Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity

Abstract

BOTH thyroid hormone (T3) and retinoic acid signal essential steps in development, differentiation and morphogenesis. Specific nuclear receptors for these ligands have recently been cloned1-8. Previously we have noted a close homology between the DNA-binding domains of the ε-retinoic acid receptor (RAR-ε, also designated RAR-β), the thyroid hormone receptors and the oes-trogen receptor2,9. We have now found that RAR-ε is very efficient at inducing transcription from two distinct thyroid-hormone responsive elements (TREs). Transcription induced by ligand-activated RAR-ε from a TRE can, however, be repressed by thyroid-hormone receptor in the absence of its ligand. Conversely, in the presence of its ligand, thyroid-hormone receptor will activate tran-scription from a TRE irrespective of the presence of unbound RAR. The use of hybrid receptors has shown that the DNA-binding domain of RAR is the essential target for inhibition by thyroid-hormone receptors. These data, together with in vitro DNA-binding studies, suggest that thyroid-hormone receptors may have dual regulatory roles: in the presence of hormone they function as TRE-specific transcriptional activators; in the absence of hormone, however, they can function as TRE-specific repressers.