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.
Suwanichkul
A
A
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Allander
S V
SV
Morris
S L
SL
Powell
D R
DR
D001483:Base Sequence; D001665:Binding Sites; D003907:Dexamethasone / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007328:Insulin; D009838:Oligodeoxyribonucleotides; D011965:Receptors, Glucocorticoid; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone