摘要
内质网(ER)提供了一种保守的蛋白质质量控制系统,在细胞生长和体内平衡中起着重要的作用。ER体内平衡的干扰可能起源于缺氧,葡萄糖缺乏,突变蛋白的存在,直接影响蛋白质折叠能力,并且在ER腔内引发ER应激条件下沉积未折叠和错误折叠的蛋白质。这随后激活展开的蛋白质反应(UPR)分支,其具有双重促适应或促凋亡作用,这取决于ER应激条件的持续时间的严重性和时间。本文是第一个提供所有主要的ER应激依赖性信号转导分子的分子机制的详细概述,这些分子机制是通过受损蛋白折叠的三种特异性ER跨膜受体即蛋白激酶RNA(PKR)样ER激酶(PERK)、肌醇需要酶-1(IRE1)和激活转录因子6(ATF6)激活的。ER跨膜受体依赖途径之间的分子干扰决定了最终的UPR反应,但最近的数据报道,特别是PERK过度激活对广泛疾病实体的发展和进展具有重要影响。基于这些发现,小分子,高度特异性的PERK抑制剂可以为人类疾病提供有效的突破性治疗策略。然而,在上述体外细胞和体内动物模型进行检查之后,需要对其进一步临床使用的PERK抑制剂的补充研究。未来的研究可以回答如何最小化特征性的小分子PERK抑制剂的毒性和副作用的问题,可以单独或与目前已知的治疗模式组合使用,作为突破性药物。
关键词: ER胁迫,PERK,IRE1,ATF6,体内平衡,凋亡,小分子PERK抑制剂。
Current Molecular Medicine
Title:Molecular Basis of Human Diseases and Targeted Therapy Based on Small-Molecule Inhibitors of ER Stress-Induced Signaling Pathways
Volume: 17 Issue: 2
关键词: ER胁迫,PERK,IRE1,ATF6,体内平衡,凋亡,小分子PERK抑制剂。
摘要: The Endoplasmic Reticulum (ER) provides a conserved protein quality control system and plays a fundamental role in cell growth and homeostasis. Disturbances in the ER homeostasis may originate especially from hypoxia, glucose deficiency, presence of mutant proteins, that directly impair protein folding capacity and after deposition of unfolded and misfolded proteins within ER lumen trigger ER stress conditions. This subsequently activates the Unfolded Protein Response (UPR) branches, which have a dual pro-adaptive or pro-apoptotic role depending on the severity and time of duration of ER stress conditions. This review is the first to offer a detailed overview on molecular mechanisms of all major ER stress-dependent signaling branches, that are activated through three specific ER transmembrane receptors of impaired protein folding: Protein kinase RNA (PKR)-like ER kinase (PERK), Inositol-requiring enzyme-1 (IRE1) and Activating transcription factor 6 (ATF6). Molecular crosstalk among ER transmembrane receptors-dependent pathways determines a final UPR response, but the recent data reported that especially PERK over-activation has a significant impact on the development and progression of a wide spectrum of disease entities. Based on these findings, small-molecules, highly specific PERK inhibitors may provide effective, groundbreaking treatment strategy against human diseases. However, after foregoing in vitro cellular and in vivo animal models conducted examination, supplementary investigations of PERK inhibitors are required for their further clinical use. Future research may answer the question of how to minimize toxicity and side effects of characterized small-molecule PERK inhibitors, that may be used, as breakthrough drugs, alone or in combination with currently known models of therapy.
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Cite this article as:
Molecular Basis of Human Diseases and Targeted Therapy Based on Small-Molecule Inhibitors of ER Stress-Induced Signaling Pathways, Current Molecular Medicine 2017; 17 (2) . https://dx.doi.org/10.2174/1566524017666170306122643
DOI https://dx.doi.org/10.2174/1566524017666170306122643 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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