Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element
Citation:
Finlay D., Patel S., Dickson L.M., Shapiro N., Marquez R., Rhodes C.J., Sutherland C., Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element, BMC Molecular Biology, 5, 15, 2004Download Item:
Abstract:
Background: Hepatic expression of several gene products involved in glucose metabolism, including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and insulin-like growth factor binding protein-1 (IGFBP-1), is rapidly and completely inhibited by insulin. This inhibition is mediated through the regulation of a DNA element present in each of these gene promoters, that we call the Thymine-rich Insulin Response Element (TIRE). The insulin signalling pathway that results in the inhibition of these gene promoters requires the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the molecules that connect PI 3-kinase to these gene promoters are not yet fully defined. Glycogen Synthase Kinase 3 (GSK-3) is inhibited following activation of PI 3-kinase. We have shown previously that inhibitors of GSK-3 reduce the activity of two TIRE-containing gene promoters (PEPCK and G6Pase), whose products are required for gluconeogenesis.
Results: In this report we demonstrate that in H4IIE-C3 cells, four distinct classes of GSK-3 inhibitor mimic the effect of insulin on a third TIRE-containing gene, IGFBP-1. We identify the TIRE as the minimum requirement for inhibition by these agents, and demonstrate that the target of GSK-3 is unlikely to be the postulated TIRE-binding protein FOXO-1. Importantly, overexpression of GSK-3 in cells reduces the insulin regulation of TIRE activity as well as endogenous IGFBP-1 expression.
Conclusions: These results implicate GSK-3 as an intermediate in the pathway from the insulin receptor to the TIRE. Indeed, this is the first demonstration of an absolute requirement for GSK-3 inhibition in insulin regulation of gene transcription. These data support the potential use of GSK-3 inhibitors in the treatment of insulin resistant states such as Type 2 diabetes mellitus, but suggest that it will be important to identify all TIRE-containing genes to assess potential side effects of these agents.
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http://people.tcd.ie/finlaydDescription:
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Author: Finlay, David
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Journal ArticleCollections
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BMC Molecular Biology5
15
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Full text availableKeywords:
Genetics, GSK-3, Insulin, IGFBP-1 gene transcriptionDOI:
http://dx.crossref.org/10.1186%2F1471-2199-5-15Metadata
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