Transcriptional regulation by insulin: from the receptor to the gene.

Insulin, after binding to its receptor, regulates many cellular processes and the expression of several genes. For a subset of genes, insulin exerts a negative effect on transcription; for others, the effect is positive. Insulin controls gene transcription by modifying the binding of transcription factors on insulin-response elements or by regulating their transcriptional activities. Different insulin-signaling cascades have been characterized as mediating the insulin effect on gene transcription. In this review, we analyze recent data on the molecular mechanisms, mostly in the liver, through which insulin exerts its effect. We first focus on the key transcription factors (viz. Foxo, sterol-response-element-binding protein family (SREBP), and Sp1) involved in the regulation of gene transcription by insulin. We then present current information on the way insulin downregulates and upregulates gene transcription, using as examples of downregulation phosphoenolpyruvate carboxykinase (PEPCK) and insulin-like growth factor binding protein 1 (IGFBP-1) genes and of upregulation the fatty acid synthase and malic enzyme genes. The last part of the paper focuses on the signaling cascades activated by insulin in the liver, leading to the modulation of gene transcription.

[1]  R. Hanson,et al.  C/EBP and the Control of Phosphoenolpyruvate Carboxykinase Gene Transcription in the Liver* , 1998, The Journal of Biological Chemistry.

[2]  Shwu‐Yuan Wu,et al.  SREBP-1c and Sp1 Interact to Regulate Transcription of the Gene for Phosphoenolpyruvate Carboxykinase (GTP) in the Liver* , 2004, Journal of Biological Chemistry.

[3]  J. B. Kim,et al.  Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c* , 2004, Journal of Biological Chemistry.

[4]  S. Pandey,et al.  Potential mechanism(s) involved in the regulation of glycogen synthesis by insulin , 1998, Molecular and Cellular Biochemistry.

[5]  S. Samson,et al.  Role of Sp1 in insulin regulation of gene expression. , 2002, Journal of molecular endocrinology.

[6]  J. Gustafsson,et al.  Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity. , 2002, Diabetes.

[7]  David K. Finlay,et al.  Glycogen Synthase Kinase-3 regulates IGFBP-1 gene transcription through the Thymine-rich Insulin Response Element , 2004, BMC Molecular Biology.

[8]  Y. Nishizuka,et al.  Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Kahn,et al.  Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression. , 1997, The Biochemical journal.

[10]  P. Lochhead,et al.  Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression , 2001 .

[11]  D. Powell,et al.  Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements. , 1994, The Journal of biological chemistry.

[12]  A. Barthel,et al.  Activation of Protein Kinase B/Akt Is Sufficient to Repress the Glucocorticoid and cAMP Induction of Phosphoenolpyruvate Carboxykinase Gene* , 1998, The Journal of Biological Chemistry.

[13]  T. Hunter,et al.  Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. O’Brien,et al.  Regulation of gene expression by insulin. , 1996, The Biochemical journal.

[15]  R. S. Beyer,et al.  Identification of an insulin response element in the fatty acid synthase promoter. , 1994, The Journal of biological chemistry.

[16]  R. O’Brien,et al.  Regulation of Phosphoenolpyruvate Carboxykinase and Insulin-like Growth Factor-binding Protein-1 Gene Expression by Insulin , 2000, The Journal of Biological Chemistry.

[17]  B. Spiegelman,et al.  Identification of Conserved cis-Elements and Transcription Factors Required for Sterol-regulated Transcription of Stearoyl-CoA Desaturase 1 and 2* , 1999, The Journal of Biological Chemistry.

[18]  T. Unterman,et al.  Functional analysis of glucocorticoid and insulin response sequences in the rat insulin-like growth factor-binding protein-1 promoter. , 1994, Endocrinology.

[19]  P. Ferré.  Signalisation insulinique et résistance à l’insuline , 2007 .

[20]  C. Mounier,et al.  Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta , 2008, Molecular reproduction and development.

[21]  D. Alessi,et al.  The role of PI 3-kinase in insulin action. , 1998, Biochimica et biophysica acta.

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

[23]  C. Sutherland,et al.  Activation of the Ras Mitogen-activated Protein Kinase-Ribosomal Protein Kinase Pathway Is Not Required for the Repression of Phosphoenolpyruvate Carboxykinase Gene Transcription by Insulin* , 1998, The Journal of Biological Chemistry.

[24]  R. Raghow,et al.  O-glycosylation of Sp1 and transcriptional regulation of the calmodulin gene by insulin and glucagon. , 2003, American journal of physiology. Endocrinology and metabolism.

