泛素连接酶与肿瘤关系的研究

目前认为,真核细胞内的蛋白质主要通过两种不同的蛋白酶解系统降解:溶酶体途径和泛素-蛋白酶途径.其中,约80%通过泛素-蛋白酶体途径降解.泛素连接酶是泛素-蛋白酶体系统的重要成分,它在癌形成过程中扮演着重要的角色[1].本文从细胞周期、凋亡、肿瘤治疗等方面来介绍泛素连接酶与肿瘤发生和治疗的关系.     

泛素-蛋白酶体系统与精子DNA损伤修复的研究进展

泛素-蛋白酶体系统(UPS)是体内广泛存在的一种蛋白酶体系统,由泛素(Ub)、泛素激活酶(E1)、泛素结合酶(E2)、泛素连接酶(E3)、26S蛋白酶体和去泛素化酶(DUBs)组成,能够调控体内蛋白降解。研究发现UPS除了蛋白降解功能以外,还参与细胞周期调控、免疫应答、信号传导以及DNA损伤修复等过程。精子发生要经历染色体联会、同源重组等过程,精子DNA在这些过程中易受干扰而出现损伤。近年来研究发现,UPS与精子发生当中的DNA损伤修复有关。UPS参与DNA损伤的修复机制包括:泛素化调节DNA损伤修复相关酶类、协助识别DNA损伤位点、募集损伤修复相关蛋白、启动DNA损伤修复途径、维持染色体稳定,从而保证精子发生正常进行。     

肿瘤坏死因子受体相关因子作用蛋白的生物学功能研究进展

蛋白质构象变化或基因表达量异常是疾病发生发展的重要原因之一,而肿瘤坏死因子受体相关因子作用蛋白(TRAIP/TRIP/RNF206)作为E3泛素连接酶,其结构改变及泛素酶活性变化与疾病息息相关,近年来受到越来越多关注,尤其是在DNA复制与损伤修复研究领域。TRAIP的异常表达已在多种疾病中被报道,比如肿瘤、先天性发育异...     

一种新的NF-κB信号小分子抑制物

核转录因子-κB（NF-κB）能与多种细胞基因启动子和增强子序列位点发生特异性结合，调控其转录和表达，参与众多与免疫、炎症和应激反应相关的基因转录，同时也参与细胞增殖调控和凋亡等过程。近年来研究亦现实NF-κB活性失控与人类肿瘤发生密切相关。NF-κB蛋白在胞浆内与抑制性蛋白IκB结合成无活性复合物而存在，活化时IκB先被磷酸化为IκBα，随后被泛素一蛋白酶系统（UPS：由泛素活化酶E1、泛素结合酶E2与泛素一蛋白连接酶E3等组成）经泛素化及蛋白水解而降解，NF-κB被释放出来，进而进入细胞核发挥转录调控作用。     

泛素-蛋白酶体途径与泌尿系肿瘤

介绍泛素 蛋白酶体途径的组成 ,它是由泛素以及泛素活化酶、泛素结合酶、泛素蛋白连接酶及蛋白酶体等组成及该途径的作用机制。阐述泛素 蛋白酶体途径与泌尿系肿瘤的相互关系及研究进展     

泛素-蛋白酶体系统介导的蛋白质降解对L—LTP维持期的影响

泛素-蛋白酶体系统作为细胞内局部迅速降解蛋白质的主要途径之一,其介导的蛋白质降解对LTP有重要影响。该系统可通过降解某些抑制性因子促进蛋白质合成,从而对L-LTP的维持期产生一定的正性调控作用。泛素一蛋白酶体系统本身的活性受到神经兴奋性的调节,使得蛋白质的降解作用与神经元的功能相适应。深入探讨泛素一蛋白酶体系统对L—LTP维持期的影响以及神经兴奋性对泛素一蛋白酶体系统的调控。不仅有助于更全面地了解学习记忆的分子机制。更合理地解释实验现象．还将有助于拓展认知功能障碍的治疗思路。     

类泛素化修饰在脊髓损伤中作用的研究进展

脊髓损伤临床常见且预后大多较差,损伤后病理过程相当复杂。近年来,神经系统疾病中类泛素修饰蛋白(SUMO)的作用越来越受到关注。SUMO是一类最新发现的蛋白质翻译后修饰蛋白,类泛素化修饰在人体中多个生理和病理生理学活动过程中发挥重要作用。研究结果显示脊髓损伤后脊髓水肿、脊髓缺血/再灌注、氧化应激和炎性反应等过程中多种重要的蛋白分子均存在SUMO化修饰调控机制,SUMO相关蛋白的应用亦被证明可调节氧化应激延缓神经元的死亡,其与抗氧化剂等其他脊髓治疗性化合物联合使用有望用于预防缺血性损伤的神经保护,本文拟对脊髓损伤过程中有关SUMO化修饰的最新研究作一综述。     

泛素-蛋白酶体途径与泌尿系肿瘤

介绍泛素一蛋白酶体途径的组成，它是由泛素以及泛素活化酶、泛素结合酶、泛素蛋白连接酶及蛋白酶体等组成及该途径的作用机制。阐述泛素一蛋白酶体途径与泌尿系肿瘤的相互关系及研究进展。     

NEDD4泛素连接酶家族在骨质疏松症中的研究

骨质疏松症的重要发病原因是骨重塑过程的紊乱，而介导泛素化的NEDD4泛素连接酶家族在这一过程中扮演着关键的角色。其中泛素连接酶Smurf1、Wwp1能够抑制成骨细胞分化，Smurf2则能够抑制促破骨细胞分化因子RANKL的分泌，而Wwp2却是一种成骨的正向促进因子。近年来，有关NEDD4泛素连接酶家族的研究为骨质疏松症的发病机制和治疗提供了许多新的方向。本篇综述总结了NEDD4泛素连接酶家族在骨重塑过程中的调控作用。     

