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1.
中脑黑质多巴胺能神经元特异性损伤和α突触核蛋白聚集的分子机制是帕金森病(Parkinson’s disease,PD)研究领域亟待解决的问题。蛋白质异常聚集很大程度上是由于泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)功能障碍引起的。蛋白质泛素化由一系列泛素化酶级联反应促进,并受去泛素化酶(deubiquitylases,DUBs)的反向调节。泛素化和去泛素化过程异常导致蛋白质异常聚集和包涵体形成,进而损伤神经元。近来研究报道,蛋白质的泛素化和去泛素化修饰在PD的发病机制中发挥重要作用。E3泛素连接酶促进蛋白质的泛素化,有利于α突触核蛋白的清除、促进多巴胺能神经元的存活、维持线粒体的功能等。DUBs可以去掉底物蛋白质的泛素化修饰,抑制α突触核蛋白的降解,调控线粒体的功能和神经元内铁的稳态。本文以E3泛素连接酶和DUBs为切入点,综述了蛋白质泛素化和去泛素化修饰参与多巴胺能神经元损伤机制的最新研究进展。  相似文献   

2.
泛素-蛋白酶体系统(ubiquitin-proteasome-system,UPS)是控制蛋白质降解的主要系统,也是细胞基本活动的关键调节器。去泛素化酶(deubiquitinating enzymes,DUBs)是泛素-蛋白酶体系统的组成部分,主要参与调节蛋白质泛素化和去泛素化的动态平衡,对细胞增殖、信号转导、神经病变或肿瘤发生意义重大。不同的DUBs在乳腺癌中的作用不同,最新发现去泛素化酶BAP1、OTUD3、ATXN3L主要调节乳腺癌细胞增殖,某些DUBs小分子抑制剂可以间接诱导三阴性乳腺癌细胞凋亡。本文主要综述这三个DUBs及去泛素化酶抑制剂在乳腺癌中的研究新进展,为寻找新型的乳腺癌分子靶向药物提供理论依据。  相似文献   

3.
泛素-蛋白酶体系统是细胞内蛋白质特异性降解的主要途径,参与并调控细胞周期、免疫应答、信号传递和DNA修复等真核生物体内几乎所有的生命活动。去泛素酶的存在使泛素化修饰成为可逆过程,保证了泛素系统及其相关生理过程的动态平衡,其表达紊乱也是诱发多种疾病的主要原因。对去泛素化酶进行系统、全面的研究是理解其作用机制并将其作为治疗药物靶点的前提。蛋白质组学技术的快速发展为系统深入研究去泛素化酶提供了条件,特别是在去泛素化酶的相互作用网络和底物特异性研究等方面发挥了独特的作用。因此,文中结合课题组研究工作,对去泛素化酶的分类及功能进行介绍并总结了蛋白质组学在去泛素化酶研究中的应用进展。  相似文献   

4.
Ubiquitin-specific protease 11(USP11)属于半胱氨酸蛋白酶,是去泛素化酶家族(deubiquitinating enzymes,DUBs)的重要成员之一。近年来研究表明USP11能调节细胞内众多蛋白底物的稳定性及功能,包括DNA修复蛋白、病毒RNA复制相关蛋白、TGFβ和NF-κB信号转导通路相关蛋白等,在疾病的发生发展中起着重要的作用。主要综述了USP11的结构、在细胞中的分子功能以及与肿瘤和病毒性疾病的关系,探讨了USP11作为治疗分子靶标的可能性。  相似文献   

