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.

Ayala, Julio E.; Streeper, Ryan S.; Desgrosellier, Jay S.; Durham, Susan K.; Suwanichkul, Adisak; Svitek, Christina A.; Goldman, Joshua K.; Barr, Frederic G.; Powell, David R.; O'Brien, RM

doi:10.2337/diabetes.48.9.1885

Cited by 107 publications

(80 citation statements)

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“…To generate the construct Glc-6-Pase(Ϫ1227/ϩ57/IRUmut) the IRU within the vector Glc-6-Pase(Ϫ1227/ϩ57) was mutated from Ϫ196 5Ј-CGATCAGGCTGTTTTTGTGTGCCTGTTTTTCTATTTTACG-3Ј Ϫ156 to 5Ј-CGATCAGGCTCGAGTTGTGTGCCTCTTTTTCTCTTTTACG-3Ј (mutated nucleotides are underlined). These mutations replace residues that are critical for mediating effects of insulin via related insulin response sequences (T(G/A)TTT) (11,14,15,20) and include mutations of nucleotides that have been shown to be critical for the binding of recombinant FKHR to the IRU (27). The construct pGL(PDH) was created by cloning nt Ϫ929 to ϩ79 of the E1␣-subunit of the human pyruvate dehydrogenase (E1␣-PDH) gene into the HindIII/XhoI sites of pGL3.…”

Section: Methodsmentioning

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).…”

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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).…”

mentioning

confidence: 99%

“…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). In the present paper, we report that FKHR is able to stimulate and that PKB is able to decrease basal and dexamethasone/cAMP-stimulated Glc-6-Pase promoter activity.…”

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confidence: 99%

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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

306

108

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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...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

306

108

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“…A carbohydrate response element identified in the mouse and rat G6pc promoters is not conserved in the human G6PC promoter [32]. However, the mechanism by which insulin suppresses both mouse G6pc-and human G6PC-luciferase fusion gene expression in human HepG2 hepatoma cells appears identical [33]. Likewise, the synthetic glucocorticoid, dexamethasone, equally stimulates mouse G6pc-and human G6PC-luciferase fusion gene expression in rat H4IIE hepatoma cells (Fig.…”

Section: Resultsmentioning

confidence: 96%

Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

et al. 2008

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FOXO transcription factors at the interface of metabolism and cancer

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Fernández-Marcos

2017

Intl Journal of Cancer

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Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer. FOXOs are transcription factors that orchestrate programs of gene expression known to control a variety of processes in response to cellular stress. Genes regulated by this family of proteins are involved in the regulation of cellular energy production, oxidative stress resistance and cell viability and proliferation. Accordingly, FOXO factors have been shown to play an important role in the suppression of tumour growth and in the regulation of metabolic homeostasis. There is emerging evidence that deregulation of FOXO factors might account for the association between insulin resistance-related metabolic disorders and cancer.

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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.

Cited by 107 publications

References 8 publications

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

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

Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

FOXO transcription factors at the interface of metabolism and cancer

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