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首页> 外文期刊>The FEBS journal >The endogenous retinoid metabolite S-4-oxo-9-cis-13,14-dihydro-retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo
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The endogenous retinoid metabolite S-4-oxo-9-cis-13,14-dihydro-retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo

机译：内源性类维生素A代谢物S-4-oxo-9-cis-13,14-二氢-视黄酸在体内外均激活视黄酸受体信号

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摘要

Retinoic acid receptor (RAR) and retinoid X receptor are ligand-induced transcription factors that belong to the nuclear receptor family. The receptors are activated by small hydrophobic compounds, such as all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Interestingly, these receptors are also targets for a number of exogenous compounds. In this study, we characterized the biological activity of the 9-cis-substituted retinoic acid metabolite, S-4-oxo-9-cis-13,14-dihydro-retinoic acid (S-4o9cDH-RA). The endogenous levels of this metabolite in wild-type mice and rats were found to be higher than those of all-trans-retinoic acid, especially in the liver. Using cell-based luciferase reporter systems, we showed that S-4o9cDH-RA activates the transcription of retinoic acid response element-containing genes in several cell types, both from a simple 2xDR5 element and from the promoter of the natural retinoid target gene RARbeta2. In addition, quantitative RT-PCR analysis demonstrated that S-4o9cDH-RA treatment significantly increases the endogenous mRNA levels of the RAR target gene RARbeta2. Utilizing a limited proteolytic digestion assay, we showed that S-4o9cDH-RA induces conformational changes to both RARalpha and RARbeta in the same manner as does all-trans-retinoic acid, suggesting that S-4o9cDH-RA is indeed an endogenous ligand for these receptors. These in vitro results were corroborated in an in vivo system, where S-4o9cDH-RA induced morphological changes similar to those of all-trans-retinoic acid in the developing chicken wing bud. When locally applied to the wing bud, S-4o9cDH-RA induced digit pattern duplications in a dose-dependent fashion. The results illustrate that S-4o9cDH-RA closely mimics all-trans-retinoic acid with regard to pattern respecification. Finally, using quantitative RT-PCR analysis, we showed that S-4o9cDH-RA induces the transcription of several retinoic acid-regulated genes in chick wing buds, including Hoxb8, RARbeta2, shh, Cyp26 and bmp2. Although S-4o9cDH-RA was less potent when compared with all-trans-retinoic acid, the findings clearly demonstrate that S-4o9cDH-RA has the capacity to bind and activate nuclear retinoid receptors and regulate gene transcription both in vitro and in vivo.
机译：维甲酸受体（RAR）和维甲酸X受体是配体诱导的转录因子，属于核受体家族。受体分别由小的疏水化合物（例如全反式视黄酸和9-顺式视黄酸）激活。有趣的是，这些受体也是许多外源化合物的靶标。在这项研究中，我们表征了9-顺式视黄酸代谢产物S-4-oxo-9-顺13-13，14-二氢-视黄酸（S-4o9cDH-RA）的生物活性。发现在野生型小鼠和大鼠中这种代谢物的内源性水平高于全反式维甲酸的内源性水平，尤其是在肝脏中。使用基于细胞的荧光素酶报告系统，我们显示S-4o9cDH-RA激活了几种细胞类型中包含视黄酸响应元件的基因的转录，这两种基因均来自简单的2xDR5元件以及天然类维生素A靶基因RARbeta2的启动子。此外，定量RT-PCR分析表明，S-4o9cDH-RA处理显着提高了RAR目标基因RARbeta2的内源性mRNA水平。利用有限的蛋白水解消化试验，我们发现S-4o9cDH-RA诱导RARalpha和RARbeta的构象变化的方式与全反式维甲酸相同，表明S-4o9cDH-RA确实是这些蛋白的内源性配体受体。这些体外结果在体内系统中得到了证实，在该系统中，S-4o9cDH-RA在发育中的鸡翅芽中诱导了类似于全反式维甲酸的形态变化。当局部施用于翼芽时，S-4o9cDH-RA以剂量依赖的方式诱导手指图案重复。结果表明，S-4o9cDH-RA在模式重新指定方面非常类似于全反式维甲酸。最后，使用定量RT-PCR分析，我们显示S-4o9cDH-RA诱导雏鸡翅膀芽中几个视黄酸调节基因的转录，包括Hoxb8，RARbeta2，shh，Cyp26和bmp2。尽管与全反式维甲酸相比，S-4o9cDH-RA的效力较弱，但该发现清楚地表明，S-4o9cDH-RA在体外和体内均具有结合和激活核类视黄醇受体并调节基因转录的能力。

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