[25]  Robert A. Harris,et al.  Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. , 2004, Diabetes.

[26]  H. Sul,et al.  Upstream Stimulatory Factors Bind to Insulin Response Sequence of the Fatty Acid Synthase Promoter USF1 IS REGULATED (*) , 1995, The Journal of Biological Chemistry.

[27]  E. Brown,et al.  Analysis of the genes involved in the insulin transmembrane mitogenic signal in Chinese hamster ovary cells, CHO-K1, utilizing insulin-independent mutants. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Fukuda,et al.  Transcriptional regulation of insulin receptor gene promoter in rat hepatocytes. , 2001, Biochemical and biophysical research communications.

[29]  Marie C. M. Lin,et al.  Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. , 2003, Diabetes.

[30]  N. Wong,et al.  Effects of Glucose and Insulin on Rat Apolipoprotein A-I Gene Expression* , 1998, The Journal of Biological Chemistry.

[31]  Richard A. Roth,et al.  Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1* , 1999, The Journal of Biological Chemistry.

[32]  R. O’Brien,et al.  Central Role for Phosphatidylinositide 3-Kinase in the Repression of Glucose-6-phosphatase Gene Transcription by Insulin* , 1998, The Journal of Biological Chemistry.

[33]  I. Shimomura,et al.  Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Unterman,et al.  Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription , 2001, The Journal of Biological Chemistry.

[35]  D. Accili,et al.  Insulin Stimulates Phosphorylation of the Forkhead Transcription Factor FKHR on Serine 253 through a Wortmannin-sensitive Pathway* , 1999, The Journal of Biological Chemistry.

[36]  J. K. Oeser,et al.  The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct* , 2003, The Journal of Biological Chemistry.

[37]  A. Hamsten,et al.  Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway. , 2001, Diabetes.

[38]  P. Espenshade,et al.  Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. , 1998, Molecular cell.

[39]  M. Kasuga,et al.  Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. , 2002, The Journal of clinical investigation.

[40]  Peter F. Johnson,et al.  Insulin Suppresses Transactivation by CAAT/Enhancer-binding Proteins β (C/EBPβ) , 2001, The Journal of Biological Chemistry.

[41]  A. Keeton,et al.  Insulin-regulated expression of Egr-1 and Krox20: dependence on ERK1/2 and interaction with p38 and PI3-kinase pathways. , 2003, Endocrinology.

[42]  B. Shilo,et al.  Insulin induces transcription of target genes through the hypoxia‐inducible factor HIF‐1α/ARNT , 1998, The EMBO journal.

[43]  Pixu Liu,et al.  A Nucleoprotein Complex containing CCAAT/Enhancer-binding Protein β Interacts with an Insulin Response Sequence in the Insulin-like Growth Factor-binding Protein-1 Gene and Contributes to Insulin-regulated Gene Expression* , 2001, The Journal of Biological Chemistry.

[44]  T. Osborne,et al.  Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins. , 1997, Journal of lipid research.

[45]  D. Müller-Wieland,et al.  MAP Kinases Erk1/2 Phosphorylate Sterol Regulatory Element-binding Protein (SREBP)-1a at Serine 117 in Vitro * , 2000, The Journal of Biological Chemistry.

[46]  M. Noshiro,et al.  Insulin is a dominant suppressor of sterol 12 alpha-hydroxylase P450 (CYP8B) expression in rat liver: possible role of insulin in circadian rhythm of CYP8B. , 2000, Journal of biochemistry.

[47]  C. Kahn,et al.  Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells , 1997, Molecular and cellular biology.

[48]  B. Spiegelman,et al.  ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose , 1999, Molecular and Cellular Biology.

[49]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[50]  J. Horton,et al.  Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[51]  C. Christoffersen,et al.  Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor , 1997, Diabetologia.

[52]  B. Knebel,et al.  Insulin-activated Erk-mitogen-activated Protein Kinases Phosphorylate Sterol Regulatory Element-binding Protein-2 at Serine Residues 432 and 455 in Vivo* , 2004, Journal of Biological Chemistry.

[53]  A. Klippel,et al.  Protein Kinase B/Akt Mediates Effects of Insulin on Hepatic Insulin-like Growth Factor-binding Protein-1 Gene Expression through a Conserved Insulin Response Sequence* , 1998, The Journal of Biological Chemistry.

[54]  Julian Downward,et al.  PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP , 2005, Oncogene.

[55]  R. O’Brien,et al.  Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. , 1999, Diabetes.