5.
阿尔茨海默病(Alzheimer's disease, AD)是一种老年人常见的中枢神经系统退行性疾病。泛素化和去泛素化过程失调导致蛋白质异常聚集是AD发生发展的主要原因。E3泛素连接酶(E3 ubiquitin ligases,E3s)调控底物蛋白的泛素化,可促进β淀粉样蛋白(amyloid-β, Aβ)和过度磷酸化Tau蛋白的清除,改善突触及神经元的功能。去泛素化酶(deubiquitinating enzymes, DUBs)去除底物蛋白的泛素化修饰,可抑制Aβ和过度磷酸化Tau蛋白的降解,引起神经炎症。因为E3s和DUBs并不通过单一途径来促进或者抑制AD的发生发展,所以本文以E3s和DUBs所属亚族为切入点,综述了E3s和DUBs在AD中作用机制的最新研究进展。  相似文献   

6.
泛素化修饰(ubiquitination modification)广泛存在于真核生物,通过26S蛋白酶体降解途径或信号传递等,改变蛋白质稳定性、定位和活性等功能,参与细胞的周期、转录、炎症、肿瘤和免疫等各项功能,是一类复杂的动态调控系统.泛素化调节是一个可逆过程,被泛素连接酶(ubiquitin ligase,E3)...  相似文献   

7.
泛素-蛋白酶体途径是细胞内蛋白质降解的重要方式,调节蛋白质稳定性。去泛素化酶可以识别特定蛋白质的泛素化信号从而使底物蛋白质去泛素化,逆转蛋白质泛素化过程,进而调控细胞增殖、分化、凋亡和迁移等多种生物学功能。去泛素化酶家族的多个成员通过影响细胞增殖凋亡及对化疗药物的敏感性等,在卵巢癌的发生发展中发挥十分重要的作用。一些小分子抑制剂通过抑制去泛素化酶的活性从而起到抗肿瘤的作用,并且具有特异性强,细胞毒性较弱等优势。本综述对参与卵巢癌发生发展的去泛素化酶以及相关的小分子抑制剂做一个全面的总结,为卵巢癌的诊断和治疗提供一个新的方向。  相似文献   

8.
蛋白质泛素化是一种可逆的蛋白质翻译后修饰,在信号转导和蛋白质稳定性调控中发挥关键作用。去泛素化酶调控在许多种肿瘤中的作用机制尚不清楚。本文对63种去泛素化酶在肝细胞癌病人的生存和预后进行分析,发现去泛素化酶JOSD2(josephin domain containing 2)在肝细胞癌组织中表达显著高于癌旁(P<0.0001),且与总生存期相关(P<0.05)。JOSD2属于去泛素化酶MJD(machado josephin domain)亚家族成员,该家族其它成员与肝细胞癌发生无显著的相关性。对TCGA(The Cancer Genome Atlas)数据中JOSD2高表达样本和低表达样本的差异基因进行功能富集分析,显示JOSD2高表达样本中与细胞增殖相关通路显著富集(FDR<0.05)。在肝癌细胞系中过表达JOSD2,发现其能促进肝癌细胞的存活、迁移和侵袭(P<0.01)。综上所述,本文发现去泛素化酶JOSD2在肝细胞癌组织中高表达,高表达JOSD2的肝细胞癌病人总生存期显著降低(P=0.041),过表达JOSD2能促进肝癌细胞的存活和转移,提示JOSD2可能促进肝细胞癌的转移。  相似文献   

