Cullin-RING泛素连接酶(cullin-r ING ligase,CRL)是人体内数量最多的一类泛素连接酶的统称,由cullin蛋白、RING蛋白及底物识别亚基组成。它们通过与数百种底物相互作用,形成数量庞大的CRL复合体并调控细胞内蛋白分子的泛素化降解过程...Cullin-RING泛素连接酶(cullin-r ING ligase,CRL)是人体内数量最多的一类泛素连接酶的统称,由cullin蛋白、RING蛋白及底物识别亚基组成。它们通过与数百种底物相互作用,形成数量庞大的CRL复合体并调控细胞内蛋白分子的泛素化降解过程。作者对CRL及其抑制剂在肿瘤治疗中的研究进展作一综述。展开更多
The ubiquitin-proteasome system is a key mechanism that plants use to generate adaptive responses in coping with various en- vironmental stresses. Cullin-RING (CRL) complexes represent a predominant group of ubiquitin...The ubiquitin-proteasome system is a key mechanism that plants use to generate adaptive responses in coping with various en- vironmental stresses. Cullin-RING (CRL) complexes represent a predominant group of ubiquitin E3 ligases in this system. In this review, we focus on the CRL E3s that have been implicated in abiotic stress signaling pathways in Arabidopsis. By comparing and analyzing these cases, we hope to gain a better understanding on how CRL complexes work under various settings in an attempt to decipher the clues about the regulatory mechanism of CRL E3s.展开更多
乙型肝炎病毒(hepatitis B virus,HBV)编码的X蛋白(hepatitis B virus X protein,HBx)对HBV感染的启始和维持至关重要。HBx可能作为病毒来源的接头分子,介导Cullin-RING E3泛素连接酶4(CullinRING ubiquitin E3ligase 4,CRL4)复合物对...乙型肝炎病毒(hepatitis B virus,HBV)编码的X蛋白(hepatitis B virus X protein,HBx)对HBV感染的启始和维持至关重要。HBx可能作为病毒来源的接头分子,介导Cullin-RING E3泛素连接酶4(CullinRING ubiquitin E3ligase 4,CRL4)复合物对染色体外DNA限制因子SMC5/6的降解。最近研究发现,CRL4接头分子DNA损伤结合蛋白1(DNA damage-binding protein 1,DDB1)可不依赖与HBx的相互作用而直接上调病毒的表达和复制。本研究基于HBx基因删除(X-null)的HBV重组共价闭合环状DNA(recombinant covalently closed circular DNA,rcccDNA)模型系统,在多种体外培养肝细胞系中证实上述发现。有意思的是,CRL4刺激rcccDNAX-null转染细胞抗原分泌表达的效应能被血清饥饿实验抵消。应用尾静脉高压注射小鼠模型,同样发现CRL4并不上调rcccDNAX-null在非增殖小鼠肝脏细胞中的表达。以上结果提示,细胞增殖特征与CRL4不依赖HBx上调病毒抗原分泌表达的效应密切相关,有助于HBx生物学意义的准确分析和理解。展开更多
The COP9 signalosome(CSN)is a highly conserved protein complex composed of 8 subunits(CSN1 to CSN8).The individual subunits of the CSN play essential roles in cell proliferation,tumorigenesis,cell cycle regulation,DNA...The COP9 signalosome(CSN)is a highly conserved protein complex composed of 8 subunits(CSN1 to CSN8).The individual subunits of the CSN play essential roles in cell proliferation,tumorigenesis,cell cycle regulation,DNA damage repair,angiogenesis,and microenvironmental homeostasis.The CSN complex has an intrinsic metalloprotease that removes the ubiquitin-like activator NEDD8 from cullin-RING ligases(CRLs).Binding of neddylated CRLs to CSN is sensed by CSN4 and communicated to CSN5 with the assistance of CSN6,thus leading to the activation of deneddylase.Therefore,CSN is a crucial regulator at the intersection between neddylation and ubiquitination in cancer progression.Here,we summarize current understanding of the roles of individual CSN subunits in cancer progression.Furthermore,we explain how the CSN affects tumorigenesis through regulating transcription factors and the cell cycle.Finally,we discuss individual CSN subunits as potential therapeutic targets to provide new directions and strategies for cancer therapy.展开更多
Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentall...Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.展开更多
Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obesity. Therefore here we investigate the role of the COP9 signalosome and of CHOP in ...Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obesity. Therefore here we investigate the role of the COP9 signalosome and of CHOP in the differentiation of LiSa-2 preadipocytes.展开更多
