Glycogen Synthase Kinase-3 regulates IGFBP-1 gene transcription through the Thymine-rich Insulin Response Element

BMC Molecular Biology

Calum Sutherland³  Chris J Rhodes²  Rodolfo Marquez⁴  Natalia Shpiro⁴  Lorna M Dickson²  Satish Patel¹  David Finlay³ 

[1] Ontario Cancer Institute, University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9 Canada;Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA;Department of Pathology and Neurosciences, University of Dundee, Ninewells Medical School and Hospital, Dundee, DD1 9SY United Kingdom;Division of Biological Chemistry, School of Life Sciences, University of Dundee, DD1 4EH, United Kingdom

关键词: CHIR99021;    TIRE;    IGFBP-1 gene transcription;    Insulin;    GSK-3;   

Others  :  1142021
DOI  :  10.1186/1471-2199-5-15

 received in 2004-05-14, accepted in 2004-09-06,  发布年份 2004

【 摘 要 】

Background

Hepatic expression of several gene products involved in glucose metabolism, including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and insulin-like growth factor binding protein-1 (IGFBP-1), is rapidly and completely inhibited by insulin. This inhibition is mediated through the regulation of a DNA element present in each of these gene promoters, that we call the

T

hymine-rich

I

nsulin

R

esponse

E

lement (TIRE). The insulin signalling pathway that results in the inhibition of these gene promoters requires the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the molecules that connect PI 3-kinase to these gene promoters are not yet fully defined. Glycogen Synthase Kinase 3 (GSK-3) is inhibited following activation of PI 3-kinase. We have shown previously that inhibitors of GSK-3 reduce the activity of two TIRE-containing gene promoters (PEPCK and G6Pase), whose products are required for gluconeogenesis.

Results

In this report we demonstrate that in H4IIE-C3 cells, four distinct classes of GSK-3 inhibitor mimic the effect of insulin on a third TIRE-containing gene, IGFBP-1. We identify the TIRE as the minimum requirement for inhibition by these agents, and demonstrate that the target of GSK-3 is unlikely to be the postulated TIRE-binding protein FOXO-1. Importantly, overexpression of GSK-3 in cells reduces the insulin regulation of TIRE activity as well as endogenous IGFBP-1 expression.

Conclusions

These results implicate GSK-3 as an intermediate in the pathway from the insulin receptor to the TIRE. Indeed, this is the first demonstration of an absolute requirement for GSK-3 inhibition in insulin regulation of gene transcription. These data support the potential use of GSK-3 inhibitors in the treatment of insulin resistant states such as Type 2 diabetes mellitus, but suggest that it will be important to identify all TIRE-containing genes to assess potential side effects of these agents.