蛋白酶体抑制剂与肾脏疾病的研究进展

泛素一蛋白酶体途径（ the ubiquitin - proteasome pathway,UPP）是细胞内蛋白质代谢的一个重要通路,精确地控制着细胞中多种蛋白质成分的降解,包括细胞周期调节蛋白在内的80％的细胞内蛋白质均通过此途径降解,参与基因转录和细胞周期的调节以及细胞凋亡、抗原递呈等细胞生理过程。蛋白酶体抑制剂已经用于多发性骨髓瘤的临床治疗,具有抑制多种肿瘤细胞增殖及诱导肿瘤细胞凋亡的作用,     

Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts.

Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. INTRODUCTION: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. MATERIALS AND METHODS: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3(-/-) mice. RESULTS: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3(-/-) OCs but not by caspase-7 knockdown. OCs generated from caspase-3(-/-) bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3(-/-) OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3(-/-) OCs. CONCLUSIONS: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.     

E3 ubiquitin ligase ASB17 is required for spermiation in mice

BackgroundA major goal of spermiation is to degrade the apical ectoplasmic specialization (ES) junction between Sertoli cells and elongating spermatids in preparation for the eventual disengagement of spermatids into the lumen. E3 ubiquitin ligases mediate the process of ubiquitination and the subsequent proteasomal degradation, but their specific role during spermiation remains largely unexplored.MethodsAnkyrin repeat and SOCS box protein 17 (Asb17)-knockout mice were generated via a CRISPR/Cas9 approach. Epididymal sperm parameters were assessed by a computer-assisted sperm analysis (CASA) system, and morphological analysis of testicular tissues were performed based on histological and immunostaining staining, and transmission electron microscopy (TEM). The interactions between ASB17 and Espin (ESPN) were predicted by HawkDock server and validated through protein pull-down and immunoprecipitation assays.ResultsWe report that ASB17, an E3 ligase, is required for the completion of spermiation and that mice lacking Asb17 are oligozoospermic owing to spermiation failure. ASB17-deficient mice are fertile; however, spermatids exhibit a disorganized ES junction, resulting in retention within the seminiferous epithelium. Mechanistically, ASB17 deficiency leads to excess accumulation of ESPN, an actin-binding essential structural component of the ES. We determined that ASB17 regulates the removal of the ES through ubiquitin mediated protein degradation of ESPN.ConclusionsIn summary, our study describes a role for ASB17 in the regulation of cell-cell junctions between germ cells and somatic cells in the testis. These findings establish a novel mechanism for the regulatory role of E3 ligases during spermatogenesis.     

Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation

OBJECTIVE: To review present knowledge of intracellular mechanisms and molecular regulation of muscle cachexia. SUMMARY BACKGROUND DATA: Muscle cachexia, mainly reflecting degradation of myofibrillar proteins, is an important clinical feature in patients with severe injury, sepsis, and cancer. The catabolic response in skeletal muscle may result in muscle wasting and weakness, delaying or preventing ambulation and rehabilitation in these patients and increasing the risk for pulmonary complications. RESULTS: Muscle cachexia, induced by severe injury, sepsis, and cancer, is associated with increased gene expression and activity of the calcium/calpain- and ubiquitin/proteasome-proteolytic pathways. Calcium/calpain-regulated release of myofilaments from the sarcomere is an early, and perhaps rate-limiting, component of the catabolic response in muscle. Released myofilaments are ubiquitinated in the N-end rule pathway, regulated by the ubiquitin-conjugating enzyme E2(14k) and the ubiquitin ligase E3 alpha, and degraded by the 26S proteasome. CONCLUSIONS: An understanding of the mechanisms regulating muscle protein breakdown is important for the development of therapeutic strategies aimed at treating or preventing muscle cachexia in patients with severe injury, sepsis, cancer, and perhaps other catabolic conditions as well.     

The ubiquitin-proteasome pathway: review of a novel intracellular mechanism of muscle protein breakdown during sepsis and other catabolic conditions.

SUMMARY BACKGROUND DATA: Patients with sepsis and other catabolic conditions, such as severe trauma, cancer, and fasting, suffer significant loss of body protein, the majority of which originates from skeletal muscle. Recent evidence suggests that muscle protein breakdown during sepsis is caused by upregulated activity in the ubiquitin-proteasome pathway and is associated with increased expression of the ubiquitin gene. PURPOSE: The purpose of the study was to review the role of the ubiquitin-proteasome pathway in the regulation of muscle proteolysis during sepsis and other catabolic conditions. REVIEW: Proteins that are degraded by the ubiquitin-proteasome mechanism are first conjugated to ubiquitin, a 76-amino-acid, highly conserved residue. Ubiquitinated proteins are recognized by the 26S proteasome, which is a large proteolytic complex consisting of the 19S cap complex and the 20S proteasome. The 20S proteasome is a cylindrical particle composed of four stacked rings, making it look like a barrel. The rings form a "tunnel" in which the target proteins are hydrolyzed, after which ubiquitin is released to be reused in the proteolytic pathway. A unique feature of the ubiquitin-proteasome proteolytic pathway is its energy dependency. CONCLUSIONS: An understanding of the molecular regulation of protein metabolism in patients with sepsis and other catabolic conditions is important because it may form the basis for improved treatment in the future.