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Inhibition by Insulin of Glucocorticoid-Induced Gene Transcription: Involvement of the Ligand-Binding Domain of the Glucocorticoid Receptor and Independence from the Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Pathways

Hormone and Metabolic Research Unit (C.E.P., G.G.R., F.P.L.) Louvain University Medical School Christian de Duve Institute of Cellular Pathology (ICP) B-1200 Brussels, Belgium
Department of Molecular Signaling (B.U., P.D.M.) Hagedorn Research Institute DK-2820 Gentofte, Denmark

Insulin can inhibit the stimulatory effect of glucocorticoid hormones on the transcription of genes coding for enzymes involved in glucose metabolism. We reported earlier that insulin inhibits the glucocorticoid-stimulated transcription of the gene coding for liver 6-phosphofructo-2-kinase (PFK-2). To elucidate the mechanism of these hormonal effects, we have studied the regulatory regions of the PFK-2 gene in transfection experiments. We found that both glucocorticoids and insulin act via the glucocorticoid response unit (GRU) located in the first intron. Footprinting experiments showed that the GRU binds not only the glucocorticoid receptor (GR), but also ubiquitous [nuclear factor I (NF-I)] and liver-enriched [hepatocyte nuclear factor (HNF)-3, HNF-6, CAAT/enhancer binding protein (C/EBP)] transcription factors. Site-directed mutational analysis of the GRU revealed that these factors modulate glucocorticoid action but that none of them seems to be individually involved in the inhibitory effect of insulin. We did not find an insulin response element in the GRU, but we showed that insulin targets the GR. Insulin-induced inhibition of the glucocorticoid stimulation required the ligand-binding domain of the GR. Finally, the insulin-signaling cascade involved was independent of the phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways. Together, these results suggest that insulin acts on the PFK-2 gene via another pathway and targets either the GR in its ligand-binding domain or a cofactor interacting with this domain.

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