Abstract
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 beta subunit gene (TSH-beta) 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 beta 1 expression vector significantly reduces thyroid hormone inhibition of the TSH-beta gene, indicating that endogenous retinoid receptors antagonize T3R function. Cotransfection of an RXR-alpha but not a retinoic acid receptor-alpha 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-beta 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.
Highlights
The role of retinoid X receptors (RXRs) on negative thyroid hormone response elements is not well understood
The human negative thyroid hormone response elements (nTREs) consists of two consensus half-sites situated 24 bp apart and an additional degenerate half-site (3/6) positioned 4 bp downstream from the first half-site in the first exon [20]
The more 5'-TaR half-site of this nTRE is of higher affinity than the 3'-half-site, but both sites appear to be functionally important for thyroid hormone inhibition [20, 21]
Summary
Vol 270, No 23, Issue of June 9, pp. 13899-13905, 1995 Printed in U.S.A. Ligand-dependent Antagonism by Retinoid X Receptors of Inhibitory Thyroid Hormone Response Elements*. Unlike positive TREs, addition of the ligand 9-cis retinoic acid (9-cis RA) to cells transfected with a TaR 131 expression vector significantly reduces thyroid hormone inhibition of the TSH-f3 gene, indicating that endogenous retinoid receptors antagonize TaR function. A model is proposed whereby monomeric TaR 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. Thyroid hormone mediates its effect through cis-acting response elements. The human nTRE consists of two consensus half-sites situated 24 bp apart and an additional degenerate half-site (3/6) positioned 4 bp downstream from the first half-site in the first exon [20] These sites are identical in the mouse and rat TSH-j3 genes, but their individual roles in thyroid hormone inhibition have not been fully characterized. We provide evidence that the human and mouse TSH-j3 nTREs bind monomeric TaR, and RXR, in a ligand-dependent manner, antagonizes Ta-mediated inhibition
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