RETINOIC ACID RECEPTOR RETINOID-X-RECEPTOR HETERODIMERS CAN BE ACTIVATED THROUGH BOTH SUBUNITS PROVIDING A BASIS FOR SYNERGISTIC TRANSACTIVATION AND CELLULAR-DIFFERENTIATION

The receptor for 9-cis-retinoic acid, retinoid X receptor (RXR), forms heterodimers with several nuclear receptors, including the receptor f or all-trans-retinoic acid, RAR. Previous studies have shown that reti noic acid receptor can be activated in RAR/RXR heterodimers, whereas R XR is believed to be a silent co-factor. In this report we show that e fficient growth arrest and differentiation of the human monocytic cell line U-937 require activation of both RAR and RXR. Also, we demonstra te that the allosteric inhibition of RXR is not obligatory and that RX R can be activated in the RAR/RXR heterodimer in the presence of RAR l igands. Remarkably, RXR inhibition by RAR can also be relieved by an R AR antagonist. Moreover, the dose response of RXR agonists differ betw een RXR homodimers and RAR/RXR heterodimers, indicating that these com plexes are pharmacologically distinct. Finally, the AF2 activation dom ain of both subunits contribute to activation even if only one of the receptors is associated with ligand. Our data emphasize the importance of signaling through both subunits of a heterodimer in the physiologi cal response to retinoids and show that the activity of RXR is depende nt on both the identity and the ligand binding state of its partner.