Abstract
Translational control of protein synthesis in the pancreas is important in regulating growth and the synthesis of digestive enzymes. Regulation of translation is primarily directed at the steps in initiation and involves reversible phosphorylation of initiation factors (eIFs) and ribosomal proteins. Major sites include the assembly of the eIF4F mRNA cap binding complex, the activity of guanine nucleotide exchange factor eIF2B, and the activity of ribosomal S6 kinase. All of these involve phosphorylation by different regulatory pathways. Stimulation of protein synthesis in acinar cells is primarily mediated by the phosphatidylinositol 3-kinase-mTOR pathway and involves both release of eIF4E (the limiting component of eIF4F) from its binding protein and phosphorylation of ribosomal S6 protein by S6K. eIF4E is itself phosphorylated by a distinct pathway. Inhibition of acinar protein synthesis can be mediated by inhibition of eIF2B following phosphorylation of eIF2α.
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References
Pardee A. G1 events and regulation of cell proliferation. Science 1989;246:603–608.
Schmidt E. The role of c-myc in cellular growth control. Oncogene 1999;18:2988–2996.
Scheele G. Regulation of pancreatic gene expression in response to hormones and nutritional substrates, in: The Pancreas Biology, pathobiology and disease, Scheele G, ed., Raven Press Ltd., New York, NY, 1993; pp. 103–120.
Mathews M, Sonenberg N, Hershey JW. Origins and principles of translational control, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000; pp. 1–31.
Hershey JW, Merrick WC. Pathway and mechanism of initiation of protein synthesis, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000;33–88.
Proud CG, Denton RM. Molecular mechanisms for the control of translation by insulin. Biochem J 1997;328:329–341.
Merrick WC, Nyborg J. The protein biosynthesis elongation cycle, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000; pp. 89–125.
Kimball SR. Eukaryotic initiation factore eIF2. Int J Biochem Cell Biol 1999;31:25–29.
Raught B, Gingras A-C. eIF4E activity is regulated at multiple levels. Int J Biochem Cell Biol 1999;31:43–57.
Gingras A, Raught B, Sonenberg N. eIF4 Initiation Factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Ann Rev Biochem 1999;68:913–963.
Welsh G, Stokes C, Wang X, et al. Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3-kinase. FEBS Lett 1997;410:418–422.
Quevedo C, Alcazar A, Salinas M. Two different signal transduction pathways are implicated in the regulation of initiation factor 2B activity in insulin-like growth factor-1-stimulated neuronal cells. J Biol Chem 2000;275:19,192–19,197.
Kleijn M, Proud C. The activation of eukaryotic initiation factor (eIF)2B by growth factors in PC12 cells requires MEK/ERK signalling. FEBS Lett 2000;476:262–265.
Gilligan M, Welsh G, Flynn A, et al. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J Biol Chem 1996;271:2121–2125.
Wang X, Paulin FEM, Campbell LE, et al. Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo. EMBO J 2001;20:4349–4359.
Welsh G, Proud C. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 1993;294:625–629.
Pap M, Cooper G. Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol Cell Biol 2002;22:578–586.
Singh L, Denslow N, Wahba A. Modulation of rabbit reticulocyte guanine nucleotide exchange factor activity by casein kinases 1 and 2 and glycogen synthase kinase 3. Biochemistry 1996;35:3206–3212.
Kimball S, Jefferson L. Regulation of translational initiation in mammalian cells by amino acids, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000;pp. 561–579.
Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999;13:1211–1233.
Sudhakar A, Ramachandran A, Ghosh S, et al. Phosphorylation of serine 51 in initiation factor 2alpha (eIF2alpha) promotes complex formation between eIF2alpha(P) and eIF2B and causes inhibition in the guanine nucleotide exchange activity of eIF2B. Biochemistry 2000;39:12,929–12,938.
Chen J. Heme-regulated eIF2alpha kinase, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000;pp. 529–546.
Vattem K, Staschke K, Zhu S, et al. Inhibitory sequences in the N-terminus of the double-stranded-RNA-dependent protein kinase, PKR, are important for regulating phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Eur J Biochem 2001;268:1143–1153.
Shi Y, Vattem K, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor2 alphasubunit kinase, PEK, involved in translational control. Mol Cell Biol 1998;18:7499–7509.
Harding H, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999;397:271–274.
Lin T, Kong X, Saltiel A, et al. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J Biol Chem 1995;270:18,531–18,538.
Herbert TP, Kilhams GR, Batty IH, et al. Distinct signalling pathways mediate insulin and phorbol ester-stimulated eukaryotic initiation factor 4F assembly and protein synthesis in HEK 293 cells. J Biol Chem 2000;275:11,249–11,256.
McKendrick L, Morley SJ, Pain VW, et al. Phsophorylation of eukaryotic initiation factor 4E (eIF4E) at Ser 209 is not required for protein synthesis in vitro and in vivo. Eur J Biochem 2001;268:5375–5385.
