BACKGROUND In the classical pathway of retinoic acid (RA) mediated gene transcription, RA binds to a nuclear hormone receptor dimer composed of retinoic acid receptor (RAR) and retinoid X receptor (RXR), to induce the expression of its downstream target genes. In addition to nuclear receptors, there are other intracellular RA binding proteins such as cellular retinoic acid binding proteins (CRABP1 and CRABP2) and cytochrome P450 (CYP) enzymes, whose contributions to the RA signaling pathway have not been fully understood. The objective of this study was to compare the significance of various RA binding receptors, i.e. CRABP1, CRABP2, CYP and RAR in the RA signaling pathway. In this regard, we developed a mathematical model of the RA pathway, which is one of the few models, if not the only one, that includes all main intracellular RA binding receptors. We then performed a global sensitivity analysis (GSA) to investigate the contribution of the RA receptors to RA-induced mRNA production, when the cells were treated with a wide range of RA levels, from physiological to pharmacological concentrations. RESULTS Our results show that CRABP2 and RAR are the most and the least important proteins, respectively, in controlling the model performance at physiological concentrations of RA (1-10 nM). However, at higher concentrations of RA, CYP and RAR are the most sensitive parameters of the system. Furthermore, we found that depending on the concentrations of all RA binding proteins, the rate of metabolism of RA can either change or remain constant following RA therapy. The cellular levels of CRABP1 are more important than that of CRABP2 in controlling RA metabolite formation at pharmacological conditions (RA = 0.1-1 μM). Finally, our results indicate a significant negative correlation between total mRNA production and total RA metabolite formation at pharmacological levels of RA. CONCLUSIONS Our simulations indicate that the significance of the RA binding proteins in the RA pathway of gene expression strongly depends on intracellular concentration of RA. This study not only can explain why various cell types respond to RA therapy differently, but also can potentially help develop pharmacological methods to increase the efficacy of the drug.

中文翻译：

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鉴定经典视黄酸信号通路中的影响蛋白。

背景技术在视黄酸（RA）介导的基因转录的经典途径中，RA结合由视黄酸受体（RAR）和类维生素A X受体（RXR）组成的核激素受体二聚体，以诱导其下游靶基因的表达。除核受体外，还有其他细胞内RA结合蛋白，例如细胞视黄酸结合蛋白（CRABP1和CRABP2）和细胞色素P450（CYP）酶，它们对RA信号通路的作用尚未完全了解。这项研究的目的是比较RA信号通路中各种RA结合受体（即CRABP1，CRABP2，CYP和RAR）的重要性。在这方面，我们开发了RA通路的数学模型，这是为数不多的模型之一，即使不是唯一的一种，包括所有主要的细胞内RA结合受体。然后，我们进行了全局敏感性分析（GSA），以研究当从生理到药理学浓度的各种RA水平处理细胞时，RA受体对RA诱导的mRNA产生的贡献。结果我们的结果表明CRABP2和RAR分别是控制RA生理浓度（1-10 nM）时模型性能的最重要和最不重要的蛋白质。但是，在较高的RA浓度下，CYP和RAR是系统最敏感的参数。此外，我们发现，根据所有RA结合蛋白的浓度，RA治疗后，RA的代谢率可以改变或保持恒定。在药理条件下（RA = 0.1-1μM），在控制RA代谢物形成方面，CRABP1的细胞水平比CRABP2更为重要。最后，我们的结果表明，在RA的药理水平上，总mRNA产生与总RA代谢物形成之间存在显着的负相关。结论我们的模拟表明，RA结合蛋白在基因表达的RA途径中的重要性在很大程度上取决于RA的细胞内浓度。这项研究不仅可以解释为什么各种细胞类型对RA治疗的反应不同，而且还可以潜在地帮助开发药理方法以提高药物的疗效。我们的结果表明，在RA的药理水平上，总mRNA产生与总RA代谢物形成之间存在显着的负相关。结论我们的模拟表明，RA结合蛋白在基因表达的RA途径中的重要性在很大程度上取决于RA的细胞内浓度。这项研究不仅可以解释为什么各种细胞类型对RA治疗的反应不同，而且还可以潜在地帮助开发药理方法以提高药物的疗效。我们的结果表明，在RA的药理水平上，总mRNA产生与总RA代谢物形成之间存在显着的负相关。结论我们的模拟表明，RA结合蛋白在基因表达的RA途径中的重要性在很大程度上取决于RA的细胞内浓度。这项研究不仅可以解释为什么各种细胞类型对RA治疗的反应不同，而且还可以潜在地帮助开发药理方法以提高药物的疗效。