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Diabetes 53:899-910, 2004
© 2004 by the American Diabetes Association, Inc.
Protein Kinase B-
Inhibits Human Pyruvate Dehydrogenase Kinase-4 Gene Induction by Dexamethasone Through Inactivation of FOXO Transcription Factors
1 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
2 Departments of Medicine and Physiology and Biophysics, University of Illinois at Chicago College of Medicine and VA Chicago Healthcare System, Chicago, Illinois
Starvation and diabetes increase pyruvate dehydrogenase kinase-4 (PDK4) expression, which conserves gluconeogenic substrates by inactivating the pyruvate dehydrogenase complex. Mechanisms that regulate PDK4 gene expression, previously established to be increased by glucocorticoids and decreased by insulin, were studied. Treatment of HepG2 cells with dexamethasone increases the relative abundance of PDK4 mRNA, and insulin blocks this effect. Dexamethasone also increases human PDK4 (hPDK4) promoter activity in HepG2 cells, and insulin partially inhibits this effect. Expression of constitutively active PKB
abrogates dexamethasone stimulation of hPDK4 promoter activity, while coexpression of constitutively active FOXO1a or FOXO3a, which are mutated to alanine at the three phosphorylation sites for protein kinase B (PKB), disrupts the ability of PKB to inhibit promoter activity. A glucocorticoid response element for glucocorticoid receptor (GR) binding and three insulin response sequences (IRSs) that bind FOXO1a and FOXO3a are identified in the hPDK4 promoter. Mutation of the IRSs reduces the ability of glucocorticoids to stimulate PDK4 transcription. Transfection studies with E1A, which binds to and inactivates p300/CBP, suggest that interactions between p300/CBP and GR as well as FOXO factors are important for glucocorticoid-stimulated hPDK4 expression. Insulin suppresses the hPDK4 induction by glucocorticoids through inactivation of the FOXO factors.
Address correspondence and reprint requests to Dr. Robert A. Harris, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 4053, Indianapolis, IN 46202-5122. E-mail: raharris{at}iupui.edu
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