New connections in the regulation of PEPCK gene expression by insulin.

Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP) and glucocorticoids stimulate transcription of the PEPCK gene whereas insulin and phorbol esters have a dominant inhibitory effect. Wortmannin, an inhibitor of 1-phosphatidylinositol 3-kinase (PI 3-kinase), blocks the inhibition of glucocorticoid- and cAMP-stimulated PEPCK gene transcription by insulin. By contrast, although phorbol esters mimic the action of insulin on the regulation of PEPCK gene transcription, wortmannin does not block the effect of these agents. Thus PI 3-kinase is required for the regulation of PEPCK gene expression by insulin but not by phorbol esters. In liver cells, insulin administration stimulates the activity of multiple protein kinases, including the p42/p44 Mitogen Activated Protein (MAP) kinase and the p70/p85 ribosomal protein S6 kinase. Selective inhibition of the activation of either kinase, utilizing the compounds PD98059 and rapamycin respectively, does not affect insulin regulation of PEPCK gene transcription. Thus regulation of PEPCK gene transcription requires PI 3-kinase but does not require the activation of either p42/p44 MAP kinase or p70/p85 ribosomal protein S6 kinase.

[1]  J. Wang,et al.  Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes , 1995, Molecular and cellular biology.

[2]  John Koontzll.  Insulin as a Growth Factor in Rat Hepatoma Cells , 1987 .

[3]  Anne J. Ridley,et al.  The small GTP-binding protein rac regulates growth factor-induced membrane ruffling , 1992, Cell.

[4]  A. Toker,et al.  Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. , 1994, The Journal of biological chemistry.

[5]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[6]  M. White,et al.  The IRS-1 signaling system. , 1994, Trends in biochemical sciences.

[7]  R. O’Brien,et al.  Phosphatidylinositol 3-Kinase, but Not p70/p85 Ribosomal S6 Protein Kinase, Is Required for the Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression by Insulin , 1995, The Journal of Biological Chemistry.

[8]  P. Hawkins,et al.  PDGF stimulates an increase in GTP–Rac via activation of phosphoinositide 3-kinase , 1995, Current Biology.

[9]  P. Libby,et al.  PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells , 1989, Cell.

[10]  M. White,et al.  Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. O’Brien,et al.  Regulation of gene expression by insulin. , 1991, Physiological reviews.

[12]  D. Stumpo,et al.  The inhibition of phosphoenolpyruvate carboxykinase (guanosine triphosphate) gene expression by insulin is not mediated by protein kinase C. , 1987, Molecular endocrinology.

[13]  S. Narumiya,et al.  Inhibition of PMA-induced, LFA-1-dependent lymphocyte aggregation by ADP ribosylation of the small molecular weight GTP binding protein, rho , 1993, The Journal of cell biology.

[14]  J. Bos,et al.  Involvement of p21ras in activation of extracellular signal-regulated kinase 2 , 1992, Nature.

[15]  D. Stumpo,et al.  Identification of c-fos sequences involved in induction by insulin and phorbol esters. , 1988, The Journal of biological chemistry.

[16]  D. Stumpo,et al.  Insulin and growth factor effects on c-fos expression in normal and protein kinase C-deficient 3T3-L1 fibroblasts and adipocytes. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. O’Brien,et al.  Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription. , 1990, Science.

[18]  K. Yamamoto,et al.  Glucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids. , 1993, The Journal of biological chemistry.

[19]  L. Cantley,et al.  A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity , 1993, Molecular and cellular biology.

[20]  R. O’Brien,et al.  Molecular Physiology and Genetics of NIDDM: Importance of Metabolic Staging , 1992, Diabetes Care.

[21]  X. F. Zhang,et al.  Raf meets Ras: completing the framework of a signal transduction pathway. , 1994, Trends in biochemical sciences.

[22]  K.,et al.  The effect of phorbol esters and diacylglycerol on expression of the phosphoenolpyruvate carboxykinase (GTP) gene in rat hepatoma H4IIE cells. , 1986, The Journal of biological chemistry.

[23]  F. Bosch,et al.  Epidermal growth factor inhibits phosphoenolpyruvate carboxykinase gene expression in rat hepatocytes in primary culture , 1993, FEBS letters.

