DIFFERENTIAL REGULATION OF THE HUMAN THYROTROPIN ALPHA-SUBUNIT PROMOTER BY THYROID-HORMONE RECEPTORS ALPHA-1 AND BETA-1

The differential tissue expression of thyroid hormone receptor (TR) is oforms implies that they fulfil different roles in mediating triiodoth yronine (T-3) regulation. We have examined the differential roles of T R isoforms in mediating T-3-dependent repression of the human thyrotro pin (TSH)-alpha subunit gene promoter in vitro, and have assessed TR b inding characteristics using gel mobility shift assays. Expression of transfected TR in JEG-3 cells revealed that TRalpha 1 and TRbeta 1 dif ferentially inhibited TSHalpha subunit expression in the presence of T 3, With TRP I twice as potent as TRalpha 1. TRalpha 2 antagonized T-3- dependent repression when coexpressed with TRalpha 1 and TRbeta 1. Gel mobility shift assays, performed in the presence and absence of JEG-3 nuclear extract, demonstrated that TRbeta 1 bound with higher affinit y to the wild-type TSHalpha negative thyroid hormone response element (nTRE) than TRalpha 1. In vivo, the differential DNA binding of TR var iants to nTREs may determine the ability of receptors to mediate T-3-d ependent repression.