Differential regulation of the human thyrotropin alpha-subunit promoter by thyroid hormone receptors alpha1 and beta1.

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)-alpha 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 TRalpha1 and TRbeta1 differentially inhibited TSHalpha subunit expression in the presence of T3, with TRbeta1 twice as potent as TRalpha1. TRalpha2 antagonized T3-dependent repression when coexpressed with TRalpha1 and TRbeta1. Gel mobility shift assays, performed in the presence and absence of JEG-3 nuclear extract, demonstrated that TRbeta1 bound with higher affinity to the wild-type TSHalpha negative thyroid hormone response element (nTRE) than TRalpha1. In vivo, the differential DNA binding of TR variants to nTREs may determine the ability of receptors to mediate T3-dependent repression.