Phosphorylation and Inhibition of Rat Glucocorticoid Receptor Transcriptional Activation by Glycogen Synthase Kinase-3 (GSK-3)

Rogatsky, Inez; Waase, Carine L.M.; Garabedian, Michael J.

doi:10.1074/jbc.273.23.14315

Cited by 115 publications

(34 citation statements)

References 46 publications

(42 reference statements)

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“…Therefore, it is possible that GSK-3 inhibitors have effects on GR activity independent of the promoter studied. However, Rogatsky et al (40) also found that the inhibition of GSK-3 by overexpression of PKB actually enhances gene activation by rat GR, consistent with the phosphorylation of GR by GSK-3 causing inhibition of GR activity. However, the overexpression of GSK-3␣ in H4IIE cells does not affect basal or dexamethasone-induced levels of G6Pase or PEPCK gene expression (Fig.…”

Section: Gsk-3 Inhibitors Have Therapeutic Potential For the Treatmenmentioning

confidence: 93%

“…Therefore, the molecular target(s) of GSK-3 must be required for the PEPCK and G6Pase promoters to function. The glucocorticoid receptor (GR) is reported to be a substrate for GSK-3 in vitro and in rat cells (40), with ϳ40% reduction in GR transcriptional activity caused by the overexpression of GSK-3. Therefore, it is possible that GSK-3 inhibitors have effects on GR activity independent of the promoter studied.…”

Section: Gsk-3 Inhibitors Have Therapeutic Potential For the Treatmenmentioning

confidence: 99%

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Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

et al. 2001

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A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized. T he cellular actions of insulin include increased glucose transport, glycogen synthesis, and lipogenesis and decreased gluconeogenesis, glycogen, and fat breakdown. The result is reduced hepatic glucose output and increased peripheral glucose utilization. In type 2 diabetes, most of the intracellular actions of insulin are reduced or absent (1-3), yet the identity of the lesions underlying insulin resistance is not clear. To find ways to combat insulin resistance, much research focuses on the insulin-regulated signaling pathways that normally mediate glucose production and/or glucose utilization and that connect the insulin receptor to the proteins that directly mediate each action of insulin. The initial step in insulin signaling involves the binding of insulin to its specific cell surface receptor and activation of the tyrosine kinase activity of the receptor, followed by the phosphorylation of a small subset of proteins, including a group of proteins termed insulin receptor substrates (4). From this point, multiple signaling cascades are activated including the p42/p44 mitogen-activated protein (MAP) kinase cascade, the phosphatidylinositol (PI) 3-kinase-mTOR-p70 S6 kinase cascade, and the PI 3-kinase-PI 3,4,5-Tris phosphate-dependent kinase (PDK)-protein kinase B (PKB) cascade (rev. in 5). The activation of PKB by PDK-1 (5-8) leads to the phosphorylation of multiple cellular proteins including glycogen synt...

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Section: Gsk-3 Inhibitors Have Therapeutic Potential For the Treatmenmentioning

confidence: 93%

Section: Gsk-3 Inhibitors Have Therapeutic Potential For the Treatmenmentioning

confidence: 99%

Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

et al. 2001

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“…c-Jun (41), c-Myc, C/EBP␤, ␤-catenin (see Ref. 17), glucocorticoid receptor (42), and androgen receptor (43)(44)(45)). A dual function of GSK-3 has been suggested regarding NFB where phosphorylation at two different sites results either in stabilization or in proteolytic degradation (46).…”

Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Interacts with and Phosphorylates Estrogen Receptor α and Is Involved in the Regulation of Receptor Activity

Medunjanin

Hermani

Servi³

et al. 2005

Journal of Biological Chemistry

125

116

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“…The pCMV-4 control plasmid was a gift from D. Russell. The plasmids were generated in the authors laboratories and included pCDNA3-Flag-JBD, pCGN/GSK-3wt, pCGN/GSK-3 ⌬9 , and pCGN/GSK-3 Y216F (32)(33)(34). Cells were plated at a density of 40% in triplicate wells, using six-well plates.…”

Section: Methodsmentioning

confidence: 99%

Alleviating the Suppression of Glycogen Synthase Kinase-3β by Akt Leads to the Phosphorylation of cAMP-response Element-binding Protein and Its Transactivation in Intact Cell Nuclei

Salas

Reddy

Clifford

et al. 2003

Journal of Biological Chemistry

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Glycogen synthase kinase-3␤ (GSK-3␤) activity is suppressed when it becomes phosphorylated on serine 9 by protein kinase B (Akt). To determine how GSK-3␤ activity opposes Akt function we used various methods to alleviate GSK-3␤ suppression in prostate carcinoma cells. In some experiments, LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (a kinase involved in activating Akt) and tumor necrosis factor-␣ (TNF-␣) were used to activate GSK-3␤. In other experiments mutant forms of GSK-3␤, GSK-3␤ ⌬9 (a constitutively active deletion mutant of GSK-3␤) and GSK-3␤ Y216F (an inactive point mutant of GSK-3␤) were used to alter GSK-3␤ activity. LY294002, TNF-␣, and overexpression of wild-type GSK-3␤ or of GSK-3␤

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Phosphorylation and Inhibition of Rat Glucocorticoid Receptor Transcriptional Activation by Glycogen Synthase Kinase-3 (GSK-3)

Cited by 115 publications

References 46 publications

Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

Glycogen Synthase Kinase-3 Interacts with and Phosphorylates Estrogen Receptor α and Is Involved in the Regulation of Receptor Activity

Alleviating the Suppression of Glycogen Synthase Kinase-3β by Akt Leads to the Phosphorylation of cAMP-response Element-binding Protein and Its Transactivation in Intact Cell Nuclei

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