Insulin and epidermal growth factor suppress basal glucose-6-phosphatase catalytic subunit gene transcription through overlapping but distinct mechanisms.

Onuma H, Oeser JK, Nelson BA, Wang Y, Flemming BP, Scheving LA, Russell WE, O'Brien RM
Biochem J. 2009 417 (2): 611-20

PMID: 18847435 · PMCID: PMC2929524 · DOI:10.1042/BJ20080999

The G6Pase (glucose-6-phosphatase catalytic subunit) catalyses the final step in the gluconeogenic and glycogenolytic pathways, the hydrolysis of glucose-6-phosphate to glucose. We show here that, in HepG2 hepatoma cells, EGF (epidermal growth factor) inhibits basal mouse G6Pase fusion gene transcription. Several studies have shown that insulin represses basal mouse G6Pase fusion gene transcription through FOXO1 (forkhead box O1), but Stoffel and colleagues have recently suggested that insulin can also regulate gene transcription through FOXA2 (forkhead box A2) [Wolfrum, Asilmaz, Luca, Friedman and Stoffel (2003) Proc. Natl. Acad. Sci. 100, 11624-11629]. A combined GR (glucocorticoid receptor)-FOXA2 binding site is located between -185 and -174 in the mouse G6Pase promoter overlapping two FOXO1 binding sites located between (-188 and -182) and (-174 and -168). Selective mutation of the FOXO1 binding sites reduced the effect of insulin, whereas mutation of the GR/FOXA2 binding site had no effect on the insulin response. In contrast, selective mutation of the FOXO1 and GR/FOXA2 binding sites both reduced the effect of EGF. The effect of these mutations was additive, since the combined mutation of both FOXO1 and GR/FOXA2 binding sites reduced the effect of EGF to a greater extent than the individual mutations. These results suggest that, in HepG2 cells, GR and/or FOXA2 are required for the inhibition of basal G6Pase gene transcription by EGF but not insulin. EGF also inhibits hepatic G6Pase gene expression in vivo, but in cultured hepatocytes EGF has the opposite effect of stimulating expression, an observation that may be explained by a switch in ErbB receptor sub-type expression following hepatocyte isolation.

MeSH Terms (20)

Animals Binding Sites Biocatalysis Cells, Cultured Epidermal Growth Factor Gene Expression Regulation, Enzymologic Glucose-6-Phosphatase Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 3-alpha Hepatocyte Nuclear Factor 3-beta Humans Insulin Liver Male Mice Mutation Promoter Regions, Genetic Protein Subunits Rats Transcription, Genetic

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