9.
肿瘤的侵袭和转移是加剧肿瘤恶化的主要原因,也是导致患者预后不良的根本原因。近年来大量研究发现,大部分肿瘤的转移都依赖于上皮间质转化(epithelial-mesenchymal transition, EMT)的发生,此外EMT也与肿瘤干性和肿瘤耐药等诸多肿瘤恶性行为密切相关,因此有效的抑制EMT的发生将可能极大的有利于肿瘤的治疗。去泛素化酶(deubiquitinating enzymes, DUBs)的主要功能之一就是通过移除底物蛋白质上泛素链,避免其通过泛素蛋白酶体途径降解,来维持细胞内蛋白质水平的动态平衡。去泛素化酶作为调节蛋白质泛素化修饰的一类重要酶类,其异常表达或酶活性的改变通常都会导致疾病的发生。众多研究发现,部分去泛素化酶在肿瘤侵袭和转移过程中表达失衡,在肿瘤转移的过程中扮演着重要的角色。EMT是指由上皮型细胞转变为间质型细胞的动态细胞生物学过程,在该过程中涉及到例如Snial1、Slug、ZEB1等EMT相关转录因子和细胞表面的例如E-钙黏着蛋白、N-钙黏着蛋白等分子标志物表达水平的变化。这些蛋白质通常具有不稳定性,易被降解等特征。EMT过程的发生,涉及到许多蛋白质稳定性的调节,而去泛素化酶作为一类维持蛋白质稳定的重要酶类,在调节这些蛋白质的稳定性方面发挥着重要的作用。EMT的发生也与TGF-β通路、Wnt通路等细胞内众多信号通路的异常活化密不可分,去泛素化酶通过介导这些信号通路的活化,从而间接的调节EMT发生发展。去泛素化酶通过调节EMT相关分子或EMT相关信号通路等多种方式直接或间接影响EMT进展,因此,通过靶向于去泛素化酶抑制肿瘤的侵袭和转移,将为肿瘤治疗提供新的治疗手段和方案,从而有效的推动肿瘤的治疗。本文主要就去泛素化酶在调节EMT相关分子以及信号通路等方面,阐述去泛素化酶在EMT过程中所发挥的重要作用及其作为肿瘤治疗靶点的可能性。  相似文献   

10.
泛素在真核生物体内广泛存在,泛素化修饰是转录后的修饰方式之一;组蛋白是染色质的主要成分之一,与基因的表达有密切关系。组蛋白的泛素化修饰与经典的蛋白质的泛素调节途径不同,不会导致蛋白质的降解,但是能够招募核小体到染色体、参与X染色体的失活、影响组蛋白的甲基化和基因的转录。组蛋白的去泛素化修饰同样与染色质的结构及基因表达密切相关。组蛋白的泛素化和磷酸化、乙酰化、甲基化修饰之间还存在协同和级联效应。  相似文献   

11.
Renal cell carcinoma (RCC) accounts for around 3% of cancers in the UK, and both incidence and mortality are increasing with the aging population. RCC can be divided into several subtypes: conventional RCC (the most common, comprising 75% of all cases), papillary RCC (15%) and chromophobe RCC (5%). Renal oncocytoma is a benign tumor and accounts for 5% of RCC. Cancer and epigenetics are closely associated, with DNA hypermethylation being widely accepted as a feature of many cancers. In this study the DNA methylation profiles of chromophobe RCC and renal oncocytomas were investigated by utilizing the Infinium HumanMethylation450 BeadChips. Cancer-specific hypermethylation was identified in 9.4% and 5.2% of loci in chromophobe RCC and renal oncocytoma samples, respectively, while the majority of the genome was hypomethylated. Thirty (hypermethylated) and 41 (hypomethylated) genes were identified as differentially methylated between chromophobe RCC and renal oncocytomas (p < 0.05). Pathway analysis identified some of the differentially hypermethylated genes to be involved in Wnt (EN2), MAPK (CACNG7) and TGFβ (AMH) signaling, Hippo pathway (NPHP4), and cell death and apoptosis (SPG20, NKX6-2, PAX3 and BAG2). In addition, we analyzed ccRCC and papillary RCC data available from The Cancer Genome Atlas portal to identify differentially methylated loci in chromophobe RCC and renal oncocytoma in relation to the other histological subtypes, providing insight into the pathology of RCC subtypes and classification of renal tumors.  相似文献   

