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Molecular mechanisms for the control of translation by insulin.
Abstract
Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5'-untranslated regions (5'-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5'-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.
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Selected References
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- O'Brien RM, Granner DK. Regulation of gene expression by insulin. Physiol Rev. 1996 Oct;76(4):1109–1161. [PubMed] [Google Scholar]
- Hammond ML, Bowman LH. Insulin stimulates the translation of ribosomal proteins and the transcription of rDNA in mouse myoblasts. J Biol Chem. 1988 Nov 25;263(33):17785–17791. [PubMed] [Google Scholar]
- Rosenwald IB, Lazaris-Karatzas A, Sonenberg N, Schmidt EV. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol. 1993 Dec;13(12):7358–7363. [PMC free article] [PubMed] [Google Scholar]
- Wilson SB, Back DW, Morris SM, Jr, Swierczynski J, Goodridge AG. Hormonal regulation of lipogenic enzymes in chick embryo hepatocytes in culture. Expression of the fatty acid synthase gene is regulated at both translational and pretranslational steps. J Biol Chem. 1986 Nov 15;261(32):15179–15182. [PubMed] [Google Scholar]
- Manzella JM, Rychlik W, Rhoads RE, Hershey JW, Blackshear PJ. Insulin induction of ornithine decarboxylase. Importance of mRNA secondary structure and phosphorylation of eucaryotic initiation factors eIF-4B and eIF-4E. J Biol Chem. 1991 Feb 5;266(4):2383–2389. [PubMed] [Google Scholar]
- White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994 Jan 7;269(1):1–4. [PubMed] [Google Scholar]
- Tavaré JM, Siddle K. Mutational analysis of insulin receptor function: consensus and controversy. Biochim Biophys Acta. 1993 Jul 28;1178(1):21–39. [PubMed] [Google Scholar]
- Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG, Jr, Glasheen E, Lane WS, Pierce JH, White MF. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173–177. [PubMed] [Google Scholar]
- Pronk GJ, de Vries-Smits AM, Buday L, Downward J, Maassen JA, Medema RH, Bos JL. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras. Mol Cell Biol. 1994 Mar;14(3):1575–1581. [PMC free article] [PubMed] [Google Scholar]
- Bonfini L, Migliaccio E, Pelicci G, Lanfrancone L, Pelicci PG. Not all Shc's roads lead to Ras. Trends Biochem Sci. 1996 Jul;21(7):257–261. [PubMed] [Google Scholar]
- Hosomi Y, Shii K, Ogawa W, Matsuba H, Yoshida M, Okada Y, Yokono K, Kasuga M, Baba S, Roth RA. Characterization of a 60-kilodalton substrate of the insulin receptor kinase. J Biol Chem. 1994 Apr 15;269(15):11498–11502. [PubMed] [Google Scholar]
- Denton RM, Tavaré JM. Does mitogen-activated-protein kinase have a role in insulin action? The cases for and against. Eur J Biochem. 1995 Feb 1;227(3):597–611. [PubMed] [Google Scholar]
- Porras A, Muszynski K, Rapp UR, Santos E. Dissociation between activation of Raf-1 kinase and the 42-kDa mitogen-activated protein kinase/90-kDa S6 kinase (MAPK/RSK) cascade in the insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells. J Biol Chem. 1994 Apr 29;269(17):12741–12748. [PubMed] [Google Scholar]
- White MF. The IRS-signalling system in insulin and cytokine action. Philos Trans R Soc Lond B Biol Sci. 1996 Feb 29;351(1336):181–189. [PubMed] [Google Scholar]
- Fry MJ. Structure, regulation and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1994 Jul 18;1226(3):237–268. [PubMed] [Google Scholar]
- Kohn AD, Kovacina KS, Roth RA. Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J. 1995 Sep 1;14(17):4288–4295. [PMC free article] [PubMed] [Google Scholar]
