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 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.
Cohen
O
O
Thyroid Unit, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Flynn
T R
TR
Wondisford
F E
FE
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D005809:Genes, Regulator; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D047488:Retinoid X Receptors; D013963:Thyroid Hormones / Q000494:pharmacology*; D013972:Thyrotropin / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
D008024:Ligands; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D013963:Thyroid Hormones; D014157:Transcription Factors; D014212:Tretinoin; D013972:Thyrotropin; D004247:DNA