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 (T REs). We examine here the role of human TR-beta 2, a TR isoform with c entral nervous system-restricted expression, in the regulation of targ et genes whose expression are decreased by tri-iodothyronine (T-3), Us ing transient transfection studies, we found that TR-beta 2 achieved s ignificantly greater ligand-independent activation on the thyrotropin- releasing hormone (TRH) and common glycoprotein alpha-subunit genes th an either TR-beta 1 or TR-alpha 1. A chimeric TR-beta isoform containi ng the TR-beta 2 amino terminus linked to the TR-beta 2 DNA-and ligand -binding domains functioned like the TR-beta 2 isoform on these promot ers, confirming that the amino terminus of TR-beta 2 was both necessar y and sufficient to mediate this effect. By constructing deletion muta nts of the TR-beta 2 amino terminus, we demonstrate that amino acids 8 9-116 mediate this function. This domain, important in ligand-independ ent activation on negative TREs, is discrete from a previously describ ed activation domain in the amino-terminal portion of TR-beta 2. We co nclude that the central nervous system-restricted TR-beta 2 isoform ha s a unique effect on negative regulation by T-3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-beta 2.