Kimball SR, Jurasinski CV, Lawrence Jr. JC, et al. Insulin estimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G. Am J Physiol 1997;272:C754-C759.
Meyuhas O, Hornstein E. Translational control of TOP mRNAs, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000;pp. 671–693.
Jefferies H, Fumagalli S, Dennis P, et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J 1997;16:3693–3704.
Meyuhas O. Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem 2000;267:6321–6330.
Shima H, Pende M, Chen Y, et al. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 1998;17:6649–6659.
Burnett P, Barrow R, Cohen N, et al. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 1998;95:1432–1437.
Alessi D, Kozlowski M, Weng Q, et al. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol 1998;8:69–81.
Pullen N, Dennis P, Andjelkovich M, et al. Phosphorylation and activation of p70 s6k by PDK1. Science 1998;279:707–710.
Fumagallis S, Thomas G. S6 phosphorylation and signal transduction, in Translational Control of Gene Expression, Mathews M, ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000;pp. 695–717.
Ballou L, Luther H, Thomas G. MAP2 kinase and 70k S6 kinase lie on distinct signaling pathways. Nature 1991;349:348–350.
Burgering B, Coffer P. Protein kinase B (c-Akt) in phosphotidylinositol-3-OH kinase signal transduction. Nature 1995;376:599–602.
Girard-Globa A, Bourdel B, Lardeux B. Regulation of protein synthesis and enzyme accumulation in the rat pancreas by amount and timing of dietary protein. J Nutrition 1980;110:1380–1390.
Volkl A, Poort C. Circadian rhythm of protein synthesis activity in the exocrine pancreas of fed and starved rats. J Cell Sci 1983;61:467–473.
Sans M, Brunkan C, D’Alecy L, et al. Feeding and fasting affect protein synthesis in mouse pancreas by regulating translational effectors. Pancreas 2001;23: 458.
Korc M, Bailey A, Williams JA. Regulation of protein synthesis in normal and diabetic rat pancreas by cholecystokinin. Am J Physiol 1981;241:G116-G121.
Korc M, Iwamoto Y, Sankaran H, et al. Insulin action in pancreatic acini from streptozotocin-treated rats. I. Stimulation of protein synthesis. Am J Physiol 1981;240:G56-G62.
Okabayashi Y, Moessner J, Logsdon CD, et al. Insulin and other stimulants have nonparallel translational effects on protein synthesis. Diabetes 1987;36:1054–1060.
Matozaki T, Martinez J, Williams J. A new CCK analogue differentiates two functionally distinct CCK receptors in rat and mouse pancreatic acini. Am J Physiol 1989;4:G594-G600.
Perkins P, Pandol S. Cholecystokinin-induced changes in polysome structure regulate protein synthesis in pancreas. Biochim Biophys Acta 1992;1136:265–271.
Williams JA. Intracellular signaling mechanisms activated by cholecystokinin-regulating synthesis and secretion of digestive enzymes in pancreatic acinar cells. Annu Rev Physiol 2001;63:77–97.
Korc M. Regulation of pancreatic protein synthesis by cholecystokinin and calcium. Am J Physiol 1982;243:G69-G75.
Perkins P, Bahrami L, Lenhard L, et al. Intracellular mechanisms involved in short-term regulation of net protein synthesis in pancreatic acini. Biochim Biophys Acta 1991;1092:145–152.
Perkins P, Park J, Pandol S. The role of calcium in the regulation of protein synthesis in the exocrine pancreas. Pancreas 1997;14:133–141.
Sans M, Kimball S, Williams J. Effect of CCK and intracellular calcium to regulate eIF2B and protein synthesis in rat pancreatic acinar cells. Am J Physiol 2002;282:267–276.
Bargado M, Groblewski G, Williams J. Regulation of protein synthesis by cholecystokinin in rat pancreatic acini involves PHAS-I and the p70 S6 kinase pathway. Gastroenterology 1998;115:733–742.
Bragado MJ, Tashiro M, Williams JA. Regulation of the initiation of pancreatic digestive enzyme protein synthesis by cholecystokinin in rat pancreas in vivo. Gastroenterology 2000;119:1731–1739.
Sung CK, Williams JA. Cholecystokinin stimulates a specific ribosomal S6 kinase in rat pancreatic acini. Pancreas 1990;5:668–676.
Bragado MJ, Groblewski GE, Williams JA. p70s6k is activated by CCK in rat pancreatic acini. Am J Physiol 1997;273:C101-C109.
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Sans, M.D., Williams, J.A. Translational control of protein synthesis in pancreatic acinar cells. Int J Gastrointest Canc 31, 107–115 (2002). https://doi.org/10.1385/IJGC:31:1-3:107
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DOI: https://doi.org/10.1385/IJGC:31:1-3:107