12.
囊性肾细胞癌5例超声特征及诊断体会   总被引:1,自引:0,他引:1  
目的:提高对囊性肾细胞癌的认识。方法:回顾我院5例经病理诊断为囊性肾细胞癌病例的超声图像、临床症状和预后随访。结果:肿瘤声像图在肾囊肿的基础上,分为(1)单房囊肿型(2例),囊壁见光斑,不均匀增厚,或乳突状突起。(2)多房囊肿型(2例)。(3)低回声实体型(1例)。CDFI、CDF在肿瘤的周围、内部及囊壁均无明显异常血流信号。5例患者均无明显临床症状,特别是血尿,全部为透明细胞癌,均行根治性切除术,无淋巴转移,均无复发和转移。结论:囊性肾细胞癌是一种罕见的肾细胞癌,是少血管性肿瘤,一般为早期,临床上一般无症状,预后较好。超声显示复杂性囊肿在临床上要引起重视。  相似文献   

13.
Zinc is an indispensable trace element which is vital for the functioning of numerous cellular processes like cell replication and growth. Cellular zinc homeostasis is tightly regulated by zinc transporters involved in zinc influx and efflux processes. Notwithstanding, the association of zinc transporters with the aggressiveness of cancer, especially renal cell carcinoma (RCC), is unknown. In view of the fact, the present study was initiated to ascertain whether ZIP10 transporter expression is modulated during RCC progression. A total of 57 samples of RCC and corresponding normal renal tissue were analyzed for ZIP10 gene expression by real time PCR. We observed significantly higher expression of ZIP10 mRNA (P = 0.002) in high grade clear cell RCC tissue (Grades III & IV) as compared to low grade clear cell RCC tissue (Grades I & II). A significant difference was also observed in the ZIP10 expression in different types of RCC (P = 0.001). This is the first study which shows a significant correlation between ZIP10 mRNA expressions with aggressiveness of RCC. Therefore, ZIP10 mRNA expression could be used as a possible biomarker for the aggressive behavior of RCC and a promising target of novel treatment strategies.  相似文献   

14.
自噬和泛素-蛋白酶体系统作为细胞内最重要的两大降解途径,对细胞稳态及细胞正常生理功能的维持都具有十分重要的作用。目前,越来越多的证据显示,这两大降解途径之间存在多种交联方式。首先,自噬和泛素-蛋白酶体系统都能以泛素作为共同标签,从而将泛素化底物降解;其次,泛素化的蛋白酶体可以通过自噬被清除,自噬相关蛋白质也可以通过蛋白酶体系统被降解;再次,这两条途径在细胞内能协同降解同一种底物;最后,它们之间可以相互调节活性,任一条途径被干扰都将影响另一条途径的活性。自噬和泛素-蛋白酶体系统之间的交联对细胞稳态的维持至关重要。交联失调不仅导致细胞功能异常,还可引起多种疾病的发生。本文主要对自噬和泛素-蛋白酶体系统之间的交联方式及其分子机制进行阐述,有助于深入了解细胞的分解代谢过程,进一步理解细胞稳态的维持机制,继而加深对相关疾病病理机制的认识。  相似文献   

15.
揈应用生物信息学分析,筛选获得1个肾癌组织中高表达,而在癌旁正常组织中低表达的新基因CXorf36(chromosome X open reading frame 36),并用RT PCR方法,在组织和细胞系中加以验证.与肾癌组织相比,3种肾癌细胞系中该基因mRNA的表达丰度很低.为观察CXorf36基因表达产物在哺乳动物细胞内的亚定位,构建了pEGFP N1-CXorf36融合表达载体,转染786-O细胞,其融合蛋白均匀分布于细胞浆.氨基酸序列比对分析显示, CXorf36蛋白与小鼠来源的猜测蛋白LOC75905具有79%的同源性,而小鼠LOC75905蛋白可能是一种水解酶.因此,推测CXorf36蛋白是通过其水解酶活性,在肿瘤的发生、生长或侵袭过程中发挥重要作用.进一步关于CXorf36基因功能的研究,如其在肿瘤组织中的定位、对细胞生物学功能的影响,及其寻找相互作用分子的实验等仍在进行中.  相似文献   