【 授权许可】

   
2004 Finlay et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Stewart CE, Rotwein P: Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 1996, 76(4):1005-1026.
• [2]Lee PDK, Giudice LC, Conover CA, Powell DR: IGFBP-1: Recent findings and new directions. Proc Soc Exp Biol Med 1997, 216:319-357.
• [3]Frystyk J, Orskov H: IGF-I, IGF-II, IGF-binding proteins and Diabetes. In International Textbook of Diabetes Mellitus. Volume 1. 2nd edition. Edited by Alberti KGMM, Zimmet P, DeFronzo RA, Keen H. John Wiley and Sons Ltd; 1997::417-436.
• [4]Lewitt MS, Denyer GS, Cooney GJ, Baxter RC: Insulin-like growth factor-binding protein-1 modulates blood glucose levels. Endocrinology 1991, 129(4):2254-2256.
• [5]Crossey PA, Jones JS, Miell JP: Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance. Diabetes 2000, 49(3):457-465.
• [6]Busby WH, Snyder DK, Clemmons DR: Radioimmunoassay of a 26,000-dalton plasma insulin-like growth factor-binding protein: control by nutritional variables. J Clin Endocrinol Metab 1988, 67(6):1225-1230.
• [7]Straus DS, Ooi GT, Orlowski CC, Rechler MM: Expression of the genes for insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins-1 and -2 in fetal rat under conditions of intrauterine growth retardation caused by maternal fasting. Endocrinology 1991, 128(1):518-525.
• [8]Bereket A, Lang CH, Wilson TA: Alterations in the growth hormone-IGF axis in insulin dependent diabetes mellitus. Horm Metab Res 1999, 31:172-181.
• [9]Ooi GK, Brown DR, Suh D-S, Tseng LY-H, Rechler MM: Cycloheximide stabilises IGFBP-1 mRNA and inhibits IGFBP-1 transcription in H4IIE cells. J Biol Chem 1993, 268:16664-16672.
• [10]Patel S, Lochhead PA, Rena G, Fumagalli S, Pende M, Kozma S, Thomas GM, Sutherland C: Insulin regulation of IGF-binding protein-1 gene expression is dependent on mammalian target of rapamycin (mTOR), but independent of S6K activity. J Biol Chem 2002, 277(12):9889-9895.
• [11]Avruch J: Insulin signal transduction through protein kinase cascades. Mol Cell Biochem 1998, 182:31-48.
• [12]Leslie NR, Biondi RM, Alessi DR: Pi-regulated kinases and PI phosphatases. Chem Rev 2001, 101(8):2365-2380.
• [13]Sutherland C, Leighton IA, Cohen P: Inactivation of glycogen synthase kinase-3β by phosphorylation; new kinase connections in insulin and growth factor signalling. Biochem J 1993, 296:15-19.
• [14]Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of GSK3 by insulin mediated by protein kinase B. Nature 1995, 378:785-789.
• [15]Welsh GI, Miller CM, Loughlin AJ, Price NT, Proud CG: Regulation of eIF2B: GSK3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett 1998, 421(2):125-130.
• [16]Cichy SB, Uddin S, Danilkovitch A, Guo S, Klippel A, Unterman TG: PKB mediates effects of insulin on hepatic IGFBP1 gene expression through a conserved insulin response sequence. J Biol Chem 1998, 273(11):6482-6487.
• [17]O'Brien RM, Granner DK: Regulation of gene expression by insulin. Physiol Rev 1996, 76:1109-1161.
• [18]Vander Kooi BT, Streeper RS, Svitek CA, Oeser JK, Powell DR, O'Brien RM: The Three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct. J Biol Chem 2003, 278(14):11782-11793.
• [19]Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, et al.: Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 2003, 423(6939):550-555.
• [20]Sutherland C, O'Brien RM, Granner DK: Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of Phosphoenolpyruvate Carboxykinase gene expression by insulin. J Biol Chem 1995, 270(26):15501-15506.
• [21]Dickens M, Svitek CA, Culbert AA, O'Brien RM, Tavare JM: Central Role for PI 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J Biol Chem 1998, 273:20144-20149.
• [22]Guo S, Rena G, Cichy S, He X, Cohen P, Unterman TG: Phosphorylation of Ser 256 by PKB disrupts transactivation by FKHR and mediates effects of insulin on IGFBP-1 promoter activity through a conserved insulin response sequence. J Biol Chem 1999, 274(24):17184-17192.