- Ming XF, Burgering BM, Wennström S, Claesson-Welsh L, Heldin CH, Bos JL, Kozma SC, Thomas G. Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature. 1994 Sep 29;371(6496):426–429. [PubMed] [Google Scholar]
- Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. [PubMed] [Google Scholar]
- Bos JL. A target for phosphoinositide 3-kinase: Akt/PKB. Trends Biochem Sci. 1995 Nov;20(11):441–442. [PubMed] [Google Scholar]
- Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem. 1996 Sep 6;271(36):21920–21926. [PubMed] [Google Scholar]
- Hemmings BA. Akt signaling: linking membrane events to life and death decisions. Science. 1997 Jan 31;275(5300):628–630. [PubMed] [Google Scholar]
- Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997 Jan 31;275(5300):665–668. [PubMed] [Google Scholar]
- James SR, Downes CP, Gigg R, Grove SJ, Holmes AB, Alessi DR. Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J. 1996 May 1;315(Pt 3):709–713. [PMC free article] [PubMed] [Google Scholar]
- Frech M, Andjelkovic M, Ingley E, Reddy KK, Falck JR, Hemmings BA. High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity. J Biol Chem. 1997 Mar 28;272(13):8474–8481. [PubMed] [Google Scholar]
- Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567–570. [PubMed] [Google Scholar]
- Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996 Dec 2;15(23):6541–6551. [PMC free article] [PubMed] [Google Scholar]
- Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261–269. [PubMed] [Google Scholar]
- Weng QP, Andrabi K, Klippel A, Kozlowski MT, Williams LT, Avruch J. Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5744–5748. [PMC free article] [PubMed] [Google Scholar]
- Dennis PB, Pullen N, Kozma SC, Thomas G. The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol Cell Biol. 1996 Nov;16(11):6242–6251. [PMC free article] [PubMed] [Google Scholar]
- Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995 Aug 17;376(6541):599–602. [PubMed] [Google Scholar]
- Yano H, Nakanishi S, Kimura K, Hanai N, Saitoh Y, Fukui Y, Nonomura Y, Matsuda Y. Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. J Biol Chem. 1993 Dec 5;268(34):25846–25856. [PubMed] [Google Scholar]
- Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem. 1994 Feb 4;269(5):3568–3573. [PubMed] [Google Scholar]
- Mollinedo F, Gajate C, Flores I. Involvement of phospholipase D in the activation of transcription factor AP-1 in human T lymphoid Jurkat cells. J Immunol. 1994 Sep 15;153(6):2457–2469. [PubMed] [Google Scholar]
- Cross MJ, Stewart A, Hodgkin MN, Kerr DJ, Wakelam MJ. Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. Wortmannin is not a specific inhibitor of phosphatidylinositol 3-kinase. J Biol Chem. 1995 Oct 27;270(43):25352–25355. [PubMed] [Google Scholar]
- Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC, Jr, Abraham RT. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 1996 Oct 1;15(19):5256–5267. [PMC free article] [PubMed] [Google Scholar]
- Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994 Jul;14(7):4902–4911. [PMC free article] [PubMed] [Google Scholar]
- Welsh GI, Foulstone EJ, Young SW, Tavaré JM, Proud CG. Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase. Biochem J. 1994 Oct 1;303(Pt 1):15–20. [PMC free article] [PubMed] [Google Scholar]
- Moule SK, Edgell NJ, Welsh GI, Diggle TA, Foulstone EJ, Heesom KJ, Proud CG, Denton RM. Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells. Biochem J. 1995 Oct 15;311(Pt 2):595–601. [PMC free article] [PubMed] [Google Scholar]
- Cross DA, Alessi DR, Vandenheede JR, McDowell HE, Hundal HS, Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J. 1994 Oct 1;303(Pt 1):21–26. [PMC free article] [PubMed] [Google Scholar]
- Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. [PubMed] [Google Scholar]
- Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. [PMC free article] [PubMed] [Google Scholar]
- Flynn A, Proud G. Insulin-stimulated phosphorylation of initiation factor 4E is mediated by the MAP kinase pathway. FEBS Lett. 1996 Jul 1;389(2):162–166. [PubMed] [Google Scholar]
- Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol. 1996;14:483–510. [PubMed] [Google Scholar]
- Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995 Oct 5;377(6548):441–446. [PubMed] [Google Scholar]
- Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12574–12578. [PMC free article] [PubMed] [Google Scholar]
- Sabatini DM, Pierchala BA, Barrow RK, Schell MJ, Snyder SH. The rapamycin and FKBP12 target (RAFT) displays phosphatidylinositol 4-kinase activity. J Biol Chem. 1995 Sep 8;270(36):20875–20878. [PubMed] [Google Scholar]
- Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995 Jan 13;270(2):815–822. [PubMed] [Google Scholar]
- Abraham RT. Phosphatidylinositol 3-kinase related kinases. Curr Opin Immunol. 1996 Jun;8(3):412–418. [PubMed] [Google Scholar]
- Zheng XF, Schreiber SL. Target of rapamycin proteins and their kinase activities are required for meiosis. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3070–3075. [PMC free article] [PubMed] [Google Scholar]
- Pain VM. Initiation of protein synthesis in eukaryotic cells. Eur J Biochem. 1996 Mar 15;236(3):747–771. [PubMed] [Google Scholar]
- Proud CG. Peptide-chain elongation in eukaryotes. Mol Biol Rep. 1994 May;19(3):161–170. [PubMed] [Google Scholar]
- Stansfield I, Jones KM, Tuite MF. The end in sight: terminating translation in eukaryotes. Trends Biochem Sci. 1995 Dec;20(12):489–491. [PubMed] [Google Scholar]
- Merrick WC. Mechanism and regulation of eukaryotic protein synthesis. Microbiol Rev. 1992 Jun;56(2):291–315. [PMC free article] [PubMed] [Google Scholar]
- Chaudhuri J, Si K, Maitra U. Function of eukaryotic translation initiation factor 1A (eIF1A) (formerly called eIF-4C) in initiation of protein synthesis. J Biol Chem. 1997 Mar 21;272(12):7883–7891. [PubMed] [Google Scholar]
- Rhoads RE, Joshi B, Minich WB. Participation of initiation factors in the recruitment of mRNA to ribosomes. Biochimie. 1994;76(9):831–838. [PubMed] [Google Scholar]
- Price N, Proud C. The guanine nucleotide-exchange factor, eIF-2B. Biochimie. 1994;76(8):748–760. [PubMed] [Google Scholar]
- Flynn A, Oldfield S, Proud CG. The role of the beta-subunit of initiation factor eIF-2 in initiation complex formation. Biochim Biophys Acta. 1993 Jul 18;1174(1):117–121. [PubMed] [Google Scholar]
- Gaspar NJ, Kinzy TG, Scherer BJ, Hümbelin M, Hershey JW, Merrick WC. Translation initiation factor eIF-2. Cloning and expression of the human cDNA encoding the gamma-subunit. J Biol Chem. 1994 Feb 4;269(5):3415–3422. [PubMed] [Google Scholar]
- Kimball SR, Vary TC, Jefferson LS. Regulation of protein synthesis by insulin. Annu Rev Physiol. 1994;56:321–348. [PubMed] [Google Scholar]
- Kimball SR, Jefferson LS. Effect of diabetes on guanine nucleotide exchange factor activity in skeletal muscle and heart. Biochem Biophys Res Commun. 1988 Oct 31;156(2):706–711. [PubMed] [Google Scholar]
- Jeffrey IW, Kelly FJ, Duncan R, Hershey JW, Pain VM. Effect of starvation and diabetes on the activity of the eukaryotic initiation factor eIF-2 in rat skeletal muscle. Biochimie. 1990 Oct;72(10):751–757. [PubMed] [Google Scholar]
- Karinch AM, Kimball SR, Vary TC, Jefferson LS. Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. Am J Physiol. 1993 Jan;264(1 Pt 1):E101–E108. [PubMed] [Google Scholar]
