摘要
Parkin,又名PARK2,自发现初始便与帕金森病(Parkinson’s disease,PD)密切相关。Parkin被认为是一种神经保护性基因。随着对其结构的深入了解,揭开了作为E3泛素连接酶的面纱。Parkin参与调控细胞周期、线粒体动态平衡和能量代谢等细胞进程,并与许多疾病息息相关,甚至在同一通路中发挥完全相反的作用,即细胞增殖和凋亡,表明这必是一个作用极其广泛且重要的基因。本文概述了Parkin的发现和结构及其自身抑制的特点,重点阐述其作为E3泛素连接酶参与的泛素化过程和进而引起的自噬、降解蛋白质、改变蛋白质亚细胞定位和蛋白质间互作等。这些或许都作为Parkin预防PD和抑制肿瘤的基础。在此基础上,总结了Parkin异常导致PD的两方面原因:蛋白质质量控制异常和线粒体功能障碍,并延展了Parkin异常致使线粒体功能障碍所引起的心血管及肾的疾病;Parkin与癌症的内在联系也从Parkin作为一种肿瘤抑制因子、调控细胞周期、细胞凋亡及转移、氧化应激及能量代谢等方面展开了介绍。并对其研究进行了展望,通过保持Parkin的活性状态或增强其表达,可能达到改善PD病人病情的目的。但Parkin抑制肿瘤生长的机制仍尚待破译,且要加强Parkin在介导PD与癌症风险间关系的潜在作用的研究。这些后续的深入研究为在相关疾病的诊断与治疗中作为靶标分子的应用奠定了基础。
Parkin,also known as PARK2,has been closely related to Parkinson’s disease(PD)since its discovery.It is considered to be a neuroprotective gene.With the in-depth understanding for its structure,Parkin has been unveiled as an E3 ubiquitin ligase.Parkin is involved in the regulation of cell cycle,mitochondrial homeostasis,energy metabolism and other cellular processes,and is closely related to many diseases.It even plays completely opposite roles in the same pathway,namely cell proliferation and apoptosis,indicating that this must be a gene with an extremely broad and important role.This article summarizes the discovery and structure of Parkin and its self-inhibiting characteristics,focusing on the ubiquitination process that it participates in as E3 ubiquitin ligase and the resulting autophagy,protein degradation,changes in protein subcellular localization and protein interaction.These may all serve as the basis for Parkin to prevent PD and suppress tumors.On this basis,two reasons for Parkin abnormalities leading to PD are summarized:abnormal protein quality control and mitochondrial dysfunction,and extended to cardiovascular and kidney diseases caused by the abnormality of Parkin due to mitochondrial dysfunction.The internal connection between Parkin and cancer is also introduced from the aspects of Parkin as a tumor suppressor,regulating cell cycle,apoptosis and metastasis,oxidative stress and energy metabolism.By maintaining the active state of Parkin or enhancing its expression,it may be possible to improve the condition of PD patients.But the mechanism of Parkin’s inhibition of tumor growth remains to be deciphered,and the potential role of Parkin in mediating the relationship between PD and cancer risk should be strengthened.These follow-up in-depth studies and their role in the diagnosis and treatment of related diseases and application of target molecules laid the foundation.
作者
朱宸阅
原喜霞
李铁松
ZHU Chen-Yue;YUAN Xi-Xia;LI Tie-Song(College of Life Sciences,Lamprey Research Center,Key Laboratory of Liaoning Provincial Biotechnology and Drug Discovery,Liaoning Normal University,Dalian 116081,Liaoning,China)
出处
《中国生物化学与分子生物学报》
CAS
CSCD
北大核心
2021年第3期289-299,共11页
Chinese Journal of Biochemistry and Molecular Biology
基金
国家自然科学基金项目(No.31501907)
辽宁省教育厅科学技术基金项目(No.L2015287)
全国大学生创新创业训练计划项目(No.201910165174,No.S202010165013)资助。
关键词
PARKIN
PARK2
E3泛素连接酶
帕金森病
癌症
Parkin
Parkinson’s disease gene 2(PARK2)
E3 ubiquitin ligase
Parkinson’s disease(PD)
cancer