• [23]Rena G, Prescott AR, Guo S, Cohen P, Unterman TG: Roles of the forkhead in rhabdomyosarcoma (FKHR)phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem J 2001, 354:605-612.
• [24]Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR, Cohen P: Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J 2002, 21(9):2263-2271.
• [25]Band CJ, Posner BI: PI 3-kinase and p70S6 kinase are required for insulin but not bisperoxovanadium 1,10-phenanthroline inhibition of IGFBP gene expression. J Biol Chem 1997, 272(1):138-145.
• [26]Patel S, Lochhead PA, Rena G, Sutherland C: Antagonistic effects of phorbol esters on insulin regulation of IGFBP-1 but not glucose-6-phosphatase gene expression. Biochem J 2001, 359(3):611-619.
• [27]Patel S, Lipina C, Sutherland C: Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element. FEBS Lett 2003, 549:72-76.
• [28]Lochhead PA, Coghlan MP, Rice SQJ, Sutherland C: Inhibition of GSK3 selectively reduces G6Pase and PEPCK gene expression. Diabetes 2001, 50:937-947.
• [29]Coghlan MP, Culbert AA, Cross DAE, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Cox LR, et al.: Selective small molecule inhibitors of GSK-3 modulate glycogen metabolism and gene transcription. Chemistry and Biology 2000, 7:793-803.
• [30]Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C: Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity. J Med Chem 1999, 42(15):2909-2919.
• [31]Zaharevitz DW, Gussio R, Leost M, Senderowicz AM, Lahusen T, Kunick C, Meijer L, Sausville EA: Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res 1999, 59(11):2566-2569.
• [32]Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, et al.: Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 2001, 276(1):251-260.
• [33]Bain J, McLauchlan H, Elliott M, Cohen P: The specificities of protein kinase inhibitors; an update. Biochem J 2003, 371:199-204.
• [34]Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, et al.: Selective GSK-3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 2003, 52(3):588-595.
• [35]Cohen P, Goedert M: GSK-3 inhibitors: Development and potential for the treatment of disease. Nat Rev Drug Disc 2004, in press.
• [36]Hall RK, Yamasaki T, Kucera T, Waltner-Law M, O'Brien RM, Granner DK: Regulation of Phosphoenolpyruvate Carboxykinase and Insulin-like Growth Factor-binding Protein-1 Gene Expression by Insulin. J Biol Chem 2000, 275:30169-30175.
• [37]Nitsch D, Boshart M, Schutz G: Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elements. Proc Natl Acad Sci 1993, 90:5479-5483.
• [38]Beurton F, Bandyopadhyay U, Dieumegard B, Barouki R, Aggerbeck M: Delineation of the insulin-responsive sequence in the rat aspartate aminotransferase gene: binding sites for HNF3 and NF-I. Biochem J 1999, 343:687-695.
• [39]Zhang J, Ou J, Bashmakov Y, Horton JD, Brown MS, Goldstein JL: Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes. Proc Natl Acad Sci 2001, 98(7):3756-3761.
• [40]Nadal A, Marrero PF, Haro D: Down-regulation of mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase gene by insulin. Role of the forkhead transcription factor FKHRL1. Biochem J 2002, 366(2):289-297.
• [41]Barthel A, Schmoll D, Kruger KD, Bahrenberg G, Walther R, Roth RA, Joost HG: Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. Biochem Biophys Res Commun 2001, 285(4):897-902.
• [42]Frame S, Cohen P: GSK3 takes centre stage more than 20 years after its discovery. Biochem J 2001, 359:1-16.
• [43]Liu C, Li Y, Semenov M, Han C, Baeg G-H, Tan Y, Zhang Z, Lin X, He X: Control of b-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002, 108:837-847.
• [44]Amit S, Hatzubai A, Birman Y, Anderson JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I: Axin-mediated CKI phosphorylation of b-catenin at Ser-45: a molecular switch for the wnt pathway. Genes Dev 2002, 16:1066-1076.
• [45]Nikolakaki E, Coffer PJ, Hemelsoet R, Woodgett JR, Defize LHK: GSK3 phosphorylates jun family members in vitro and negatively regulates their transactivating potential in intact cells. Oncogene 1993, 8:833-840.