- Welsh GI, Proud CG. Regulation of protein synthesis in Swiss 3T3 fibroblasts. Rapid activation of the guanine-nucleotide-exchange factor by insulin and growth factors. Biochem J. 1992 May 15;284(Pt 1):19–23. [PMC free article] [PubMed] [Google Scholar]
- Proud CG. PKR: a new name and new roles. Trends Biochem Sci. 1995 Jun;20(6):241–246. [PubMed] [Google Scholar]
- Chen JJ, London IM. Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Trends Biochem Sci. 1995 Mar;20(3):105–108. [PubMed] [Google Scholar]
- Rowlands AG, Panniers R, Henshaw EC. The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2. J Biol Chem. 1988 Apr 25;263(12):5526–5533. [PubMed] [Google Scholar]
- Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294(Pt 3):625–629. [PMC free article] [PubMed] [Google Scholar]
- Hughes K, Ramakrishna S, Benjamin WB, Woodgett JR. Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. Biochem J. 1992 Nov 15;288(Pt 1):309–314. [PMC free article] [PubMed] [Google Scholar]
- Borthwick AC, Wells AM, Rochford JJ, Hurel SJ, Turnbull DM, Yeaman SJ. Inhibition of glycogen synthase kinase-3 by insulin in cultured human skeletal muscle myoblasts. Biochem Biophys Res Commun. 1995 May 25;210(3):738–745. [PubMed] [Google Scholar]
- Moule SK, Welsh GI, Edgell NJ, Foulstone EJ, Proud CG, Denton RM. Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J Biol Chem. 1997 Mar 21;272(12):7713–7719. [PubMed] [Google Scholar]
- Welsh GI, Wilson C, Proud CG. GSK3: a SHAGGY frog story. Trends Cell Biol. 1996 Jul;6(7):274–279. [PubMed] [Google Scholar]
- Welsh GI, Patel JC, Proud CG. Peptide substrates suitable for assaying glycogen synthase kinase-3 in crude cell extracts. Anal Biochem. 1997 Jan 1;244(1):16–21. [PubMed] [Google Scholar]
- Singh LP, Denslow ND, Wahba AJ. Modulation of rabbit reticulocyte guanine nucleotide exchange factor activity by casein kinases 1 and 2 and glycogen synthase kinase 3. Biochemistry. 1996 Mar 12;35(10):3206–3212. [PubMed] [Google Scholar]
- Nikolakaki E, Coffer PJ, Hemelsoet R, Woodgett JR, Defize LH. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. Oncogene. 1993 Apr;8(4):833–840. [PubMed] [Google Scholar]
- Fiol CJ, Williams JS, Chou CH, Wang QM, Roach PJ, Andrisani OM. A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. J Biol Chem. 1994 Dec 23;269(51):32187–32193. [PubMed] [Google Scholar]
- Sutherland C, Cohen P. The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 1994 Jan 24;338(1):37–42. [PubMed] [Google Scholar]
- Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993 Nov 15;296(Pt 1):15–19. [PMC free article] [PubMed] [Google Scholar]
- Mèndez R, Myers MG, Jr, White MF, Rhoads RE. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mol Cell Biol. 1996 Jun;16(6):2857–2864. [PMC free article] [PubMed] [Google Scholar]
- Welsh GI, Stokes CM, Wang X, Sakaue H, Ogawa W, Kasuga M, Proud CG. Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3-kinase. FEBS Lett. 1997 Jun 30;410(2-3):418–422. [PubMed] [Google Scholar]
- Welsh GI, Miyamoto S, Price NT, Safer B, Proud CG. T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3. J Biol Chem. 1996 May 10;271(19):11410–11413. [PubMed] [Google Scholar]
- Gilligan M, Welsh GI, Flynn A, Bujalska I, Diggle TA, Denton RM, Proud CG, Docherty K. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J Biol Chem. 1996 Jan 26;271(4):2121–2125. [PubMed] [Google Scholar]
- Hinnebusch AG. Translational control of GCN4: an in vivo barometer of initiation-factor activity. Trends Biochem Sci. 1994 Oct;19(10):409–414. [PubMed] [Google Scholar]
- Geballe AP, Morris DR. Initiation codons within 5'-leaders of mRNAs as regulators of translation. Trends Biochem Sci. 1994 Apr;19(4):159–164. [PubMed] [Google Scholar]
- Kimball SR, Jurasinski CV, Lawrence JC, Jr, Jefferson LS. Insulin stimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G. Am J Physiol. 1997 Feb;272(2 Pt 1):C754–C759. [PubMed] [Google Scholar]
