HETERODIMERIC RECEPTOR COMPLEXES DETERMINE 3,5,3'-TRIIODOTHYRONINE AND RETINOID SIGNALING SPECIFICITIES

Thyroid hormone receptors (TRs) and retinoic acid receptors (RARs) have been shown to interact with nuclear auxiliary proteins resulting in heteromeric complexes that bind strongly to their responsive elements. Recently the retinoid X receptors (RXRs) have been identified as one class of these nuclear proteins. RXRs strongly increase binding of TRs and RARs to a synthetic thyroid hormone (and retinoic acid) responsive element. Here results show that the binding of the heteromeric complexes to various natural response elements is highly specific and dictated by the partner of RXR in the complex. TR-alpha and TR-beta formed complexes with RXR-alpha that strongly and selectively bound to natural thyroid hormone responsive elements, i.e. those from the rat alpha-myosin heavy chain gene and the rat malic enzyme gene. RXR-alpha complexes with RAR-alpha, RAR-beta, and RAR-gamma bound selectively to retinoic acid responsive elements from the human RAR-beta-2 gene (hRAR-beta-2), the gene of the rat cellular retinol binding protein I and the human apolipoprotein Al gene. Under the conditions used here RXR-alpha by itself did not bind to any of the responsive elements tested. Although TRs and RARs formed heterodimers with RXR in solution, these complexes were strongly stabilized by specific, high affinity response elements, but not by low affinity response elements. Transfection analyses showed strong synergism between receptors that formed effective heterodimers in transcriptional activation on several but not all response elements. Overall, these data demonstrate that RARs and TRs are unlikely to function as monomers or homodimers on the response elements investigated here and require RXRs or comparable proteins for effective response element activation.