• [46]Morton S, Davis RJ, McLaren A, Cohen P: A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. EMBO J 2003, 22(15):3876-3886.
• [47]Rogatsky I, Waase CLM, Garabedian MJ: Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activity by GSK-3. J Biol Chem 1998, 273(23):14315-14321.
• [48]Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR: Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000, 14:2501-2514.
• [49]Fiol CJ, Williams JS, Chou CH, Wang QM, Roach PJ, Andrisani OM: A secondary phopshorylation of CREB at Ser-129 is required for the cAMP-mediated control of gene expression. A role for GSK3 in the control of gene expression. J Biol Chem 1994, 269:32187-32193.
• [50]Grimes CA, Jope RS: CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem 2001, 78(6):1219-12132.
• [51]Ross SE, Erickson RL, Hemati N, MacDougald OA: GSK3 is an insulin-regulated C/EBPalpha kinase. Mol Cell Biol 1999, 19(12):8433-8441.
• [52]Guo S, Cichy SB, He X, Yang Q, Ragland M, Ghosh AK, Johnson PF, Unterman TG: Insulin suppresses transactivation by C/EBPbeta: Signaling to p300/CBP by protein kinase B disrupts interaction with the major activation domain of C/EBPbeta. J Biol Chem 2001, 276:8516-8523.
• [53]Duong DT, Waltner-Law ME, Sears R, Sealy L, Granner DK: Insulin inhibits hepatocellular glucose production by utilizing LIP to disrupt the association of CBP and RNA polymerase II with the PEPCK gene promoter. J Biol Chem 2002, 277(35):32234-32242.
• [54]Tabata I, Schluter J, Gulve EA, Holloszy JO: Lithium increases susceptibility of muscle glucose transport to stimulation by various agents. Diabetes 1994, 43(7):903-907.
• [55]Chen X, McMahon EG, Gulve EA: Stimulatory effect of lithium on glucose transport in rat adipocytes is not mediated by elevation of IP1. Am J Physiol 1998, 275(2):E272-E277.
• [56]Orena SJ, Torchia AJ, Garofalo RS: Inhibition of GSK3 stimulates glycogen synthase and glucose transport by distinct mechanisms in 3T3-L1 adipocytes. J Biol Chem 2000, 275(21):15765-15772.
• [57]Henriksen EJ, Kinnick TR, Teachey MK, O'Keefe MP, Ring D, Johnson KW, Harrison SD: Modulation of Muscle Insulin Resistance by Selective Inhibition of Glycogen Synthase Kinase-3 in Zucker Diabetic Fatty Rats. Am J Physiol Endocrinol Metab 2003, 285(1):E98-E105.
• [58]Nikoulina SE, Ciaraldi TP, Mudaliar S, Carter L, Johnson K, Henry RR: Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle. Diabetes 2002, 51(7):2190-2198.
• [59]Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, Damico C, Shulman GI: Effects of a novel GSK3 inhibitor on insulin stimulated glucose metabolism in ZDF (fa/fa) rats. Diabetes 2002, 51:2903-2910.
• [60]Hoeflich KP, Luo J, Rubie EA, Tsao M-S, Jin O, Woodgett JR: Requirement for GSK3beta in cell surival and NFkB activation. Nature 2000, 406:86-90.
• [61]Salinas PC, Hall AC: Lithium and synaptic plasticity. Bipolar Disord 1999, 1(2):87-90.
• [62]Jimenez-Vasquez PA, Overstreet DH, Mathe AA: Neuropeptide Y in male and female brains of flinders sensitive line, a rat model of depression. Effects ofelectroconvulsive stimuli. JOURNAL OF PSYCHIATRIC RESEARCH 2000, 34(6):405-412.
• [63]Mattson MP: Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000, 1(2):120-129.
• [64]Cross DAE, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD: Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 2001, 77(1):94-102.
• [65]Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe RT, et al.: Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science 2001, 291:134-137.
• [66]Goff DA, Harrison DS, Nuss JM, Ring D: Inhibitors of GSK-3. US PAT 2002, 6:147-185.
• [67]Forest CD, O'Brien RM, Lucas PC, Magnuson MA, Granner DK: Regulation of PEPCK gene expression by insulin. Use of the stable transfection approach to locate an insulin responsive sequence. Molecular Endocrinology 1990, 4(9):1302-1310.