- Pause A, Belsham GJ, Gingras AC, Donzé O, Lin TA, Lawrence JC, Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762–767. [PubMed] [Google Scholar]
- Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N, Lawrence JC., Jr PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science. 1994 Oct 28;266(5185):653–656. [PubMed] [Google Scholar]
- Belsham GJ, Brownsey RW, Denton RM. Reversibility of the insulin-stimulated phosphorylation of ATP citrate lyase and a cytoplasmic protein of subunit Mr 22000 in adipose tissue. Biochem J. 1982 Apr 15;204(1):345–352. [PMC free article] [PubMed] [Google Scholar]
- Diggle TA, Moule SK, Avison MB, Flynn A, Foulstone EJ, Proud CG, Denton RM. Both rapamycin-sensitive and -insensitive pathways are involved in the phosphorylation of the initiation factor-4E-binding protein (4E-BP1) in response to insulin in rat epididymal fat-cells. Biochem J. 1996 Jun 1;316(Pt 2):447–453. [PMC free article] [PubMed] [Google Scholar]
- Proud CG. Protein phosphorylation in translational control. Curr Top Cell Regul. 1992;32:243–369. [PubMed] [Google Scholar]
- Hentze MW. eIF4G: a multipurpose ribosome adapter? Science. 1997 Jan 24;275(5299):500–501. [PubMed] [Google Scholar]
- Belsham GJ, Brownsey RW, Hughes WA, Denton RM. Anti-insulin receptor antibodies mimic the effects of insulin on the activities of pyruvate dehydrogenase and acetylCoA carboxylase and on specific protein phosphorylation in rat epididymal fat cells. Diabetologia. 1980 Apr;18(4):307–312. [PubMed] [Google Scholar]
- Denton RM, Brownsey RW, Belsham GJ. A partial view of the mechanism of insulin action. Diabetologia. 1981 Oct;21(4):347–362. [PubMed] [Google Scholar]
- Blackshear PJ, Nemenoff RA, Avruch J. Insulin and growth factors stimulate the phosphorylation of a Mr-22000 protein in 3T3-L1 adipocytes. Biochem J. 1983 Jul 15;214(1):11–19. [PMC free article] [PubMed] [Google Scholar]
- Hu C, Pang S, Kong X, Velleca M, Lawrence JC., Jr Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3730–3734. [PMC free article] [PubMed] [Google Scholar]
- Haghighat A, Mader S, Pause A, Sonenberg N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 1995 Nov 15;14(22):5701–5709. [PMC free article] [PubMed] [Google Scholar]
- Mader S, Lee H, Pause A, Sonenberg N. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mol Cell Biol. 1995 Sep;15(9):4990–4997. [PMC free article] [PubMed] [Google Scholar]
- Rau M, Ohlmann T, Morley SJ, Pain VM. A reevaluation of the cap-binding protein, eIF4E, as a rate-limiting factor for initiation of translation in reticulocyte lysate. J Biol Chem. 1996 Apr 12;271(15):8983–8990. [PubMed] [Google Scholar]
- Lin TA, Kong X, Saltiel AR, Blackshear PJ, Lawrence JC., Jr 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 Aug 4;270(31):18531–18538. [PubMed] [Google Scholar]
- Graves LM, Bornfeldt KE, Argast GM, Krebs EG, Kong X, Lin TA, Lawrence JC., Jr cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7222–7226. [PMC free article] [PubMed] [Google Scholar]
- Azpiazu I, Saltiel AR, DePaoli-Roach AA, Lawrence JC. Regulation of both glycogen synthase and PHAS-I by insulin in rat skeletal muscle involves mitogen-activated protein kinase-independent and rapamycin-sensitive pathways. J Biol Chem. 1996 Mar 1;271(9):5033–5039. [PubMed] [Google Scholar]
- Diggle TA, Denton RM. Comparison of the effects of insulin and adrenergic agonists on the phosphorylation of an acid-soluble 22 kDa protein in rat epididymal fat-pads and isolated fat-cells. Biochem J. 1992 Mar 15;282(Pt 3):729–736. [PMC free article] [PubMed] [Google Scholar]
