We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Evidence for the Involvement of Protein Kinase B but Not Foxa2 in the Inhibition of Glucose-6-Phosphatase catalytic Subunit Gene Transcription by Insulin.
- Authors
Onuma, Hiroshi; Oeser, James K.; O'Brien, Richard M.
- Abstract
The glucose-6-phosphatase catalytic subunit (G6Pase) plays a key role in hepatic glucose production (HGP). The transcription factor that mediates the inhibitory action of insulin on G6Pase gene transcription is a potential target for therapies designed to reduce HGP in diabetic patients, but the identity of this factor and the signal transduction pathway through which insulin mediates its action have been controversial. Several investigators have suggested that protein kinase B (PKB) mediates the action of insulin on G6Pase gene expression on the basis of the observation that overexpression of constitutively active PKB mimics the effect of insulin by suppressing G6Pase fusion gene expression whereas overexpression of dead kinase PKB has no effect. However, we and other investigators find that overexpression of both constitutively active and dead kinase PKB suppresses G6Pase fusion gene expression. While the reason for this discrepancy is unclear, we show here that the recently described PKB inhibitor, Inhibitor VIII, inhibits the effect of insulin on basal G6Pase fusion gene expression in the human HepG2 hepatoma cell line suggesting that PKB is required for this action of insulin. It has previously been proposed that PKB suppresses G6Pase gene expression by stimulating the phosphorylation and nuclear exclusion of the transcription factor FOXO1. However, more recently Stoffel and colleagues have suggested that the target of PKB action is actually the transcription factor Foxa2. To address this controversy we have performed a mutational analysis of two overlapping FOXO1 and Foxa2 binding sites in the G6Pase promoter. The data demonstrate that the action of insulin correlates with FOXO1 but not Foxa2 binding. In addition, we show that when wild type Foxa2 and a mutant form of Foxa2, containing a mutation in the putative PKB phosphorylation site, are overexpressed in HepG2 ceils they are both equally efficacious at stimulating basal G6Pase fusion gene expression. However, both impair the effect of insulin on basal and glucocorticoid-stimulated G6Pase fusion gene expression. In contrast overexpression of FOXO1 in HepG2 cells stimulates G6Pase fusion gene expression and the magnitude of the insulin response is unaltered again suggesting that FOXO1 rather than Foxa2 mediates this action of insulin.
- Subjects
PROTEIN kinases; GLUCOSE-6-phosphatase; INSULIN; DIABETES; TRANSCRIPTION factors; PEOPLE with diabetes
- Publication
Diabetes, 2007, Vol 56, pA346
- ISSN
0012-1797
- Publication type
Article