SAG(Sensitive to Apoptosis Gene),also known as RBX2(RING box protein 2),ROC2(Regulator of Cullins 2),or RNF7(RING Finger Protein 7),was originally cloned in our laboratory as a redox inducible antioxi-dant protein and...SAG(Sensitive to Apoptosis Gene),also known as RBX2(RING box protein 2),ROC2(Regulator of Cullins 2),or RNF7(RING Finger Protein 7),was originally cloned in our laboratory as a redox inducible antioxi-dant protein and later characterized as the second member of the RBX/ROC RING component of the SCF(SKP1-CUL-F-box Proteins)E3 ubiquitin ligase.When acting alone,SAG scavenges oxygen radicals by forming inter-and intra-molecular disulfide bonds,whereas by forming a complex with other components of the SCF E3 ligase,SAG promotes ubiquitination and degradation of a number of protein substrates,includ-ing c-JUN,DEPTOR,HIF-1α,IκBα,NF1,NOXA,p27,and procaspase-3,thus regulating various signaling path-ways and biological processes.Specifically,SAG pro-tects cells from apoptosis,confers radioresistance,and plays an essential and non-redundant role in mouse embryogenesis and vasculogenesis.Furthermore,stress-inducible SAG is overexpressed in a number of human cancers and SAG overexpression correlates with poor patient prognosis.Finally,SAG transgenic expression in epidermis causes an early stage inhibi-tion,but later stage promotion,of skin tumorigenesis triggered by DMBA/TPA.Given its major role in pro-moting targeted degradation of tumor suppressive proteins,leading to apoptosis suppression and accel-erated tumorigenesis,SAG E3 ligase appears to be an attractive anticancer target.展开更多
Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Pho...Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Phosphorylation,either of substrates or receptors of CRLs,can alter their interaction.Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases,most often tumorigenesis.These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases,along with the regulation of the stability of specific oncoproteins and tumor suppressors.This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination,and most importantly its influence on tumorigenesis,to provide new directions and strategies for tumor therapy.展开更多
文摘Cullin-RING泛素连接酶(cullin-r ING ligase,CRL)是人体内数量最多的一类泛素连接酶的统称,由cullin蛋白、RING蛋白及底物识别亚基组成。它们通过与数百种底物相互作用,形成数量庞大的CRL复合体并调控细胞内蛋白分子的泛素化降解过程。作者对CRL及其抑制剂在肿瘤治疗中的研究进展作一综述。
基金supported by the "New Century Excellent Talents"program of the Ministry of Education, China [NCET-10-0153]the China Postdoctoral Visiting-Scholar Fellowship (201104519+4 种基金20100481042)the Ministry of Environmental Protection of the PRC (2011467032)a National Institutes of Health grant (GM47850)the National Science Foundation (NSF) Plant Genome Program (DBI0922604)the NSF 2010 program (MCB-0929100)
文摘The ubiquitin-proteasome system is a key mechanism that plants use to generate adaptive responses in coping with various en- vironmental stresses. Cullin-RING (CRL) complexes represent a predominant group of ubiquitin E3 ligases in this system. In this review, we focus on the CRL E3s that have been implicated in abiotic stress signaling pathways in Arabidopsis. By comparing and analyzing these cases, we hope to gain a better understanding on how CRL complexes work under various settings in an attempt to decipher the clues about the regulatory mechanism of CRL E3s.
