O. Cohen et al., LIGAND-DEPENDENT ANTAGONISM BY RETINOID-X RECEPTORS OF INHIBITORY THYROID-HORMONE RESPONSE ELEMENTS, The Journal of biological chemistry, 270(23), 1995, pp. 13899-13905
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.