TY - JOUR
T1 - Ligand-dependent antagonism by retinoid X receptors of inhibitory thyroid hormone response elements
AU - Cohen, Ohad
AU - Flynn, Timothy R.
AU - Wondisford, Fredric E.
PY - 1995/6/9
Y1 - 1995/6/9
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.270.23.13899
DO - 10.1074/jbc.270.23.13899
M3 - Article
C2 - 7775449
AN - SCOPUS:0029058453
SN - 0021-9258
VL - 270
SP - 13899
EP - 13905
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 23
ER -