Fuller Peter J, Yang Jun, Young Morag J
Centre for Endocrinology and MetabolismHudson Institute of Medical Research and the Monash University Department of Molecular Translational Science, Clayton, Victoria, Australia
Centre for Endocrinology and MetabolismHudson Institute of Medical Research and the Monash University Department of Molecular Translational Science, Clayton, Victoria, Australia.
J Endocrinol. 2017 Jul;234(1):T23-T34. doi: 10.1530/JOE-17-0060.
The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in the distal nephron, and subsequently in many other tissues. Nuclear receptor (NR) signalling is modified by interactions with coregulatory proteins that serve to enhance or inhibit the gene transcriptional responses. Over 400 coregulatory proteins have been described for the NR super family, many with functional roles in signalling, cellular function, physiology and pathophysiology. Relatively few coregulators have however been described for the MR although recent studies have demonstrated both ligand and/or tissue selectivity for MR-coregulator interactions. A full understanding of the cell, ligand and promoter-specific requirements for MR-coregulator signalling is an essential first step towards the design of small molecular inhibitors of these protein-protein interactions. Tissue-selective steroidal or non-steroidal modulators of the MR are also a desired therapeutic goal. Selectivity, as for other steroid hormone receptors, will probably depend on differential expression and recruitment of coregulatory proteins.
30年前盐皮质激素受体（MR）的克隆开启了一个新时代的研究，该研究旨在探讨远曲小管中靶基因的MR信号调控过程，随后扩展到许多其他组织。核受体（NR）信号传导通过与共调节蛋白的相互作用而被修饰，这些共调节蛋白可增强或抑制基因转录反应。对于NR超家族，已描述了400多种共调节蛋白，其中许多在信号传导、细胞功能、生理学和病理生理学中发挥功能作用。然而，针对MR的共调节因子描述相对较少，尽管最近的研究表明MR与共调节因子的相互作用存在配体和/或组织选择性。全面了解细胞、配体和启动子对MR-共调节因子信号传导的特异性要求，是设计这些蛋白质-蛋白质相互作用小分子抑制剂的关键第一步。MR的组织选择性甾体或非甾体调节剂也是一个理想的治疗目标。与其他类固醇激素受体一样，选择性可能取决于共调节蛋白的差异表达和募集。
