MECHANISMS FOR SYNERGISTIC ACTIVATION OF THYROID-HORMONE RECEPTOR ANDRETINOID-X RECEPTOR ON DIFFERENT RESPONSE ELEMENTS

The thyroid hormone receptors (TR) form heterodimers with the retinoid X receptors (RXR) and activate target genes through thyroid-responsiv e elements (TRE). Heterodimerization elevates the DNA binding efficien cy and thus can result in functional synergism between TR and RXR. Her e we demonstrate that DNA sequences dictate the cooperative activation between TR and RXR despite the high affinity binding of the heterodim er to those TREs. We provide evidence that the C-terminal activation d omain of RXR can modulate the triiodothyronine (T-3) responsiveness of TR/RXR heterodimers on reporter genes without altering the DNA bindin g properties of the heterodimers. The modulation function of this rela tively small region is under the control of specific TRE sequences and promoter context. These data indicate that this C-terminal region of RXR is likely involved in receptor-cellular factor(s) interactions. Fi nally, we propose that the synergistic activation by TR and RXR is ach ieved through elevated DNA binding and, dependent on the DNA sequence, the interaction of RXR with other transcription factors.