GLUCOCORTICOIDS AND INSULIN REGULATE EXPRESSION OF THE HUMAN GENE FORINSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-1 THROUGH PROXIMAL PROMOTER ELEMENTS

Glucocorticoids stimulate, while insulin inhibits, the hepatic transcr iption of insulin-like growth factor-binding protein-1 (IGFBP-1). In t he present studies, human HEP G2 hepatoma cells were transiently trans fected with human (h)IGFBP-1 promoter constructs. Activity of a constr uct containing the first 1205 base pairs (bp) of the hIGFBP-1 promoter was stimulated 6-9.5-fold by dexamethasone, and this increase was inh ibited similar to 76% by insulin. Deletion and site-directed mutations of the hIGFBP-1 promoter (a) identified two glucocorticoid response e lements, located within the first 200 bp of the promoter, which are es sential for dexamethasone-stimulated promoter activity and which speci fically bind human glucocorticoid receptor; (b) showed that a recently characterized insulin-responsive element, located similar to 110 bp 5 ' to the transcription start site (Suwanichkul, A., Morris, S. L., and Powell, D. R. (1993) J. Biol. Chem. 268, 17063-17068), confers the en tire inhibitory effect of insulin not only on basal but also on glucoc orticoid-stimulated promoter activity; and (c) showed that this insuli n-responsive element is essential for maximal glucocorticoid-stimulate d activity. These studies suggest that the interaction of proteins tha t bind to a cluster of cis elements located in the first 200 bp of the hIGFBP-1 promoter are of major importance in modulating the opposing effects of glucocorticoids and insulin on he patic hIGFBP-1 expression .