Differential Regulation of the Human Thyrotropin α-Subunit Promoter by Thyroid Hormone Receptors α 1 and β 1

The differential tissue expression of thyroid hormone receptor (TR) isoforms implies that they fulfil different roles in mediating triiodothyronine (T₃) regulation. We have examined the differential roles of TR isoforms in mediating T₃-dependent repression of the human thyrotropin (TSH)-α subunit gene promoter in vitro, and have assessed TR binding characteristics using gel mobility shift assays. Expression of transfected TR in JEG-3 cells revealed that TRα₁ and TRβ₁ differentially inhibited TSHα subunit expression in the presence of T.₃, with TRβ₁ twice as potent as TRα₁. TRα₂ antagonized T₃-dependent repression when coexpressed with TRα₁ and TRβ₁. Gel mobility shift assays, performed in the presence and absence of JEG-3 nuclear extract, demonstrated that TRβ₁ bound with higher affinity to the wild-type TSHα negative thyroid hormone response element (nTRE) than TRα₁. In vivo, the differential DNA binding of TR variants to nTREs may determine the ability of receptors to mediate T₃-dependent repression.