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

Patel, Satish; Lochhead, Pamela A.; Rena, Graham; Fumagalli, Stefano; Pende, Mario; Kozma, Sara C.; Thomas, George; Sutherland, Calum

doi:10.1074/jbc.m109870200

Cited by 41 publications

(67 citation statements)

References 62 publications

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“…Thus, several such studies have concluded that insulin regulates the expression of these genes through distinct pathways. For example, insulin regulation of IGFBP-1 gene expression (81,82), although not PEPCK (83) or G6Pase (43) gene expression, is dependent on the mammalian target of rapamycin. Moreover, it is likely that the regulation of these genes is highly complex, given the large number of kinase inhibitors/activators that can affect their expression (84 -86).…”

Section: Discussionmentioning

confidence: 99%

The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct

Kooi

Streeper

Svitek

et al. 2003

Journal of Biological Chemistry

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Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by insulin requires two distinct promoter regions, designated A (located between ؊231 and ؊199) and B (located between ؊198 and ؊159), that together form an insulin response unit. Region A binds hepatocyte nuclear factor-1, which acts as an accessory factor to enhance the effect of insulin, mediated through region B, on G6Pase gene transcription. We have previously shown that region B binds the transcriptional activator FKHR (FOXO1a) in vitro. Chromatin immunoprecipitation assays demonstrate that FKHR also binds the G6Pase promoter in situ and that insulin inhibits this binding. Region B contains three insulin response sequences (IRSs), designated IRS 1, 2, and 3, that share the core sequence T(G/A)TTTT. However, detailed analyses reveal that these three G6Pase IRSs are functionally distinct. Thus, FKHR binds IRS 1 with high affinity and IRS 2 with low affinity but it does not bind IRS 3. Moreover, in the context of the G6Pase promoter, IRS 1 and 2, but not IRS 3, are required for the insulin response. Surprisingly, IRS 3, as well as IRS 1 and IRS 2, can each confer an inhibitory effect of insulin on the expression of a heterologous fusion gene, indicating that, in this context, a transcription factor other than FKHR, or its orthologs, can also mediate an insulin response through the T(G/A)TTTT motif.

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Section: Discussionmentioning

confidence: 99%

The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct

Kooi

Streeper

Svitek

et al. 2003

Journal of Biological Chemistry

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“…A dissociation between TOR kinase activity and rapamycin action has been already described (40,41). Additionally, a recent example of discrepancy between rapamycin inhibition and p70S6K activity could be found in (42). At any rate, an inhibitor of a S6K cellular pool should be enough to explain the profound physiological effect of rapamycin on chemotaxis.…”

Section: Human Neutrophils Express P70s6k and Gm-csf Increasesmentioning

confidence: 99%

Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils

Lehman

Calvo

Gómez‐Cambronero

2003

Journal of Biological Chemistry

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“…Transient transfections. A reporter construct encompassing a luciferase cDNA under the control of a thymidine kinase gene promoter containing the IGFBP1 thymine-rich insulin response element (BP1-TIRE) was transfected with or without an expression construct for glutathione-S-transferase-FOXO1 (pEBG-FOXO1) into HL1c cells as previously described (26,33). Cells were incubated for 16 h with hormones as indicated in the figure legends before harvesting and assaying for luciferase activity.…”

Section: Methodsmentioning

confidence: 99%

“…6). Cells tranfected with BP1-TIRE (a FOXO reporter construct) express luciferase activity that is reduced ϳ50% by incubation with insulin (26). The expression of a glutathione S-transferase-FOXO1 fusion protein induces luciferase expression, but this remains sensitive to repression by insulin (Fig.…”

Section: Akti-1/2 Is a Specific Inhibitor Of Pkb␣ And Pkb␤mentioning

confidence: 99%

“…However the importance of PKB and/or FOXO in the regulation of these genes has been questioned (18,28). For example, overexpression of dominant-negative PKB does not block insulin action on PEPCK (29) or G6Pase (22) and inhibitors of mTOR will block insulin regulation of IGFBP1 but not PKB or FOXO (21,26), while inhibitors of GSK3 (also downstream of PKB) will inhibit these genes without regulating FOXO activity (30,31). It is also suggested that insulin can Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0343.…”

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Characterization of a Protein Kinase B Inhibitor In Vitro and in Insulin-Treated Liver Cells

et al. 2007

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OBJECTIVE-Abnormal expression of the hepatic gluconeogenic genes (glucose-6-phosphatase [G6Pase] and PEPCK) contributes to hyperglycemia. These genes are repressed by insulin, but this process is defective in diabetic subjects. Protein kinase B (PKB) is implicated in this action of insulin. An inhibitor of PKB, Akt inhibitor (Akti)-1/2, was recently reported; however, the specificity and efficacy against insulin-induced PKB was not reported. Our aim was to characterize the specificity and efficacy of Akti-1/2 in cells exposed to insulin and then establish whether inhibition of PKB is sufficient to prevent regulation of hepatic gene expression by insulin.RESEARCH DESIGN AND METHODS-Akti-1/2 was assayed against 70 kinases in vitro and its ability to block PKB activation in cells exposed to insulin fully characterized.RESULTS-Akti-1/2 exhibits high selectivity toward PKB␣ and PKB␤. Complete inhibition of PKB activity is achieved in liver cells incubated with 1-10 mol/l Akti-1/2, and this blocks insulin regulation of PEPCK and G6Pase expression. Our data demonstrate that only 5-10% of maximal insulin-induced PKB is required to fully repress PEPCK and G6Pase expression. Finally, we demonstrate reduced insulin sensitivity of these gene promoters in cells exposed to submaximal concentrations of Akti-1/2; however, full repression of the genes can still be achieved by high concentrations of insulin.CONCLUSIONS-This work establishes the requirement for PKB activity in the insulin regulation of PEPCK, G6Pase, and a third insulin-regulated gene, IGF-binding protein-1 (IGFBP1); suggests a high degree of functional reserve; and identifies Akti-1/2 as a useful tool to delineate PKB function in the liver. Diabetes 56:2218-2227, 2007 P rotein kinase B (PKB) is a member of the AGC family of protein kinases (1-3). In mammals, there are three isoforms (PKB␣, PKB␤, and PKB␥) (1). PKB is activated following induction of phosphatidylinositol 3 (PI3) kinase activity and the resultant generation of the lipid second messengers PI 3,4,5 trisphosphate and PI 3,4 bisphosphate (4). These lipids bind to the PH domain of PKB, altering its conformation and permitting access to upstream protein kinases (5). Phosphoinositide-dependent protein kinase-1 phosphorylates PKB at Thr 308 (6), and a second phosphorylation (at Ser 473 ) occurs through the action of an alternative kinase, such as the rapamycin-insensitive mTOR complex 2 (TORC2) (7). Therefore, most growth factors, including platelet-derived growth factor, epidermal growth factor, and insulin, which are potent activators of PI3 kinase, also strongly induce PKB in cells.One of the first substrates of PKB to be characterized was GSK3, as part of the insulin signaling pathway that regulates glycogen metabolism (8). Since then, multiple potential substrates of PKB have been proposed including the proapoptotic protein Bad (9,10), the tuberous sclerosis complex (TSC)2 gene product (11), the Rab-GAP AS160 (12), proline-rich Akt substrate of 40 kDa (PRAS40) (13), and the key forkhead transcription ...

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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

Cited by 41 publications

References 62 publications

The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct

The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct

Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils

Characterization of a Protein Kinase B Inhibitor In Vitro and in Insulin-Treated Liver Cells

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