The human insulin gene contains multiple transcriptional elements that respond to glucocorticoids

Glucocorticoids inhibit insulin expression in cultured pancreatic islet cel ls. In this study, me provide evidence that transcriptional downregulation of insulin gene expression by glucocorticoids is the result of synergistic interaction between various elements of the insulin promoter. Similar syner gistic effects on insulin gene transcription were previously reported for o ther key insulin regulators, cyclic adenosine monophosphate:(cAMP) and gluc ose. Transfection of CAT constructs containing different segments of the in sulin promoter into the pancreatic cell line, HIT T-15 2.2.2, demonstrated that dexamethasone decreased CAT activity in all constructs tested. However , differences were found in the relative sensitivities of the Various const ructs . Glucocorticoid inhibition of expression from plasmids containing A elements may result from decreased expression of the pancreatic homeodomain protein STF-1. However, a different mechanism must be invoked for insulin promoter constructs lacking A sites, which nevertheless still demonstrated negative regulation. Glucocorticoid-induced inhibition of one of these regi ons (-882 to -342) was seen to require pancreas-specific factors, because i nhibition was observed in HIT T-15:2.2.2 cells but not in the nonpancreatic COS-1 cells. We conclude, therefore, that the human insulin gene contains multiple transcriptional elements that respond to glucocorticoids, some of which require beta cell-specific factors.