scholar, 9Alarcon C. Lincoln B. Rhodes C.J. J. Biol. Chem. 1993; 268: 4276-4280Abstract Full Text PDF PubMed Google Scholar). This occurs through an increase in the activity of the general translation machinery, largely through protein phosphorylation regulation of eukaryotic initiation factor (eIF) activity (10Rhoads R.E. J. Biol. Chem. 1999; 274: 30337-30340Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). In β-cells, glucose stimulation of general translation has been shown to occur through the regulation of the activity of two basal translation factors, eIF-2B and PHAS-1/eIF-4E-BP (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Xu G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). However, glucose-stimulated proinsulin biosynthesis can increase in a specific control mechanism the general of glucose protein in this that specific translational regulation of preproinsulin mRNA the translational regulation of mRNAs can elements untranslated regions the translation of the mRNA is regulated by intracellular levels through an in the 5′-UTR T.A. N. of an response that a This mRNA translation in response to through an interaction with a response elements in chain mRNAs from the preproinsulin mRNA has of the rat preproinsulin mRNA the presence of a in the 5′-UTR that to in the 5′-UTR of preproinsulin mRNAs Docherty K. J. 8: Scholar, C. Rhodes C.J. and in and R. G. Scholar). of preproinsulin mRNA the presence of a the 3′-UTR that between the signal and the the 3′-UTR of mRNAs been shown to necessary for the regulation of mRNA translation, and stability C.J. R. Curr. Opin. Cell Biol. PubMed Scopus Google Scholar). These consistent with a for the untranslated regions of the preproinsulin mRNA in regulating its specific translation in response to glucose, which has been in this mRNA was of the mRNAs to specifically regulated at the translational (4Itoh N. Okamoto H. Nature. 1980; 283: 100-102Crossref PubMed Scopus (227) Google Scholar). However, the the mechanism of this regulation has remained of glucose protein synthesis in pancreatic islet β-cells, which in a of increasing proinsulin Glucose stimulates increases in general protein synthesis in pancreatic islet β-cells, most by the phosphorylation of general translation initiation (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Xu G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). there is an general control mechanism to newly synthesized for the β-cell secretory via the signal most through the signal interaction and of SRP-mediated of translation M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, C. Steiner D.F. A. 2000; PubMed Scopus (144) Google Scholar). of these general to the of proinsulin synthesis and not for the specific of glucose-induced preproinsulin mRNA this a recombinant of a proinsulin in rat revealed that the specific translational regulation of proinsulin biosynthesis by glucose was largely elements that in the untranslated regions of preproinsulin mRNA. 5′-UTR of preproinsulin mRNA an most in a Docherty K. J. 8: Scholar, C. Rhodes C.J. and in and R. G. that was necessary for the specific stimulation of proinsulin biosynthesis translation in response to 3′-UTR of preproinsulin mRNA an most the that a to suppress glucose-induced proinsulin biosynthesis to stabilize the preproinsulin mRNA in a pancreatic islet β-cell-specific manner. the 5′- and 3′-UTRs of preproinsulin mRNA acted to markedly the proinsulin biosynthesis translation in a of the proinsulin of a between the 5′- and 3′-UTRs of preproinsulin mRNA for translational control of proinsulin biosynthesis with the basal translational that an interaction between the and the A. N. of Scholar). the in this a for the translation of the preproinsulin in there two is an of glucose the β-cell translational machinery, mostly at the initiation phase (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google in an increase in protein is at a signal interaction M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, N. Oberg C. Welsh M. Biochem. J. 1991; 275: 23-28Crossref PubMed Scopus (6) Google Scholar, P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google which is to an in biosynthesis of for the pancreatic β-cell secretory of which proinsulin is However, the specific translational control of proinsulin biosynthesis by glucose is via the of preproinsulin mRNA. the glucose glucose, the 5′-UTR a increase in translation of preproinsulin and there is an of preproinsulin mRNA translation at the 3′-UTR, via an interaction with the in the 3′-UTR