A unique role of the beta-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping of a novel amino-terminal domain important for ligand-independent activation.

Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-beta2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-beta2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein alpha-subunit genes than either TR-beta1 or TR-alpha1. A chimeric TR-beta isoform containing the TR-beta2 amino terminus linked to the TR-alpha1 DNA- and ligand-binding domains functioned like the TR-beta2 isoform on these promoters, confirming that the amino terminus of TR-beta2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-beta2 amino terminus, we demonstrate that amino acids 89-116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-beta2. We conclude that the central nervous system-restricted TR-beta2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-beta2.