PROMOTER-DEPENDENT SYNERGY BETWEEN GLUCOCORTICOID RECEPTOR AND STAT5 IN THE ACTIVATION OF BETA-CASEIN GENE-TRANSCRIPTION

Steroid hormone receptors and Stat factors comprise two distinct famil ies of inducible transcription factors. Activation of a member of each family, namely the glucocorticoid receptor by glucocorticoids and Sta t5 by prolactin, is required for the efficient induction of the expres sion of milk protein genes in the mammary epithelium. We have studied the mode of interaction between Stat5 and the glucocorticoid receptor in the activation of beta-casein gene transcription. The functional ro le of potential half-palindromic glucocorticoid receptor-binding sites mapped previously in the promoter region was investigated. beta-Casei n gene promoter chloramphenicol acetyltransferase constructs containin g mutations and deletions in these sites were tested for their respons iveness to the synergistic effect of prolactin and dexamethasone emplo ying COS-7 cells or HC11 mammary epithelial cells. Synergism depended on promoter regions containing intact binding sites for the glucocorti coid receptor and Stat5. The carboxyl terminal transactivation domains of Stat5a and Stat5b were not required for this synergism. Our result s suggest that in lactogenic hormone response elements glucocorticoid receptor molecules bound to nonclassical half-palindromic sites gain c ompetence as transcriptional activators by the interaction with Stat5 molecules binding to vicinal sites.