文摘乙型肝炎病毒(hepatitis B virus,HBV)编码的X蛋白(hepatitis B virus X protein,HBx)对HBV感染的启始和维持至关重要。HBx可能作为病毒来源的接头分子,介导Cullin-RING E3泛素连接酶4(CullinRING ubiquitin E3ligase 4,CRL4)复合物对染色体外DNA限制因子SMC5/6的降解。最近研究发现,CRL4接头分子DNA损伤结合蛋白1(DNA damage-binding protein 1,DDB1)可不依赖与HBx的相互作用而直接上调病毒的表达和复制。本研究基于HBx基因删除(X-null)的HBV重组共价闭合环状DNA(recombinant covalently closed circular DNA,rcccDNA)模型系统,在多种体外培养肝细胞系中证实上述发现。有意思的是,CRL4刺激rcccDNAX-null转染细胞抗原分泌表达的效应能被血清饥饿实验抵消。应用尾静脉高压注射小鼠模型,同样发现CRL4并不上调rcccDNAX-null在非增殖小鼠肝脏细胞中的表达。以上结果提示,细胞增殖特征与CRL4不依赖HBx上调病毒抗原分泌表达的效应密切相关,有助于HBx生物学意义的准确分析和理解。
基金This work was supported by the National Natural Science Foundation of China(Grant No.81872080)Jiangsu Provincial Medical Talent(Grant No.ZDRCA 2016055)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘The COP9 signalosome(CSN)is a highly conserved protein complex composed of 8 subunits(CSN1 to CSN8).The individual subunits of the CSN play essential roles in cell proliferation,tumorigenesis,cell cycle regulation,DNA damage repair,angiogenesis,and microenvironmental homeostasis.The CSN complex has an intrinsic metalloprotease that removes the ubiquitin-like activator NEDD8 from cullin-RING ligases(CRLs).Binding of neddylated CRLs to CSN is sensed by CSN4 and communicated to CSN5 with the assistance of CSN6,thus leading to the activation of deneddylase.Therefore,CSN is a crucial regulator at the intersection between neddylation and ubiquitination in cancer progression.Here,we summarize current understanding of the roles of individual CSN subunits in cancer progression.Furthermore,we explain how the CSN affects tumorigenesis through regulating transcription factors and the cell cycle.Finally,we discuss individual CSN subunits as potential therapeutic targets to provide new directions and strategies for cancer therapy.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81602072,81902380,81820108022,and 81625018)Innovation Program of Shanghai Municipal Education Commission(Grant No.2019-01-07-00-10-E00056)+5 种基金Program of Shanghai Academic/Technology Research Leader(Grant No.18XD1403800)National High Technology Research and Development Program of China(Grant No.2015AA021107-019)Scientific Research Project of Shanghai Science and Technology Commission(Grant No.18411960600)Shanghai Technological Innovation Action Projects(Grant No.18411950800)Shanghai‘Rising Stars of Medical Talent’Youth Development Program,Outstanding Youth Medical Talents,2018the Shanghai Sailing Program(Grant No.17YF1405000).
文摘Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.
文摘Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obesity. Therefore here we investigate the role of the COP9 signalosome and of CHOP in the differentiation of LiSa-2 preadipocytes.
基金supported by the NCI grants(CA118762 and CA156744)to Yi Sun.
文摘SAG(Sensitive to Apoptosis Gene),also known as RBX2(RING box protein 2),ROC2(Regulator of Cullins 2),or RNF7(RING Finger Protein 7),was originally cloned in our laboratory as a redox inducible antioxi-dant protein and later characterized as the second member of the RBX/ROC RING component of the SCF(SKP1-CUL-F-box Proteins)E3 ubiquitin ligase.When acting alone,SAG scavenges oxygen radicals by forming inter-and intra-molecular disulfide bonds,whereas by forming a complex with other components of the SCF E3 ligase,SAG promotes ubiquitination and degradation of a number of protein substrates,includ-ing c-JUN,DEPTOR,HIF-1α,IκBα,NF1,NOXA,p27,and procaspase-3,thus regulating various signaling path-ways and biological processes.Specifically,SAG pro-tects cells from apoptosis,confers radioresistance,and plays an essential and non-redundant role in mouse embryogenesis and vasculogenesis.Furthermore,stress-inducible SAG is overexpressed in a number of human cancers and SAG overexpression correlates with poor patient prognosis.Finally,SAG transgenic expression in epidermis causes an early stage inhibi-tion,but later stage promotion,of skin tumorigenesis triggered by DMBA/TPA.Given its major role in pro-moting targeted degradation of tumor suppressive proteins,leading to apoptosis suppression and accel-erated tumorigenesis,SAG E3 ligase appears to be an attractive anticancer target.
基金supported by the State Key Program of National Natural Science Foundation of China(No.81830107 to Qiaojun He)grant from the National Natural Science Foundation of China(No.81973354 to Meidan Ying)
文摘Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Phosphorylation,either of substrates or receptors of CRLs,can alter their interaction.Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases,most often tumorigenesis.These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases,along with the regulation of the stability of specific oncoproteins and tumor suppressors.This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination,and most importantly its influence on tumorigenesis,to provide new directions and strategies for tumor therapy.