[56]  R. Walther,et al.  Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. , 2000, The Journal of biological chemistry.

[57]  L. Phillips,et al.  Insulin-responsive Nuclear Proteins Facilitate Sp1 Interactions with the Insulin-like Growth Factor-I Gene* , 2001, The Journal of Biological Chemistry.

[58]  B. Posner,et al.  Phosphatidylinositol 3′-Kinase and p70s6k Are Required for Insulin but Not Bisperoxovanadium 1,10-Phenanthroline (bpV(phen)) Inhibition of Insulin-like Growth Factor Binding Protein Gene Expression , 1997, The Journal of Biological Chemistry.

[59]  Richard W. Hanson,et al.  Factors That Control the Tissue-Specific Transcription of the Gene for Phosphoenolpyruvate Carboxykinase-C , 2005, Critical reviews in biochemistry and molecular biology.

[60]  F. Sladek,et al.  The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[61]  T. Tanaka,et al.  Effects of insulin and fructose on transcriptional and post-transcriptional regulation of malic enzyme synthesis in diabetic rat liver. , 1989, Biochimica et biophysica acta.

[62]  T. Noguchi,et al.  Transcriptional regulation of fatty acid synthase gene and ATP citrate‐lyase gene by Sp1 and Sp3 in rat hepatocytes 1 , 1999, FEBS letters.

[63]  K. Nadeau,et al.  Insulin Regulation of Sterol Regulatory Element-binding Protein-1 Expression in L-6 Muscle Cells and 3T3 L1 Adipocytes* , 2004, Journal of Biological Chemistry.

[64]  A phorbol ester-insensitive AP-1 motif mediates the stimulatory effect of insulin on rat malic enzyme gene transcription. , 1998, Molecular endocrinology.

[65]  F. Foufelle,et al.  SREBP transcription factors: master regulators of lipid homeostasis. , 2004, Biochimie.

[66]  Satoko Aratani,et al.  Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[67]  A. Fukamizu,et al.  Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. , 2003, Diabetes.

[68]  L. Phillips,et al.  Insulin-response Element-binding Protein 1 , 2004, Journal of Biological Chemistry.

[69]  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.

[70]  R. Sears,et al.  Insulin Inhibits Hepatocellular Glucose Production by Utilizing Liver-enriched Transcriptional Inhibitory Protein to Disrupt the Association of CREB-binding Protein and RNA Polymerase II with the Phosphoenolpyruvate Carboxykinase Gene Promoter* , 2002, The Journal of Biological Chemistry.

[71]  J. Goldstein,et al.  Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[72]  J. Goldstein,et al.  Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[73]  S. Stapleton,et al.  Insulin Regulation of Glucose-6-phosphate Dehydrogenase Gene Expression Is Rapamycin-sensitive and Requires Phosphatidylinositol 3-Kinase* , 1998, The Journal of Biological Chemistry.

[74]  T. Osborne,et al.  Different Sterol Regulatory Element-binding Protein-1 Isoforms Utilize Distinct Co-regulatory Factors to Activate the Promoter for Fatty Acid Synthase* , 2000, The Journal of Biological Chemistry.

[75]  M. Takiguchi,et al.  The gene for hepatocyte nuclear factor (HNF)‐4α is activated by glucocorticoids and glucagon, and repressed by insulin in rat liver , 2000, FEBS letters.

[76]  G. Ruvkun,et al.  DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Haiyun Pan,et al.  Insulin response sequence-dependent and -independent mechanisms mediate effects of insulin on glucocorticoid-stimulated insulin-like growth factor binding protein-1 promoter activity. , 2005, Endocrinology.

[78]  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.

[79]  H. Sul,et al.  Occupancy and Function of the −150 Sterol Regulatory Element and −65 E-Box in Nutritional Regulation of the Fatty Acid Synthase Gene in Living Animals , 2003, Molecular and Cellular Biology.

[80]  H. Sul,et al.  Insulin Regulation of Fatty Acid Synthase Gene Transcription: Roles of USF and SREBP‐1c , 2004, IUBMB life.

[81]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[82]  H. Baumann,et al.  Insulin Modulates STAT3 Protein Activation and Gene Transcription in Hepatic Cells* , 1996, The Journal of Biological Chemistry.

[83]  B. Spiegelman,et al.  Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. , 1998, The Journal of clinical investigation.

[84]  M. Brosnan,et al.  Hormonal Regulation of Cystathionine β-Synthase Expression in Liver* , 2002, The Journal of Biological Chemistry.