specifically increase preproinsulin mRNA stability in β-cells, which proinsulin biosynthesis at the translational by the of preproinsulin mRNA Thus, there for specific regulation of preproinsulin mRNA translation for the control of proinsulin biosynthesis by glucose in pancreatic islet β-cells. It is that elements the 5′- and 3′-UTRs of preproinsulin mRNA with factors, to in glucose-regulated proinsulin biosynthesis translation preproinsulin mRNA factors, to specific to the pancreatic the preproinsulin mRNA not specific glucose-regulated translation of the preproinsulin mRNA in glucose is for glucose-induced proinsulin biosynthesis (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google that with the elements in the 5′- and 3′-UTRs of the preproinsulin mRNA in a that to that from glucose and that these preproinsulin mRNA translation. to β-cell-specific preproinsulin untranslated regions of preproinsulin mRNAs that necessary for the regulation of proinsulin translation. studies shown that the translation of in β-cells is stimulated in response to glucose (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). a in the 5′-UTR of the mRNA two of these the prohormone and revealed a to that to in the 5′-UTR of the preproinsulin mRNA. It is that this is in glucose-induced translational regulation of and biosynthesis in β-cells to that of proinsulin C. Lincoln B. Rhodes C.J. J. Biol. Chem. 1993; 268: 4276-4280Abstract Full Text PDF PubMed Google Scholar, H. Rhodes C.J. 1996; PubMed Google Scholar, R. M. Steiner D.F. PubMed Scopus Google Scholar). However, and mRNAs the in the 3′-UTR that translational response to glucose C. Rhodes C.J. and in and R. G. a mRNA to preproinsulin mRNA Rhodes C.J. Biochem. J. Scopus Google Scholar). is that of the mechanism for glucose-induced translation control of proinsulin biosynthesis in this to the biosynthesis of for the insulin secretory that proinsulin and regulated (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). the that translational regulation of proinsulin biosynthesis to crucial in of β-cell and this is the control of insulin production in normal (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar, 2Dodson G. Steiner D. Curr. Opin. Struct. Biol. 1998; 8: 189-194Crossref PubMed Scopus (434) Google Scholar, 3Goodge K.A. Hutton J.C. Semin. Cell Dev. Biol. 2000; 11: 235-242Crossref PubMed Scopus (100) Google Scholar, K. A. J. 8: PubMed Scopus Google Scholar). there is of proinsulin biosynthesis in an of which to β-cell and of insulin C. Rhodes C.J. J. PubMed Scopus Google Scholar). is that the translational control mechanism for glucose-stimulated proinsulin biosynthesis in pancreatic β-cells a for regulating production of the in that a primary and in secretory that by of the in response to an regulation of mRNA of a by the a to and replenish intracellular stores by and maintain at optimal secretory of the Preproinsulin mRNA was of the mRNAs to specifically regulated at the translational (4Itoh N. Okamoto H. Nature. 1980; 283: 100-102Crossref PubMed Scopus (227) Google Scholar). However, the the mechanism of this regulation has remained of glucose protein synthesis in pancreatic islet β-cells, which in a of increasing proinsulin Glucose stimulates increases in general protein synthesis in pancreatic islet β-cells, most by the phosphorylation of general translation initiation (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Xu G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). there is an general control mechanism to newly synthesized for the β-cell secretory via the signal most through the signal interaction and of SRP-mediated of translation M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, C. Steiner D.F. A. 2000; PubMed Scopus (144) Google Scholar). of these general to the of proinsulin synthesis and not for the specific of glucose-induced preproinsulin mRNA translation. In this a recombinant of a proinsulin in rat revealed that the specific translational regulation of proinsulin biosynthesis by glucose was largely elements that in the untranslated regions of preproinsulin mRNA. 5′-UTR of preproinsulin mRNA an most in a Docherty K. J. 8: Scholar, C. Rhodes C.J. and in and R. G. that was necessary for the specific stimulation of proinsulin biosynthesis translation in response to 3′-UTR of preproinsulin mRNA an most the that a to suppress glucose-induced proinsulin biosynthesis to stabilize the preproinsulin mRNA in a pancreatic islet β-cell-specific manner. the 5′- and 3′-UTRs of preproinsulin mRNA acted to markedly the proinsulin biosynthesis translation in a of the proinsulin of a between the 5′- and 3′-UTRs of preproinsulin mRNA for translational control of proinsulin biosynthesis with the basal translational that an interaction between the and the A. N. of Scholar). the in this a for the translation of the preproinsulin in there two is an of glucose the β-cell translational machinery, mostly at the initiation phase (11Gilligan M. Welsh G.I. Flynn A. Bujalska I. Diggle T.A. Denton R.M. Proud C.G. Docherty K. J. Biol. Chem. 1996; 271: 2121-2125Abstract Full Text Full Text PDF PubMed Scopus (50) Google G. Marshall A. Lin T.