16.
人肾细胞癌细胞阳离子脂质体的转染效率   总被引:4,自引:0,他引:4  
以MTS染色法测定实验剂量的Lipofectin对细胞的毒性作用,以β-半乳糖苷酶基因为报告基因,通过Lipofectin而转染,用X-gal染色法,测定转染效率,结果表明实验剂量(10μg/ml)的Lipofectin对细胞生长无明显毒性。Lipofectin对多数肾细胞癌细胞的转染是有效的,且转染效率随Lipofectin 度的增高(2.5-10μg/ml)而增高,说明Lipofectin可安  相似文献   

17.
本研究旨在证实鞘脂活化蛋白C(saposin C)对雄激素受体(AR)多泛素化降解的影响及其机制. 通过将真核表达载体saposin C转染LNCaP细胞,发现saposin C上调AR的蛋白水平和转录激活活性. 进一步将野生型和突变型泛素质粒Ubwt和UbK48R分别与saposin C 共转染LNCaP细胞发现,saposin C能够促进AR蛋白的单泛素化形式的稳定性,抑制AR的多泛素化修饰及其在蛋白酶体中的降解. 其分子机制是saposin C、Ub和AR三者形成复合体,抑制了AR的进一步多泛素化过程. 同时还发现,在这一机制中,细胞内低浓度的雄激素(0.1 nmol/L)与saposin C具有协同作用.  相似文献   

18.
    
Carcinoma of the kidney is one of the most prevalent carcinoma worldwide. The majority types of carcinoma are clear cell renal cell carcinoma (CCRCC), which consist more than 80% of the cases. As a genetically diverse disease, identification of prognosis-related genes has utmost importance in the early diagnosis and prognosis of the CCRCC. In this study, we performed gene expression profiling to identify prognosis-related genes for CCRCC. In addition, we developed and validated a gene signature-based risk score to comprehensively assess the prognostic function of differentially expressed genes. Furthermore, we performed a ROC analysis to identify the optimal cut-off point for classification risk level of the patients. Univariate Cox regression models were used to assess the association between differentially expressed genes in relation to the prognosis of patients with different stages of CCRCC. Five genes were identified significantly differentially expressed in CCRCC and associated with their survival time, namely: IDUA, NDST1, SAP30L, CRYBA4, and SI. A 5-gene signature-based risk score was developed based on the Cox coefficient of the individual genes. The prognostic value of this risk score was validated in an internal testing data set. In summary, a gene-based risk score was identified and validated, which can predict CCRCC patient survival. The potential functions of this gene expression signature and individual differentially expressed gene as prognostic targets of CCRCC were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the CCRCC patients.  相似文献   

19.

Background

Formalin-fixed, paraffin-embedded (FFPE) tissues represent the most abundant resource of archived human specimens in pathology. Such tissue specimens are emerging as a highly valuable resource for translational proteomic studies. In quantitative proteomic analysis, reductive di-methylation of primary amines using stable isotopic formaldehyde variants is increasingly used due to its robustness and cost-effectiveness.

Results

In the present study we show for the first time that isotopic amine dimethylation can be used in a straightforward manner for the quantitative proteomic analysis of FFPE specimens without interference from formalin employed in the FFPE process. Isotopic amine dimethylation of FFPE specimens showed equal labeling efficiency as for cryopreserved specimens. For both FFPE and cryopreserved specimens, differential labeling of identical samples yielded highly similar ratio distributions within the expected range for dimethyl labeling. In an initial application, we profiled proteome changes in clear cell renal cell carcinoma (ccRCC) FFPE tissue specimens compared to adjacent non–malignant renal tissue. Our findings highlight increased levels of glyocolytic enzymes, annexins as well as ribosomal and proteasomal proteins.

Conclusion

Our study establishes isotopic amine dimethylation as a versatile tool for quantitative proteomic analysis of FFPE specimens and underlines proteome alterations in ccRCC.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1768-x) contains supplementary material, which is available to authorized users.  相似文献   

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