The ability of thyroid hormone receptors to sense t4 as an agonist depends on receptor isoform and on cellular cofactors.

ABSTRACT: T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TR?1 generally more responsive to T4 than was TR?1. The response to T4 vs T3 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?1 nearly equally by T4 as by T3 in vitro, indicating that TR?1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoR?, from TR?1 by T4 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 T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.

SUBMITTER: Schroeder A 

PROVIDER: S-EPMC4004778 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature