The Ability of Thyroid Hormone Receptors to Sense T4 as an Agonist Depends on Receptor Isoform and on Cellular Cofactors

T-4 (3,5,3',5'-tetraiodo-L-thyronine) is classically viewed as a prohormone that must be converted to the T-3 (3,5,3' -triiodo-L-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T-4 and to T-3 differed for the different thyroid hormone receptor (TR) isoforms, with TR alpha 1 generally more responsive to T-4 than was TR beta 1. The response to T-4 vs T-3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TR alpha 1 nearly equally by T-4 as by T-3 in vitro, indicating that TR alpha 1 possesses an innate potential to respond efficiently to T-4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoR omega, from TR alpha 1 by T-4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T-4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.