[85]  E. Park,et al.  Conserved Amino Acids within CCAAT Enhancer-binding Proteins (C/EBPα and β) Regulate Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression* , 2002, The Journal of Biological Chemistry.

[86]  R. Aebersold,et al.  Crucial Step in Cholesterol Homeostasis Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein that Facilitates Retention of SREBPs in ER , 2002, Cell.

[87]  T. Jiang,et al.  Modulation of carbohydrate response element-binding protein gene expression in 3T3-L1 adipocytes and rat adipose tissue. , 2004, American journal of physiology. Endocrinology and metabolism.

[88]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[89]  M. Kasuga,et al.  Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. , 2002, Diabetes.

[90]  J. Girard,et al.  Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. , 2005, Biochimie.

[91]  A. Fukamizu,et al.  SREBPs suppress IRS-2-mediated insulin signalling in the liver , 2004, Nature Cell Biology.

[92]  J. M. Agati,et al.  Assessment of the Roles of Mitogen-activated Protein Kinase, Phosphatidylinositol 3-Kinase, Protein Kinase B, and Protein Kinase C in Insulin Inhibition of cAMP-induced Phosphoenolpyruvate Carboxykinase Gene Transcription* , 1998, The Journal of Biological Chemistry.

[93]  G. Rena,et al.  Insulin Regulation of Insulin-like Growth Factor-binding Protein-1 Gene Expression Is Dependent on the Mammalian Target of Rapamycin, but Independent of Ribosomal S6 Kinase Activity* , 2002, The Journal of Biological Chemistry.

[94]  M. Crossley,et al.  Mammalian Krüppel-like transcription factors: more than just a pretty finger. , 1999, Trends in biochemical sciences.

[95]  G. Ness,et al.  Identification of insulin-responsive regions in the HMG-CoA reductase promoter. , 2004, Biochemical and biophysical research communications.

[96]  Guoxun Chen,et al.  Trace: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition Central Role for Liver X Receptor in Insulin-mediated Activation of Srebp-1c Transcription and Stimulation of Fatty Acid Synthesis in Liver. Recommended Citation , 2022 .

[97]  R. Sato,et al.  Sterol Regulatory Element-binding Protein Negatively Regulates Microsomal Triglyceride Transfer Protein Gene Transcription* , 1999, The Journal of Biological Chemistry.

[98]  M. White,et al.  Insulin-induced egr-1 and c-fos Expression in 32D Cells Requires Insulin Receptor, Shc, and Mitogen-activated Protein Kinase, but Not Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Activation* , 1996, The Journal of Biological Chemistry.

[99]  M. Hollenberg,et al.  Activation of Apolipoprotein AI Gene Expression by Protein Kinase A and Kinase C through Transcription Factor, Sp1* , 2000, The Journal of Biological Chemistry.

[100]  J. Paulauskis,et al.  Hormonal regulation of mouse fatty acid synthase gene transcription in liver. , 1989, The Journal of biological chemistry.

[101]  E. De Fabiani,et al.  Identification and characterization of cis-acting elements conferring insulin responsiveness on hamster cholesterol 7alpha-hydroxylase gene promoter. , 2000, The Biochemical journal.

[102]  R. Roth,et al.  Activation of protein kinase B/cAkt in hepatocytes is sufficient for the induction of expression of the gene encoding glucokinase. , 2000, The Biochemical journal.

[103]  G. Schweizer-Groyer,et al.  Multiple liver-enriched trans-acting factors interact with the glucocorticoid- (GRU) and cAMP-(CRU) responsive units within the h-IGFBP-1 promoter. , 1995, Progress in growth factor research.

[104]  Brian A. Hemmings,et al.  Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a) , 2001, Molecular and Cellular Biology.

[105]  G. Ruvkun,et al.  Phosphatidylinositol 3-Kinase Signaling Inhibits DAF-16 DNA Binding and Function via 14-3-3-dependent and 14-3-3-independent Pathways* , 2001, The Journal of Biological Chemistry.

[106]  E. Cánepa,et al.  Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression* , 2004, Journal of Biological Chemistry.

[107]  T. Hurd,et al.  Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation. , 2002, The Biochemical journal.

[108]  P. Iynedjian,et al.  Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. , 2000, The Biochemical journal.

[109]  M. Hollenberg,et al.  Epidermal Growth Factor Induction of Apolipoprotein A-I Is Mediated by the Ras-MAP Kinase Cascade and Sp1* , 2001, The Journal of Biological Chemistry.

[110]  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.