[24]  G. Crabtree,et al.  Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases , 1992, Cell.

[25]  T. Sasaki,et al.  Involvement of rho p21 and its inhibitory GDP/GTP exchange protein (rho GDI) in cell motility , 1993, Molecular and cellular biology.

[26]  R. O’Brien,et al.  Regulation of phosphoenolpyruvate carboxykinase gene expression by insulin. Use of the stable transfection approach to locate an insulin responsive sequence. , 1990, Molecular endocrinology.

[27]  E. Nishida,et al.  Insulin and 12-O-tetradecanoylphorbol-13-acetate activation of two immunologically distinct myelin basic protein/microtubule-associated protein 2 (MBP/MAP2) kinases via de novo phosphorylation of threonine and tyrosine residues. , 1991, The Journal of biological chemistry.

[28]  M. Benito,et al.  Phosphoenolpyruvate carboxykinase and glucose-6-phosphate dehydrogenase expression in fetal hepatocyte primary cultures under proliferative conditions. , 1992, Experimental cell research.

[29]  R. O’Brien,et al.  Potential convergence of insulin and cAMP signal transduction systems at the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter through CCAAT/enhancer binding protein (C/EBP). , 1994, The Journal of biological chemistry.

[30]  R. Davis,et al.  Signal transduction by the epidermal growth factor receptor after functional desensitization of the receptor tyrosine protein kinase activity. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Maller,et al.  Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II , 1988, Nature.

[32]  A. Aronheim,et al.  Positive and negative regulation of insulin gene transcription. , 1993, Biochemical Society transactions.

[33]  M. White,et al.  Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1 , 1993, Molecular and cellular biology.

[34]  C. Proud,et al.  Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase. , 1994, The Biochemical journal.

[35]  A. Bridges,et al.  A synthetic inhibitor of the mitogen-activated protein kinase cascade. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Norman,et al.  The small GTPases Rac and Rho as regulators of secretion in mast cells , 1995, Current Biology.

[37]  M. Birnbaum,et al.  The Effects of Wortmannin on Rat Skeletal Muscle , 1995, The Journal of Biological Chemistry.

[38]  T. Shimazu,et al.  Effects of wortmannin on increased glucose transport by insulin and norepinephrine in primary culture of brown adipocytes. , 1994, Biochemical and biophysical research communications.

[39]  J. L. Messina,et al.  Evidence for diverse roles of protein kinase-C in the inhibition of gene expression by insulin: the tyrosine aminotransferase, albumin, and phosphoenolpyruvate carboxykinase genes. , 1994, Endocrinology.

[40]  M. Ridderstråle,et al.  Essential role of phosphatidylinositol 3‐kinase in insulin‐induced activation and phosphorylation of the cGMP‐inhibited cAMP phosphodiesterase in rat adipocytes studies using the selective inhibitor wortmannin , 1994, FEBS letters.

[41]  S. Ferrari,et al.  S6 phosphorylation and the p70s6k/p85s6k. , 1994, Critical reviews in biochemistry and molecular biology.

[42]  Denton Rm.  Early events in insulin actions. , 1986 .

[43]  J. Tavaré,et al.  Does mitogen-activated-protein kinase have a role in insulin action? The cases for and against. , 1995, European journal of biochemistry.

[44]  P. Dent,et al.  The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle , 1990, Nature.

[45]  J. Avruch,et al.  Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. , 1992, Science.

[46]  Y. Yazaki,et al.  Upstream Mechanisms of Glycogen Synthase Activation by Insulin and Insulin-like Growth Factor-I , 1995, The Journal of Biological Chemistry.

[47]  U. Rapp,et al.  Differential Raf requirement for activation of mitogen-activated protein kinase by growth factors, phorbol esters, and calcium. , 1994, The Journal of biological chemistry.

[48]  P. Cohen,et al.  Okadaic acid: a new probe for the study of cellular regulation. , 1990, Trends in biochemical sciences.

[49]  P. Angrand,et al.  Response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids depends on the integrity of the cAMP pathway. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[50]  R. Plevin,et al.  Evidence for a role of phosphatidylinositol 3-kinase in the regulation of glucose transport in Xenopus oocytes. , 1994, The Journal of biological chemistry.

