title: Hepatocyte nuclear factor 1 and the glucocorticoid receptor synergistically activate transcription of the rat insulin-like growth factor binding protein-1 gene.
abstract: The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of proteins that bind IGF-I and IGF-II and modulate their biological activities. IGFBP-1 is distinctive among the IGFBPs in its rapid regulation in response to metabolic and hormonal changes. The synthetic glucocorticoid, dexamethasone, increases IGFBP-1 mRNA abundance and gene transcription in rat liver and in H4-II-E rat hepatoma cells. A glucocorticoid response element (GRE) located at nucleotide (nt) -91/-77 is required for dexamethasone to stimulate rat IGFBP-1 promoter activity in transient transfection assays in H4-II-E cells. In addition to the GRE, three accessory regulatory sites [a putative hepatocyte nuclear factor-1 (HNF-1) site (nt -62/-50), an insulin-response element (nt -108/-99), and an upstream site (nt -252/-236)] are involved in dexamethasone stimulation under some, but not all, circumstances. The present study begins to address the mechanism by which transcription factors bound to the putative HNF-1 site act synergistically with the glucocorticoid receptor (GR) bound to the GRE. In gel shift assays, HNF-1alpha and HNF-1beta in H4-II-E extracts bind to the palindromic HNF-1 site. Both half-sites are required. Overexpression of HNF-1beta enhances dexamethasone-stimulated promoter activity. Both the HNF-1 site and the GRE must be intact for stimulation to occur. By contrast, overexpression of HNF-1alpha does not enhance dexamethasone-stimulated promoter activity, although, as also observed with overexpression of HNF-1beta, it inhibits basal promoter activity. Thus, the synergistic effects of HNF-1beta and the GR on dexamethasone-stimulated promoter activity require that they are bound to the HNF-1 site and the GRE, respectively, and may involve protein-protein interactions between the transcription factors, or between them and the basal transcription machinery or a steroid receptor coactivator. Synergy between the ubiquitously expressed GR and HNF-1, which is developmentally regulated and expressed in a limited number of tissues, provides a possible mechanism for tissue- and development-specific regulation of glucocorticoid action.
authors.affiliation: Molecular and Cellular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Suh
authors.forename: M M
authors.initials: MM
authors.lastname: Rechler
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D009687:Nuclear Proteins; D011257:Pregnancy Proteins / Q000187:drug effects / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496489:Hnf1a protein, rat; D009687:Nuclear Proteins; D011257:Pregnancy Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C489170:pregnancy-associated alpha 1-glycoprotein, rat; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D003907:Dexamethasone