THE DIFFERENTIAL HORMONE-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF THYROID-HORMONE RECEPTOR ISOFORMS IS MEDIATED BY INTERPLAY OF THEIR DOMAINS

Human thyroid hormone nuclear receptor isoforms (TR alpha 1 and TR bet a 1) express differentially in a tissue-specific and development-depen dent manner. It is unclear whether these two isoforms have differentia l functions. We analyzed their interaction with a thyroid hormone resp onse element with half-site binding motifs arranged in an everted repe at separated by six nucleotides (F2). Despite extensive sequence homol ogies, the two isoforms bound to F2 with different affinities and rati os of homodimer/monomer. Using F2-containing reporter gene, we found t hat the transcriptional activity of TR beta 1 was similar to 6-fold hi gher than that of TR alpha 1. The lower activity of TR alpha 1 was not due to differences in expression of the two isoforms because similar nuclear localization patterns were observed. To understand the structu ral determinants responsible for these differences, we constructed chi meric receptors in which hinge regions (domain D), hormone binding dom ains (domain E), and domains (D + E) were sequentially interchanged an d their activities were compared. Chimeric TRs containing the domains D, E or (D + E) of TR beta 1 showed increased propensities to form hom odimers and mediated higher transactivation activities than TR alpha 1 . Thus, differential transactivation activities of TR isoforms are med iated by interplay of their domains and could serve as an important re gulatory mechanism to achieve diversity and specificity of pleiotropic T-3 effect.