POSITIVE COTRANSCRIPTIONAL REGULATION OF INTESTINAL CALBINDIN-D28K GENE-EXPRESSION BY 1,25-DIHYDROXYVITAMIN-D3 AND GLUCOCORTICOIDS

The steroid hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] induces expression of the gene encoding calbindin-D28K, a protein involved in intestinal Ca2+ transport. Glucocorticoids stimulate intestinal development and function, and presumed interaction with 1,25-(OH)2D3 has been intensively studied. Most studies involved administration of high doses of glucocorticoids in vivo, which inhibits intestinal Ca2+ transport by an unknown mechanism. However, it is now known from studies of the duodenal organ culture model that low concentrations of glucocorticoids enhance 1,25-(OH)2D3-dependent calbindin-D28K biosynthesis and Ca2+ transport. High concentrations mimic the action of administered glucocorticoids in vivo, suggesting that a distinct pharmacological or toxic mechanism causes inhibition of Ca2+ absorption. This report further shows that dexamethasone (DEX) rapidly enhanced calbindin-D28K gene expression, that is de novo calbindin-D28K mRNA biosynthesis. DEX also markedly reduced the actions of RNA and protein synthesis inhibitors on calbindin-D28K gene expression, although no evidence for an action of DEC or 1,25-(OH)2D3 at the translational level was obtained. Ca2+ transport activity was highly correlated with calbindin-D28K concentration regardless of treatment. Washout permitted complete reversal of inhibition, verifying the specificity of inhibitor activity. These results appear to show positive cotranscriptional regulation of calbindin-D28K gene expression by 1,25-(OH)2D3 and glucocorticoids. The use of this model should continue to clarify the interactive roles of nuclear-acting hormones on the Ca2+ absorptive mechanism and on complex physiological and pathological processes in general.