Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements.

Glucocorticoids stimulate, while insulin inhibits, the hepatic transcription of insulin-like growth factor-binding protein-1 (IGFBP-1). In the present studies, human HEP G2 hepatoma cells were transiently transfected with human (h)IGFBP-1 promoter constructs. Activity of a construct containing the first 1205 base pairs (bp) of the hIGFBP-1 promoter was stimulated 6-9.5-fold by dexamethasone, and this increase was inhibited approximately 76% by insulin. Deletion and site-directed mutations of the hIGFBP-1 promoter (a) identified two glucocorticoid response elements, located within the first 200 bp of the promoter, which are essential for dexamethasone-stimulated promoter activity and which specifically bind human glucocorticoid receptor; (b) showed that a recently characterized insulin-responsive element, located approximately 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 entire inhibitory effect of insulin not only on basal but also on glucocorticoid-stimulated promoter activity; and (c) showed that this insulin-responsive element is essential for maximal glucocorticoid-stimulated activity. These studies suggest that the interaction of proteins that 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 hepatic hIGFBP-1 expression.