Botling J, Castro D S, Oberg F, Nilsson K, Perlmann T
Laboratory of Tumor Biology, Department of Pathology, Uppsala University, S-751 85 Uppsala, Sweden.
J Biol Chem. 1997 Apr 4;272(14):9443-9. doi: 10.1074/jbc.272.14.9443.
The receptor for 9-cis-retinoic acid, retinoid X receptor (RXR), forms heterodimers with several nuclear receptors, including the receptor for all-trans-retinoic acid, RAR. Previous studies have shown that retinoic acid receptor can be activated in RAR/RXR heterodimers, whereas RXR is believed to be a silent co-factor. In this report we show that efficient growth arrest and differentiation of the human monocytic cell line U-937 require activation of both RAR and RXR. Also, we demonstrate that the allosteric inhibition of RXR is not obligatory and that RXR can be activated in the RAR/RXR heterodimer in the presence of RAR ligands. Remarkably, RXR inhibition by RAR can also be relieved by an RAR antagonist. Moreover, the dose response of RXR agonists differ between RXR homodimers and RAR/RXR heterodimers, indicating that these complexes are pharmacologically distinct. Finally, the AF2 activation domain 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 physiological response to retinoids and show that the activity of RXR is dependent on both the identity and the ligand binding state of its partner.
9-顺式视黄酸的受体——视黄酸X受体（RXR），可与多种核受体形成异源二聚体，包括全反式视黄酸的受体RAR。先前的研究表明，视黄酸受体可在RAR/RXR异源二聚体中被激活，而RXR被认为是一个沉默的辅助因子。在本报告中，我们表明人类单核细胞系U-937的有效生长停滞和分化需要RAR和RXR两者的激活。此外，我们证明RXR的变构抑制并非必需，并且在存在RAR配体的情况下，RXR可在RAR/RXR异源二聚体中被激活。值得注意的是，RAR对RXR的抑制也可被RAR拮抗剂解除。此外，RXR激动剂的剂量反应在RXR同源二聚体和RAR/RXR异源二聚体之间有所不同，表明这些复合物在药理学上是不同的。最后，即使只有一个受体与配体结合，两个亚基的AF2激活结构域也有助于激活。我们的数据强调了通过异源二聚体的两个亚基进行信号传导在对视黄酸的生理反应中的重要性，并表明RXR的活性取决于其伙伴的身份和配体结合状态。
