Perlmann T, Jansson L
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Genes Dev. 1995 Apr 1;9(7):769-82. doi: 10.1101/gad.9.7.769.
In addition to its role as a 9-cis retinoic acid receptor, RXR has an important role in the regulation of multiple hormonal pathways through heterodimerization with nuclear receptors. Here, we show that two orphan receptors, NGFI-B and NURR1, which have been shown previously to interact with DNA as monomers, also can heterodimerize with RXR. These heterodimers bind selectively to a class of retinoic acid response elements composed of direct repeats spaced by 5 nucleotides. In this respect they are similar to heterodimers formed between RXR and the receptor for all-trans retinoic acid, RAR. However, whereas RXR is inhibited in the RXR-RAR heterodimer, NGFI-B/NURR1 promote efficient activation in response to RXR ligands and therefore shift RXR from a silent to an active heterodimerization partner. These data show that NGFI-B and NURR1 can increase the potential of RXR to modulate gene expression in a ligand-dependent manner by allowing a distinct class of direct repeats to serve as specific RXR response elements. Because expression of both NGFI-B and NURR1 is rapidly induced by various growth factors, these findings also suggest a novel mechanism for convergence between vitamin A or retinoid and growth factor signaling pathways.
除了作为9-顺式视黄酸受体的作用外，视黄醇X受体（RXR）通过与核受体异源二聚化，在多种激素信号通路的调节中发挥重要作用。在此，我们发现两个孤儿受体，神经生长因子诱导蛋白B（NGFI-B）和核相关因子1（NURR1），它们先前已被证明作为单体与DNA相互作用，也能与RXR异源二聚化。这些异源二聚体选择性地结合一类由间隔5个核苷酸的直接重复序列组成的视黄酸反应元件。在这方面，它们类似于RXR与全反式视黄酸受体（RAR）形成的异源二聚体。然而，在RXR-RAR异源二聚体中RXR受到抑制，而NGFI-B/NURR1能促进对RXR配体的有效激活，因此将RXR从一个沉默的异源二聚化伙伴转变为活跃型。这些数据表明，NGFI-B和NURR1可以通过使一类独特的直接重复序列作为特定的RXR反应元件，以配体依赖的方式增加RXR调节基因表达的潜力。由于NGFI-B和NURR1的表达都能被各种生长因子迅速诱导，这些发现还提示了维生素A或类视黄醇与生长因子信号通路之间汇聚的一种新机制。
