School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
Cell Commun Signal. 2019 May 2;17(1):40. doi: 10.1186/s12964-019-0352-4.
Retinoic acid (RA) is the active metabolite of vitamin A and essential for many physiological processes, particularly the induction of cell differentiation. In addition to regulating genomic transcriptional activity via RA receptors (RARs) and retinoid X receptors (RXRs), non-genomic mechanisms of RA have been described, including the regulation of ERK1/2 kinase phosphorylation, but are poorly characterised. In this study, we test the hypothesis that genomic and non-genomic mechanisms of RA are regulated independently with respect to the involvement of ligand-dependent RA receptors. A panel of 28 retinoids (compounds with vitamin A-like activity) showed a marked disparity in genomic (gene expression) versus non-genomic (ERK1/2 phosphorylation) assays. These results demonstrate that the capacity of a compound to activate gene transcription does not necessarily correlate with its ability to regulate a non-genomic activity such as ERK 1/2 phosphorylation. Furthermore, a neurite outgrowth assay indicated that retinoids that could only induce either genomic, or non-genomic activities, were not strong promoters of neurite outgrowth, and that activities with respect to both transcriptional regulation and ERK1/2 phosphorylation produced maximum neurite outgrowth. These results suggest that the development of effective retinoids for clinical use will depend on the selection of compounds which have maximal activity in non-genomic as well as genomic assays.
视黄酸（RA）是维生素 A 的活性代谢物，是许多生理过程所必需的，特别是细胞分化的诱导。除了通过视黄酸受体（RAR）和视黄醛 X 受体（RXR）调节基因组转录活性外，还描述了 RA 的非基因组机制，包括 ERK1/2 激酶磷酸化的调节，但特征描述较差。在这项研究中，我们检验了这样一个假设，即 RA 的基因组和非基因组机制在涉及配体依赖性 RA 受体方面是独立调节的。一组 28 种视黄醇（具有维生素 A 样活性的化合物）在基因组（基因表达）与非基因组（ERK1/2 磷酸化）测定方面表现出明显的差异。这些结果表明，一种化合物激活基因转录的能力不一定与其调节非基因组活性（如 ERK1/2 磷酸化）的能力相关。此外，神经突生长测定表明，只能诱导基因组或非基因组活性的视黄醇不是神经突生长的有力促进剂，而具有转录调节和 ERK1/2 磷酸化活性的化合物则能产生最大的神经突生长。这些结果表明，为临床应用开发有效的视黄醇将取决于选择在非基因组和基因组测定中均具有最大活性的化合物。