- Fadden P, Haystead TA, Lawrence JC., Jr Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J Biol Chem. 1997 Apr 11;272(15):10240–10247. [PubMed] [Google Scholar]
- Haystead TA, Haystead CM, Hu C, Lin TA, Lawrence JC., Jr Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem. 1994 Sep 16;269(37):23185–23191. [PubMed] [Google Scholar]
- Diggle TA, Schmitz-Peiffer C, Borthwick AC, Welsh GI, Denton RM. Evidence that insulin activates casein kinase 2 in rat epididymal fat-cells and that this may result in the increased phosphorylation of an acid-soluble 22 kDa protein. Biochem J. 1991 Oct 15;279(Pt 2):545–551. [PMC free article] [PubMed] [Google Scholar]
- von Manteuffel SR, Gingras AC, Ming XF, Sonenberg N, Thomas G. 4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4076–4080. [PMC free article] [PubMed] [Google Scholar]
- Scott PH, Lawrence JC., Jr Insulin activates a PD 098059-sensitive kinase that is involved in the regulation of p70S6K and PHAS-I. FEBS Lett. 1997 Jun 9;409(2):171–176. [PubMed] [Google Scholar]
- Beretta L, Gingras AC, Svitkin YV, Hall MN, Sonenberg N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 1996 Feb 1;15(3):658–664. [PMC free article] [PubMed] [Google Scholar]
- Brunn GJ, Hudson CC, Sekulić A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC, Jr, Abraham RT. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 1997 Jul 4;277(5322):99–101. [PubMed] [Google Scholar]
- von Manteuffel SR, Dennis PB, Pullen N, Gingras AC, Sonenberg N, Thomas G. The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k. Mol Cell Biol. 1997 Sep;17(9):5426–5436. [PMC free article] [PubMed] [Google Scholar]
- Lin TA, Lawrence JC., Jr Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes. J Biol Chem. 1996 Nov 22;271(47):30199–30204. [PubMed] [Google Scholar]
- Flynn A, Proud CG. The role of eIF4 in cell proliferation. Cancer Surv. 1996;27:293–310. [PubMed] [Google Scholar]
- Joshi B, Cai AL, Keiper BD, Minich WB, Mendez R, Beach CM, Stepinski J, Stolarski R, Darzynkiewicz E, Rhoads RE. Phosphorylation of eukaryotic protein synthesis initiation factor 4E at Ser-209. J Biol Chem. 1995 Jun 16;270(24):14597–14603. [PubMed] [Google Scholar]
- Flynn A, Proud CG. Serine 209, not serine 53, is the major site of phosphorylation in initiation factor eIF-4E in serum-treated Chinese hamster ovary cells. J Biol Chem. 1995 Sep 15;270(37):21684–21688. [PubMed] [Google Scholar]
- Minich WB, Balasta ML, Goss DJ, Rhoads RE. Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF-4E: increased cap affinity of the phosphorylated form. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7668–7672. [PMC free article] [PubMed] [Google Scholar]
- Bu X, Haas DW, Hagedorn CH. Novel phosphorylation sites of eukaryotic initiation factor-4F and evidence that phosphorylation stabilizes interactions of the p25 and p220 subunits. J Biol Chem. 1993 Mar 5;268(7):4975–4978. [PubMed] [Google Scholar]
- Morley SJ, Rau M, Kay JE, Pain VM. Increased phosphorylation of eukaryotic initiation factor 4 alpha during early activation of T lymphocytes correlates with increased initiation factor 4F complex formation. Eur J Biochem. 1993 Nov 15;218(1):39–48. [PubMed] [Google Scholar]
- Servant MJ, Giasson E, Meloche S. Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. J Biol Chem. 1996 Jul 5;271(27):16047–16052. [PubMed] [Google Scholar]
- Levy S, Avni D, Hariharan N, Perry RP, Meyuhas O. Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3319–3323. [PMC free article] [PubMed] [Google Scholar]
- Levenson RM, Nairn AC, Blackshear PJ. Insulin rapidly induces the biosynthesis of elongation factor 2. J Biol Chem. 1989 Jul 15;264(20):11904–11911. [PubMed] [Google Scholar]
