Roy B, Taneja R, Chambon P
Institut de Génétique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Collège de France, Illkirch, France.
Mol Cell Biol. 1995 Dec;15(12):6481-7. doi: 10.1128/MCB.15.12.6481.
Retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers bind to cognate response elements in vitro more efficiently than do RAR or RXR homodimers, and both RAR and RXR partners have been shown to activate various promoters in transiently transfected cells. We have now investigated whether ligand-dependent activation of both heterodimeric partners is involved in induced expression of endogenous RA-responsive genes and in P19 and F9 cell differentiation. On their own, low concentrations of retinoids selective for either RAR alpha, RAR beta, or RAR gamma did not induce or very inefficiently induced the expression of several RA target genes or triggered differentiation. An RXR-specific synthetic retinoid was similarly inefficient at any concentration. In contrast, at the same concentrations, various combinations of RAR (RAR alpha, RAR beta, or RAR gamma) and RXR selective retinoids resulted in synergistic induction of all retinoic acid (RA) target genes examined, as well as in cell differentiation. However, the magnitude of this synergistic activation varied depending on both the RAR-RXR combination and the promoter context of the responsive genes. Promiscuous activation of the three RARs, or concomitant activation of RAR alpha and RAR gamma, at selective retinoid concentrations also resulted in induction of gene expression and cell differentiation. Taken together, our results are consistent with the conclusion that the RAR and RXR partners of RAR-RXR heterodimers can synergistically activate transcription of RA-responsive genes and can induce differentiation of P19 and F9 cells. Our results also indicate that there is a significant degree of functional redundancy between the three RAR types which, however, varies with the nature of the RA target genes.
维甲酸受体（RAR）-维甲酸X受体（RXR）异二聚体在体外与同源反应元件的结合效率比RAR或RXR同二聚体更高，并且RAR和RXR这两个伙伴均已被证明可在瞬时转染细胞中激活各种启动子。我们现在研究了RAR-RXR异二聚体的两个伙伴的配体依赖性激活是否参与内源性RA反应基因的诱导表达以及P19和F9细胞的分化。单独使用时，对RARα、RARβ或RARγ具有选择性的低浓度类视黄醇不会诱导或非常低效地诱导几种RA靶基因的表达，也不会触发分化。RXR特异性合成类视黄醇在任何浓度下同样效率低下。相比之下，在相同浓度下，RAR（RARα、RARβ或RARγ）和RXR选择性类视黄醇的各种组合导致所检测的所有视黄酸（RA）靶基因的协同诱导，以及细胞分化。然而，这种协同激活的程度因RAR-RXR组合以及反应基因的启动子背景而异。在选择性类视黄醇浓度下，三种RAR的混杂激活或RARα和RARγ的同时激活也导致基因表达的诱导和细胞分化。综上所述，我们的结果与以下结论一致：RAR-RXR异二聚体的RAR和RXR伙伴可以协同激活RA反应基因的转录，并可以诱导P19和F9细胞的分化。我们的结果还表明，三种RAR类型之间存在显著程度的功能冗余，然而，这种冗余随RA靶基因的性质而变化。