[51]  J. Exton,et al.  Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. , 1993, The Journal of biological chemistry.

[52]  F. McCormick,et al.  A novel serine kinase activated by rac1/CDC42Hs‐dependent autophosphorylation is related to PAK65 and STE20. , 1995, The EMBO journal.

[53]  J. Exton.  Some Thoughts on the Mechanism of Action of Insulin , 1991, Diabetes.

[54]  F. Grigorescu,et al.  Involvement of phosphoinositide 3‐kinase in insulin‐ or IGF‐1‐induced membrane ruffling. , 1994, The EMBO journal.

[55]  J. Blenis,et al.  Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation , 1994, Molecular and cellular biology.

[56]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[57]  E. Krebs,et al.  Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of a myelin basic protein/microtubule-associated protein 2 kinase. , 1991, The Journal of biological chemistry.

[58]  R. O’Brien,et al.  PEPCK Gene as Model of Inhibitory Effects of Insulin on Gene Transcription , 1990, Diabetes Care.

[59]  R. Davis,et al.  MAPKs: new JNK expands the group. , 1994, Trends in biochemical sciences.

[60]  B. Margolis,et al.  Phosphatidylinositol 3′‐kinase is activated by association with IRS‐1 during insulin stimulation. , 1992, The EMBO journal.

[61]  P. Cohen,et al.  The α‐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 , 1994, FEBS letters.

[62]  A. Arcaro,et al.  Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. , 1993, The Biochemical journal.

[63]  R. Davis,et al.  Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus , 1993, The Journal of cell biology.

[64]  J. Blenis,et al.  Nuclear localization and regulation of erk- and rsk-encoded protein kinases , 1992, Molecular and cellular biology.

[65]  B. Errede,et al.  MAP kinase-related FUS3 from S. cerevisiae is activated by STE7 in vitro , 1993, Nature.

[66]  P. Cohen,et al.  MAPKAP kinase‐2; a novel protein kinase activated by mitogen‐activated protein kinase. , 1992, The EMBO journal.

[67]  C. Kahn,et al.  Insulin action and the insulin signaling network. , 1995, Endocrine reviews.

[68]  K. Siddle,et al.  Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. , 1995, The Biochemical journal.

[69]  T. Pawson,et al.  The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. , 1993, The Journal of biological chemistry.

[70]  I Gout,et al.  PI 3‐kinase is a dual specificity enzyme: autoregulation by an intrinsic protein‐serine kinase activity. , 1994, The EMBO journal.

[71]  T. Sasaki,et al.  Regulation of cytoplasmic division of Xenopus embryo by rho p21 and its inhibitory GDP/GTP exchange protein (rho GDI) , 1993, The Journal of cell biology.

[72]  B. Errede,et al.  A conserved kinase cascade for MAP kinase activation in yeast. , 1993, Current opinion in cell biology.

[73]  R. Farese,et al.  Role of protein kinase C in insulin's regulation of c-fos transcription. , 1992, The Journal of biological chemistry.

[74]  C. Kahn,et al.  Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein , 1991, Nature.

[75]  S. Stabel,et al.  Signalling from TPA to MAP kinase requires protein kinase C, raf and MEK: reconstitution of the signalling pathway in vitro. , 1994, Oncogene.

[76]  M. Kasuga,et al.  Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. , 1994, The Biochemical journal.

[77]  P. Cohen,et al.  Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases , 1991, Nature.

[78]  C. R. Kahn,et al.  Insulin Action, Diabetogenes, and the Cause of Type II Diabetes , 1994, Diabetes.

[79]  P. Cuatrecasas,et al.  Mitogen-activated Protein Kinase Kinase Inhibition Does Not Block the Stimulation of Glucose Utilization by Insulin (*) , 1995, The Journal of Biological Chemistry.

[80]  J. Gustafsson,et al.  Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene , 1990, Molecular and cellular biology.

[81]  J. Blenis,et al.  Mitogen-activated Swiss mouse 3T3 RSK kinases I and II are related to pp44mpk from sea star oocytes and participate in the regulation of pp90rsk activity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.