Ligand-dependent antagonism by retinoid X receptors of inhibitory thyroid hormone response elements

The role of retinoid X receptors (RXRs) on negative thyroid hormone response elements (nTREs) is not well understood. In this report, we demonstrate that an orientation-specific monomeric thyroid hormone receptor (T₃R) DNA-binding site mediates thyroid hormone inhibition in the thyrotropin, β subunit gene (TSH-β) from human and murine species. Unlike positive TREs, addition of the ligand 9-cis retinoic acid (9-cis RA) to cells transfected with a T₃R β1 expression vector significantly reduces thyroid hormone inhibition of the TSH-β gene, indicating that endogenous retinoid receptors antagonize T₃R function. Cotransfection of an RXR-α but not a retinoic acid receptor-α expression vector further antagonizes thyroid hormone inhibition, but only in the presence of 9-cis RA. Antagonism by RXR requires both an intact DNA- and ligand-binding domain. Removal of monomeric T₃R binding to the TSH-β nTRE also requires both RXR domains. A model is proposed whereby monomeric T₃R is removed from a nTRE by RXR occupied by its ligand 9-cis RA. This is the first report of 9-cis RA-dependent antagonism of thyroid hormone inhibition via negative TREs.