ESTROGEN AND THYROID-HORMONE INTERACTION ON REGULATION OF GENE-EXPRESSION

Estrogen receptor (ER) and thyroid hormone receptors (TRs) are ligand- dependent nuclear transcription factors that can bind to an identical half-site, AGGTCA, of their cognate hormone response elements. By in v itro transfection analysis in CV-1 cells, we show that estrogen induct ion of chloramphenicol acetyltransferase (CAT) activity in a construct containing a CAT reporter gene under the control of a minimal thymidi ne kinase (tk) promoter and a copy of the consensus ER response elemen t was attenuated by cotransfection of TR alpha 1 plus triiodothyronine treatment. This inhibitory effect of TR was ligand-dependent and isof orm-specific. Neither TR beta 1 nor TR beta 2 cotransfection inhibited estrogen-induced CAT activity, although both TR alpha and TR beta can bind to a consensus ER response element, Furthermore, cotransfection of a mutated TR alpha 1 that lacks binding to the AGGTCA sequence also inhibited the estrogen effect, Thus, the repression of estrogen actio n by liganded TR alpha 1 may involve protein-protein interactions alth ough competition of ER and TR at the DNA level cannot be excluded. A s imilar inhibitory effect of liganded TR alpha 1 on estrogen induction of CAT activity was observed in a construct containing the preproenkep halin (PPE) promoter, A study in hypophysectomized female rats demonst rated that the estrogen-induced increase in PPE mRNA levels in the ven tromedial hypothalamus was diminished by coadministration of triiodoth yronine. These results suggest that ER and TR may interact to modulate estrogen-sensitive gene expression, such as for PPE, in the hypothala mus.