THYROID HORMONE-MEDIATED ENHANCEMENT OF HETERODIMER FORMATION BETWEENTHYROID-HORMONE RECEPTOR-BETA AND RETINOID-X-RECEPTOR

A subset of nuclear receptors, including those for thyroid hormone (TR ), retinoic acid, vitamin D-3, and eicosanoids, can form heterodimers with the retinoid X receptor (RXR) on DNA regulatory elements in the a bsence of their cognate ligands. In a mammalian two-hybrid assay, we h ave found that recruitment of a VP16-RXR chimera by a Ga14-TR beta lig and-binding domain fusion is enhanced up to 50-fold by thyroid hormone (T-3). This was also observed with a mutant fusion, Ga14-TR(L454A), l acking Ligand inducible activation function (AF-2) and unable to inter act with putative coactivators, suggesting that the AF-2 activity of T R or intermediary cofactors is not involved in this effect, The wild-t ype and mutant Ga14-TR fusions also exhibited hormone-dependent recrui tment of RXR in yeast, Hormone dependent recruitment of RXR was also e vident with another Ga14-TR mutant, AHTm, which does not interact with the nuclear receptor corepressor N-CoR, suggesting that ligand-enhanc ed dimerization is not a result of T-3-induced corepressor release, Fi nally, we have shown that the interaction between RXR and TR is augmen ted by T-3 in vitro, arguing against altered expression of either part ner in vitro mediating this effect, We propose that ligand dependent h eterodimerization of TR and RXR in solution may provide a further leve l of control in nuclear receptor signaling.