LIGAND-DEPENDENT ANTAGONISM BY RETINOID-X RECEPTORS OF INHIBITORY THYROID-HORMONE RESPONSE ELEMENTS

The role of retinoid X receptors (RXRs) on negative thyroid hormone re sponse elements (nTREs) is not well understood, In this report, we dem onstrate that an orientation-specific monomeric thyroid hormone recept or (T(3)R) DNA-binding site mediates thyroid hormone inhibition in the thyrotropin beta subunit gene (TSH-beta) from human and murine specie s. Unlike positive TREs, addition of the ligand 9-cis retinoic acid (9 -cis RA) to cells transfected with a T(3)R beta 1 expression vector si gnificantly reduces thyroid hormone inhibition of the TSH-beta gene, i ndicating that endogenous retinoid receptors antagonize T(3)R function . Cotransfection of an RXR-alpha but not a retinoic acid receptor-alph a expression vector further antagonizes thyroid hormone inhibition, bu t only in the presence of 9-cis RA. Antagonism by RXR requires both an intact DNA- and ligand-binding domain, Removal of monomeric T(3)R bin ding to the TSH-beta nTRE also requires both RXR domains. A model is p roposed whereby monomeric T(3)R is removed from a nTRE by RXR occupied by its ligand 9-cis RA. This is the first report of 9-cis RA-dependen t antagonism of thyroid hormone inhibition via negative TREs.