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Growth and Development Section Molecular and Cellular Endocrinology Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892
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-1
and HNF-1ß in H4-II-E extracts bind to the palindromic HNF-1
site. Both half-sites are required. Overexpression of HNF-1ß 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-1 does not enhance dexamethasone-stimulated
promoter activity, although, as also observed with overexpression of
HNF-1ß, it inhibits basal promoter activity. Thus, the synergistic
effects of HNF-1ß 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.
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