-A. Kwon G. Munivenkatappa R.B. Hill J.R. Lawrence J.C. McDaniel M.L J. Biol. Chem. 1998; 273: 4485-4491Abstract Full Text Full Text PDF PubMed Scopus (92) Google in an increase in protein is at a signal interaction M. Scherberg N. Gilmore R. Steiner D.F. Biochem. J. 1986; 235: 454-467Crossref Scopus (144) Google Scholar, N. Oberg C. Welsh M. Biochem. J. 1991; 275: 23-28Crossref PubMed Scopus (6) Google Scholar, P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google which is to an in biosynthesis of for the pancreatic β-cell secretory of which proinsulin is However, the specific translational control of proinsulin biosynthesis by glucose is via the of preproinsulin mRNA. the glucose glucose, the 5′-UTR a increase in translation of preproinsulin and there is an of preproinsulin mRNA translation at the 3′-UTR, via an interaction with the in the 3′-UTR specifically increase preproinsulin mRNA stability in β-cells, which proinsulin biosynthesis at the translational by the of preproinsulin mRNA Thus, there for specific regulation of preproinsulin mRNA translation for the control of proinsulin biosynthesis by glucose in pancreatic islet β-cells. It is that elements the 5′- and 3′-UTRs of preproinsulin mRNA with factors, to in glucose-regulated proinsulin biosynthesis translation preproinsulin mRNA factors, to specific to the pancreatic the preproinsulin mRNA not specific glucose-regulated translation of the preproinsulin mRNA in glucose is for glucose-induced proinsulin biosynthesis (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google that with the elements in the 5′- and 3′-UTRs of the preproinsulin mRNA in a that to that from glucose and that these preproinsulin mRNA translation. to β-cell-specific preproinsulin untranslated regions of preproinsulin mRNAs that necessary for the regulation of proinsulin translation. studies shown that the translation of in β-cells is stimulated in response to glucose (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). a in the 5′-UTR of the mRNA two of these the prohormone and revealed a to that to in the 5′-UTR of the preproinsulin mRNA. It is that this is in glucose-induced translational regulation of and biosynthesis in β-cells to that of proinsulin C. Lincoln B. Rhodes C.J. J. Biol. Chem. 1993; 268: 4276-4280Abstract Full Text PDF PubMed Google Scholar, H. Rhodes C.J. 1996; PubMed Google Scholar, R. M. Steiner D.F. PubMed Scopus Google Scholar). However, and mRNAs the in the 3′-UTR that translational response to glucose C. Rhodes C.J. and in and R. G. a mRNA to preproinsulin mRNA Rhodes C.J. Biochem. J. Scopus Google Scholar). is that of the mechanism for glucose-induced translation control of proinsulin biosynthesis in this to the biosynthesis of for the insulin secretory that proinsulin and regulated (7Guest P.C. Bailyes E.M. Rutherford N.G. Hutton J.C. Biochem. J. 1991; 274: 73-78Crossref PubMed Scopus (65) Google Scholar). the that translational regulation of proinsulin biosynthesis to crucial in of β-cell and this is the control of insulin production in normal (1Rhodes C.J. LeRoith D. Taylor S.I. Olefsky J.M. Diabetes Mellitus. Lippincott Williams and Wilkins, Philidelphia, PA2000: 20-37Google Scholar, 2Dodson G. Steiner D. Curr. Opin. Struct. Biol. 1998; 8: 189-194Crossref PubMed Scopus (434) Google Scholar, 3Goodge K.A. Hutton J.C. Semin. Cell Dev. Biol. 2000; 11: 235-242Crossref PubMed Scopus (100) Google Scholar, K. A. J. 8: PubMed Scopus Google Scholar). there is of proinsulin biosynthesis in an of which to β-cell and of insulin C. Rhodes C.J. J. PubMed Scopus Google Scholar). is that the translational control mechanism for glucose-stimulated proinsulin biosynthesis in pancreatic β-cells a for regulating production of the in that a primary and in secretory that by of the in response to an regulation of mRNA of a by the a to and replenish intracellular stores by and maintain at optimal secretory of the Docherty for