Inflammation Research Center (S.V., L.D., C.L.), Flanders Institute for Biotechnology, B9052 Ghent, Belgium; and Department of Biomedical Molecular Biology (S.V., L.D., C.L.), Ghent University, B9052 Ghent, Belgium.
Endocr Rev. 2014 Aug;35(4):671-93. doi: 10.1210/er.2014-1010. Epub 2014 Jun 17.
Glucocorticoids are among the most prescribed drugs worldwide for the treatment of numerous immune and inflammatory disorders. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. There are several GR isoforms resulting from alternative RNA splicing and translation initiation of the GR transcript. Additionally, these isoforms are all subject to several transcriptional, post-transcriptional, and post-translational modifications, all of which affect the protein's stability and/or function. In this review, we summarize recent knowledge on the distinct GR isoforms and the processes that generate them. We also review the importance of all known transcriptional, post-transcriptional, and post-translational modifications, including the regulation of GR by microRNAs. Moreover, we discuss the crucial role of the putative GR-bound DNA sequence as an allosteric ligand influencing GR structure and activity. Finally, we describe how the differential composition and distinct regulation at multiple levels of different GR species could account for the wide and diverse effects of glucocorticoids.
糖皮质激素是全球范围内用于治疗多种免疫和炎症性疾病的最常用药物之一。它们通过与糖皮质激素受体 (GR) 结合发挥作用，GR 是核受体超家族的成员。GR 转录本通过选择性 RNA 剪接和翻译起始产生几种 GR 同工型。此外，这些同工型都受到几种转录后、转录后和翻译后修饰的影响，所有这些修饰都会影响蛋白质的稳定性和/或功能。在这篇综述中，我们总结了关于不同 GR 同工型及其产生过程的最新知识。我们还回顾了所有已知的转录后、转录后和翻译后修饰的重要性，包括 microRNAs 对 GR 的调节。此外，我们讨论了假定的 GR 结合 DNA 序列作为变构配体影响 GR 结构和活性的关键作用。最后，我们描述了不同 GR 物种在多个水平上的不同组成和独特调节如何解释糖皮质激素的广泛而多样的作用。