[111]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[112]  H. Sone,et al.  SREBP-1 Interacts with Hepatocyte Nuclear Factor-4α and Interferes with PGC-1 Recruitment to Suppress Hepatic Gluconeogenic Genes* , 2004, Journal of Biological Chemistry.

[113]  P. Santisteban,et al.  Insulin-induced Early Growth Response Gene (Egr-1) Mediates a Short Term Repression of Rat Malic Enzyme Gene Transcription* , 1999, The Journal of Biological Chemistry.

[114]  P. Ribaux,et al.  Analysis of the role of protein kinase B (cAKT) in insulin-dependent induction of glucokinase and sterol regulatory element-binding protein 1 (SREBP1) mRNAs in hepatocytes. , 2003, The Biochemical journal.

[115]  T. Unterman,et al.  FoxO proteins in insulin action and metabolism , 2005, Trends in Endocrinology & Metabolism.

[116]  D. E. Anderson,et al.  Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. , 2003, Biochemistry.

[117]  R. Taub,et al.  Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. , 1990, The Journal of biological chemistry.

[118]  L. Ercolani,et al.  Identification of a core motif that is recognized by three members of the HMG class of transcriptional regulators: IRE‐ABP, SRY, and TCF‐1α , 1992, Journal of cellular biochemistry.

[119]  M. White,et al.  The Pleckstrin Homology and Phosphotyrosine Binding Domains of Insulin Receptor Substrate 1 Mediate Inhibition of Apoptosis by Insulin , 1998, Molecular and Cellular Biology.

[120]  H. Fukuda,et al.  Transcriptional regulation of leptin gene promoter in rat , 1999, FEBS letters.

[121]  P. Cohen,et al.  Phosphorylation of Serine 256 by Protein Kinase B Disrupts Transactivation by FKHR and Mediates Effects of Insulin on Insulin-like Growth Factor-binding Protein-1 Promoter Activity through a Conserved Insulin Response Sequence* , 1999, The Journal of Biological Chemistry.

[122]  C. Kahn,et al.  Insulin stimulates phosphorylation of c-Jun, c-Fos, and Fos-related proteins in cultured adipocytes. , 1994, The Journal of biological chemistry.

[123]  P. Cohen,et al.  Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion , 2002, The EMBO journal.

[124]  Hitomi Matsuzaki,et al.  Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[125]  J. Goldstein,et al.  Topology of SREBP Cleavage-activating Protein, a Polytopic Membrane Protein with a Sterol-sensing Domain* , 1998, The Journal of Biological Chemistry.

[126]  X. Hua,et al.  SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis , 1994, Cell.

[127]  D. Granner,et al.  Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin , 1983, Nature.

[128]  Khan Ah,et al.  Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. , 2002 .

[129]  I. Han,et al.  Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility , 1997, Molecular and cellular biology.

[130]  P. Froguel,et al.  Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity* , 2004, Journal of Biological Chemistry.

[131]  J. Porter,et al.  Control of the synthesis of fatty-acid synthetase in rat liver by insulin, glucagon, and adenosine 3':5' cyclic monophosphate. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[132]  E. Van Obberghen,et al.  Stat 5B, Activated by Insulin in a Jak-Independent Fashion, Plays a Role in Glucokinase Gene Transcription. , 2000, Endocrinology.

[133]  D. Haro,et al.  Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1. , 2002, The Biochemical journal.

[134]  F. Stanley,et al.  A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription* , 2002, The Journal of Biological Chemistry.

[135]  X. Hua,et al.  Hairpin Orientation of Sterol Regulatory Element-binding Protein-2 in Cell Membranes as Determined by Protease Protection * , 1995, The Journal of Biological Chemistry.

[136]  H. Sul,et al.  Insulin Stimulation of the Fatty Acid Synthase Promoter Is Mediated by the Phosphatidylinositol 3-Kinase Pathway , 1998, The Journal of Biological Chemistry.

[137]  R. Hammer,et al.  Diminished Hepatic Response to Fasting/Refeeding and Liver X Receptor Agonists in Mice with Selective Deficiency of Sterol Regulatory Element-binding Protein-1c* , 2002, The Journal of Biological Chemistry.

[138]  N. Wong,et al.  Insulin induction of apolipoprotein AI, role of Sp1. , 2003, Biochemistry.

[139]  M. Foretz,et al.  Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. , 2000, The Biochemical journal.

[140]  H. Lardy,et al.  METABOLIC AND HORMONAL CONTROL OF PHOSPHOENOLPYRUVATE CARBOXYKINASE AND MALIC ENZYME IN RAT LIVER. , 1963, The Journal of biological chemistry.