The receptor-DNA complex determines the retinoid response: a mechanism for the diversification of the ligand signal.
The receptor-DNA complex determines the retinoid response: a mechanism for the diversification of the ligand signal.
复制标题
受体-DNA 复合物决定类视黄醇反应：配体信号多样化的机制。
DOI：
10.1128/mcb.16.8.4137
复制
发表时间：
1996
影响因子：
5.3
通讯作者：
Pfahl,M
中科院分区：
文献类型：
--
作者：
LaVista-Picard,N;Hobbs,PD;Pfahl,M;Dawson,MI;Pfahl,M
为了深入了解维甲酸的复杂生物反应的原理，我们分析了各种维甲酸受体-DNA复合物的配体敏感性。我们发现，不同的类维生素A受体异二聚体显示不同的激活模式与各种响应元件，而一个给定的异二聚体可以在不同的视黄酸浓度激活不同的响应元件。体外结合实验表明，相同的视黄酸受体-类维生素A X受体（RAR-RXR）异二聚体可以具有不同的配体亲和力，这取决于它所结合的反应元件。特定受体异二聚体与各种视黄酸反应元件的差异反应可以通过使用构象限制的类视黄酸来增强。RAR-和RXR-选择性类视色素也可以协同激活受体异二聚体，表明异二聚体中的两种配偶体都可以有助于配体诱导的转录激活。然而，RAR或RXR伙伴的相对影响对于每个响应元素是特定的。总之，我们的数据表明，它是受体-DNA复合物，而不是受体单独决定配体的反应。这种灵活性允许高度多效性的类维生素A反应。此外，构象限制的类维生素A可以通过在给定的反应元件的情况下差异地激活RAR或RXR组分来加重差异反应并表现出一定程度的基因选择性。
To obtain insights into the principles governing the complex biological responses to retinoids, we have analyzed the ligand sensitivities of various retinoid receptor-DNA complexes. We find that different retinoid receptor heterodimers show distinct activation patterns with various response elements while a given heterodimer can be activated at different retinoic acid concentrations on different response elements. In vitro binding experiments suggest that the same retinoic acid receptor-retinoid X receptor (RAR-RXR) heterodimer can have different ligand affinities, depending on the response element it is bound to. The differential responses of a particular receptor heterodimer with various retinoic acid responsive elements can be enhanced through the use of conformationally restricted retinoids. RAR- and RXR-selective retinoids can also synergistically activate the receptor heterodimers, indicating that both partners in the heterodimer can contribute to ligand- induced transcriptional activation. However, the relative influence of the RAR or RXR partner is specific for each response element. Together, our data demonstrate that it is the receptor-DNA complex and not the receptor alone that determines the ligand response. This flexibility allows for a highly pleiotropic retinoid response. Furthermore, conformationally restricted retinoids can accentuate the differential responses and exhibit a certain degree of gene selectivity by differentially activating the RAR or RXR component in the context of a given response element.