- Jefferies HB, Reinhard C, Kozma SC, Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441–4445. [PMC free article] [PubMed] [Google Scholar]
- Terada N, Patel HR, Takase K, Kohno K, Nairn AC, Gelfand EW. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477–11481. [PMC free article] [PubMed] [Google Scholar]
- Kaspar RL, Rychlik W, White MW, Rhoads RE, Morris DR. Simultaneous cytoplasmic redistribution of ribosomal protein L32 mRNA and phosphorylation of eukaryotic initiation factor 4E after mitogenic stimulation of Swiss 3T3 cells. J Biol Chem. 1990 Mar 5;265(7):3619–3622. [PubMed] [Google Scholar]
- Hammond ML, Merrick W, Bowman LH. Sequences mediating the translation of mouse S16 ribosomal protein mRNA during myoblast differentiation and in vitro and possible control points for the in vitro translation. Genes Dev. 1991 Sep;5(9):1723–1736. [PubMed] [Google Scholar]
- Bommer UA, Lazaris-Karatzas A, De Benedetti A, Nürnberg P, Benndorf R, Bielka H, Sonenberg N. Translational regulation of the mammalian growth-related protein P23: involvement of eIF-4E. Cell Mol Biol Res. 1994;40(7-8):633–641. [PubMed] [Google Scholar]
- Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G. Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997 Jun 16;16(12):3693–3704. [PMC free article] [PubMed] [Google Scholar]
- Patel HR, Terada N, Gelfand EW. Rapamycin-sensitive phosphorylation of ribosomal protein S17 by p70 S6 kinase. Biochem Biophys Res Commun. 1996 Oct 14;227(2):507–512. [PubMed] [Google Scholar]
- Nairn AC, Palfrey HC. Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2. J Biol Chem. 1987 Dec 25;262(36):17299–17303. [PubMed] [Google Scholar]
- Price NT, Redpath NT, Severinov KV, Campbell DG, Russell JM, Proud CG. Identification of the phosphorylation sites in elongation factor-2 from rabbit reticulocytes. FEBS Lett. 1991 May 6;282(2):253–258. [PubMed] [Google Scholar]
- Ovchinnikov LP, Motuz LP, Natapov PG, Averbuch LJ, Wettenhall RE, Szyszka R, Kramer G, Hardesty B. Three phosphorylation sites in elongation factor 2. FEBS Lett. 1990 Nov 26;275(1-2):209–212. [PubMed] [Google Scholar]
- Redpath NT, Price NT, Severinov KV, Proud CG. Regulation of elongation factor-2 by multisite phosphorylation. Eur J Biochem. 1993 Apr 15;213(2):689–699. [PubMed] [Google Scholar]
- Carlberg U, Nilsson A, Nygård O. Functional properties of phosphorylated elongation factor 2. Eur J Biochem. 1990 Aug 17;191(3):639–645. [PubMed] [Google Scholar]
- Redpath NT, Price NT, Proud CG. Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase. J Biol Chem. 1996 Jul 19;271(29):17547–17554. [PubMed] [Google Scholar]
- Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M, Erdjument-Bromage H, Tempst P, Parmer TG, Prostko CR, et al. Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proc Natl Acad Sci U S A. 1997 May 13;94(10):4884–4889. [PMC free article] [PubMed] [Google Scholar]
- Redpath NT, Proud CG. Activity of protein phosphatases against initiation factor-2 and elongation factor-2. Biochem J. 1990 Nov 15;272(1):175–180. [PMC free article] [PubMed] [Google Scholar]
- Redpath NT, Proud CG. Differing effects of the protein phosphatase inhibitors okadaic acid and microcystin on translation in reticulocyte lysates. Biochim Biophys Acta. 1991 Jun 7;1093(1):36–41. [PubMed] [Google Scholar]
- Redpath NT, Foulstone EJ, Proud CG. Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J. 1996 May 1;15(9):2291–2297. [PMC free article] [PubMed] [Google Scholar]
- Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1065–1070. [PMC free article] [PubMed] [Google Scholar]
- Klippel A, Kavanaugh WM, Pot D, Williams LT. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol. 1997 Jan;17(1):338–344. [PMC free article] [PubMed] [Google Scholar]