Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription

Streeper, Ryan S.; Eaton, Erin M.; Ebert, Daniel H.; Chapman, Stacey C.; Svitek, Christina A.; O’Brien, Richard M.

doi:10.1073/pnas.95.16.9208

Cited by 53 publications

(78 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This confirms previous reports demonstrating that the IRU of the Glc-6-Pase promoter is able to transfer insulin regulation to a heterologous promoter (5,26). In addition, we found that the overexpression of the constitutively active PKB was able to suppress the basal expression of the construct pGL(PDH-IRU) but not that of the construct pGL(PDH) (Fig.…”

Section: Fig 4 Binding Of Fkhr To the Iru Transactivates The Promotsupporting

confidence: 80%

“…Therefore, it might be that the transactivation by FKHR is enhanced by additional proteins, which bind to cis-active elements located in the Glc-6-Pase promoter, but not in the pGL(PDH-IRU) construct. Previous studies suggest that HNF-1 acts as an accessory factor for the insulin effect mediated by the IRU of the Glc-6-Pase promoter (26). A recent report (33) indicates that HNF-1 and the Forkhead protein HNF-3␤ exhibit a synergistic effect on the GLUT2 gene promoter activity.…”

Section: Discussionmentioning

confidence: 99%

“…This IRU is involved in the repression of basal and stimulated Glc-6-Pase gene transcription by insulin (5,26). The Glc-6-Pase IRU region is located between nucleotides Ϫ198 and Ϫ159 in the mouse promoter (5) and between nucleotides Ϫ196 and Ϫ156 in the human promoter (5,26,27). Recently, it has been shown that recombinant FKHR is able to bind to a double-stranded oligonucleotide probe containing this sequence (27).…”

mentioning

confidence: 99%

“…This IRU contains three potential Forkhead-binding sites with sequences similar to the insulin response sequences in the IGFBP-1 gene (5,17,26,27). This IRU is involved in the repression of basal and stimulated Glc-6-Pase gene transcription by insulin (5,26). The Glc-6-Pase IRU region is located between nucleotides Ϫ198 and Ϫ159 in the mouse promoter (5) and between nucleotides Ϫ196 and Ϫ156 in the human promoter (5,26,27).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 4 more Smart Citations

Regulation of Glucose-6-phosphatase Gene Expression by Protein Kinase Bα and the Forkhead Transcription Factor FKHR

Schmoll

Walker

Alessi

et al. 2000

Journal of Biological Chemistry

305

108

View full text Add to dashboard Cite

Glucose-6-phosphatase plays an important role in the regulation of hepatic glucose production, and insulin suppresses glucose-6-phosphatase gene expression. Recent studies indicate that protein kinase B and Forkhead proteins contribute to insulin-regulated gene expression in the liver. Here, we examined the role of protein kinase B and Forkhead proteins in mediating effects of insulin on glucose-6-phosphatase promoter activity. Transient transfection studies with reporter gene constructs demonstrate that insulin suppresses both basal and dexamethasone/cAMP-induced activity of the glucose-6-phosphatase promoter in H4IIE hepatoma cells. Both effects are partially mimicked by coexpression of protein kinase B␣. Coexpression of the Forkhead transcription factor FKHR stimulates the glucose-6-phosphatase promoter activity via interaction with an insulin response unit (IRU), and this activation is suppressed by protein kinase B. Coexpression of a mutated form of FKHR that cannot be phosphorylated by protein kinase B abolishes the regulation of the glucose-6-phosphatase promoter by protein kinase B and disrupts the ability of insulin to regulate the glucose-6-phosphatase promoter via the IRU. Mutation of the insulin response unit of the glucose-6-phosphatase promoter also prevents the regulation of promoter activity by FKHR and protein kinase B but only partially impairs the ability of insulin to suppress both basal and dexamethasone/ cAMP-stimulated promoter function. Taken together, these results indicate that signaling by protein kinase B to Forkhead proteins can account for the ability of insulin to regulate glucose-6-phosphatase promoter activity via the IRU and that other mechanisms that are independent of the IRU, protein kinase B, and Forkhead proteins also are important in mediating effects of in insulin on glucose-6-phosphatase gene expression.Glucose-6-phosphatase (Glc-6-Pase) 1 catalyzes the hydrolysis of glucose 6-phosphate to glucose, which is the terminal step of both hepatic gluconeogenesis and glycogen breakdown. Glc-6-Pase is induced in starved and diabetic animals (1, 2). In vitro models have shown that glucocorticoids and cAMP induce Glc-6-Pase gene expression. This effect is opposed by insulin, which also is able to reduce basal expression of the Glc-6-Pase gene (3-6). Identification of the signaling events that connect the insulin receptor to the Glc-6-Pase promoter, leading to the subsequent repression of gene transcription, is of particular interest because Glc-6-Pase plays a key role in the regulation of hepatic glucose production and blood glucose homeostasis.In H4IIE hepatoma cells, activation of class 1a phosphoinositide 3-kinase (PI 3-kinase), but not of the Ras/Raf/MAP kinase pathway, is necessary for the suppression of Glc-6-Pase promoter activity by insulin (6). The formation of PtdIns(3,4,5)P 3 catalyzed by PI 3-kinase has been shown to increase the activity of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and to result in a conformational change in PKB which renders it susceptible...

show abstract

Section: Fig 4 Binding Of Fkhr To the Iru Transactivates The Promotsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Regulation of Glucose-6-phosphatase Gene Expression by Protein Kinase Bα and the Forkhead Transcription Factor FKHR

Schmoll

Walker

Alessi

et al. 2000

Journal of Biological Chemistry

305

108

View full text Add to dashboard Cite

show abstract

Genetic Regulation of Glucose Metabolism

Sutherland

O’Brien

Granner

2001

Comprehensive Physiology

View full text Add to dashboard Cite

The sections in this article are: Glucagon and Insulin Action Signaling from the Cell Membrane to the Nucleus DNA Elements and Their Binding Proteins Genetic Regulation of the Hepatic Gluconeogenic Enzymes Glucose‐6‐Phosphatase Fructose‐1,6‐Bisphosphatase Phosphoenolpyruvate Carboxykinase Genetic Regulation of the Hepatic Glycolytic Enzymes Glucokinase 6‐Phosphofructo‐1‐Kinase Pyruvate Kinase 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Bisphosphatase Genetic Regulation of Other Proteins Involved in Glucose Metabolism Glyceraldehyde‐3‐Phosphate Dehydrogenase Tyrosine Aminotransferase GLUT‐1 Glucose Transporter Hexokinase II Genetic Regulation of Lipogenic Enzymes Acetyl‐CoA Carboxylase Fatty Acid Synthase Malic Enzyme Conclusions and Perspectives

show abstract