The cytosolic chaperonin T-complex protein 1-ring complex(TRiC)or chaperonin containing T-complex protein 1(CCT)is essential in de novo folding of approximately 10%of the eukaryotic,newly translated polypeptides as we...The cytosolic chaperonin T-complex protein 1-ring complex(TRiC)or chaperonin containing T-complex protein 1(CCT)is essential in de novo folding of approximately 10%of the eukaryotic,newly translated polypeptides as well as misfolded proteins.There is a close link between the TRiC/CCT cytosolic chaperonin and neurodegenerative diseases(Lopez et al.,2015).A lot of research suggests that CCT plays neuroprotective roles in neurodegenerative diseases including Huntington’s disease(Lopez et al.,2015).Either overexpression of a single or all eight subunits(CCT1-8)or treatment of the substrate-binding apical domain of yeast CCT1(ApiCCT1)prevented mutant Huntingtin aggregation and improved cellular and neuronal functions(Zhao et al.,2016).Importantly,our recent study has demonstrated that both CCT and ApiCCT could reduce mutant Huntingtin level and enhance both anterograde and retrograde axonal transport of brain-derived neurotrophic factor.These results led to restoration of the trophic status of striatal neurons from a bacterial artificial chromosome transgenic mouse model of Huntington’s disease(Zhao et al.,2016).Axonal transport is regulated by many factors including microtubule-associated protein tau,which promotes tubulin polymerization and stabilizes microtubules.Impaired interaction between tau and microtubules plays a vital role in the pathogenesis of multiple neurodegenerative diseases(Wang and Mandelkow,2016).Interestingly,tau phosphorylation is also observed in brains of several Huntington’s disease mouse models and Huntington’s disease patients(Gratuze et al.,2016).In a recent study,we explored if CCT subunit has any effect on axonal transport in a tau-dependent pathway(Chen et al.,2018b).We focused on the retrograde axonal transport of brain-derived neurotrophic factor,as neurotrophic factor-mediated signaling in the form of signaling endosome is essential in both the developing and the mature nervous system and dysregulation of trafficking of neurotrophic factors is tightly linked to disorders of the nervous system(Chen et al.,2018a).We found that the expression of a single CCT subunit(CCT5)significantly promoted retrograde axonal transport of brain-derived neurotrophic factor in primary cortical neurons.Mechanically,CCT regulated the level of cyclin-dependent kinase 5(CDK5)/p35/p25 and,subsequently contributed to CCT-induced tau phosphorylation,which induced detachment of tau from microtubules(Chen et al.,2018b)(Figure 1).展开更多
利用生物信息学数据库分析泛素样含PHD和环指结构域蛋白1(UHRF1)在恶性胸膜间皮瘤(MPM)中的表达水平及临床意义。基于TCGA数据库和GTEx数据库差异表达分析UHRF1 m RNA在MPM组织和正常肺组织中的表达水平;使用R软件分析UHRF1 mRNA表达量...利用生物信息学数据库分析泛素样含PHD和环指结构域蛋白1(UHRF1)在恶性胸膜间皮瘤(MPM)中的表达水平及临床意义。基于TCGA数据库和GTEx数据库差异表达分析UHRF1 m RNA在MPM组织和正常肺组织中的表达水平;使用R软件分析UHRF1 mRNA表达量与临床病理参数的相关性;构建Kaplan-Meier模型和单因素多因素COX回归模型分析UHRF1基因在MPM中的预后;利用TIMER2.0数据库分析UHRF1基因与免疫细胞浸润的关系;GSEA分析UHRF1基因发挥功能的主要富集通路。选取8例MPM组织及4例非MPM胸膜组织,通过RT-q PCR的方法验证UHRF1在MPM与非MPM胸膜组织的表达情况。数据库分析结果表明,与正常肺组织相比,UHRF1 m RNA在MPM组织中高表达;UHRF1高表达患者提示MPM患者预后不良;UHRF1基因表达量与CD4^(+)辅助型T细胞2、CD4^(+)效应记忆性T细胞、巨噬细胞等多种免疫细胞浸润水平具有显著的相关性(P<0.01),且显著影响MPM患者的预后。功能富集分析显示,UHRF1主要在DNA复制、蛋白酶体、同源重组等通路中起作用。在收集到的病例样本中,与非MPM胸膜组织相比,UHRF1 mRNA在MPM组织中的表达显著增高(P<0.001)。UHRF1在MPM组织中高表达,可能通过调节DNA甲基化和免疫细胞浸润来影响MPM患者预后,有望成为MPM治疗和预后评估的潜在靶点。展开更多
文摘The cytosolic chaperonin T-complex protein 1-ring complex(TRiC)or chaperonin containing T-complex protein 1(CCT)is essential in de novo folding of approximately 10%of the eukaryotic,newly translated polypeptides as well as misfolded proteins.There is a close link between the TRiC/CCT cytosolic chaperonin and neurodegenerative diseases(Lopez et al.,2015).A lot of research suggests that CCT plays neuroprotective roles in neurodegenerative diseases including Huntington’s disease(Lopez et al.,2015).Either overexpression of a single or all eight subunits(CCT1-8)or treatment of the substrate-binding apical domain of yeast CCT1(ApiCCT1)prevented mutant Huntingtin aggregation and improved cellular and neuronal functions(Zhao et al.,2016).Importantly,our recent study has demonstrated that both CCT and ApiCCT could reduce mutant Huntingtin level and enhance both anterograde and retrograde axonal transport of brain-derived neurotrophic factor.These results led to restoration of the trophic status of striatal neurons from a bacterial artificial chromosome transgenic mouse model of Huntington’s disease(Zhao et al.,2016).Axonal transport is regulated by many factors including microtubule-associated protein tau,which promotes tubulin polymerization and stabilizes microtubules.Impaired interaction between tau and microtubules plays a vital role in the pathogenesis of multiple neurodegenerative diseases(Wang and Mandelkow,2016).Interestingly,tau phosphorylation is also observed in brains of several Huntington’s disease mouse models and Huntington’s disease patients(Gratuze et al.,2016).In a recent study,we explored if CCT subunit has any effect on axonal transport in a tau-dependent pathway(Chen et al.,2018b).We focused on the retrograde axonal transport of brain-derived neurotrophic factor,as neurotrophic factor-mediated signaling in the form of signaling endosome is essential in both the developing and the mature nervous system and dysregulation of trafficking of neurotrophic factors is tightly linked to disorders of the nervous system(Chen et al.,2018a).We found that the expression of a single CCT subunit(CCT5)significantly promoted retrograde axonal transport of brain-derived neurotrophic factor in primary cortical neurons.Mechanically,CCT regulated the level of cyclin-dependent kinase 5(CDK5)/p35/p25 and,subsequently contributed to CCT-induced tau phosphorylation,which induced detachment of tau from microtubules(Chen et al.,2018b)(Figure 1).
文摘利用生物信息学数据库分析泛素样含PHD和环指结构域蛋白1(UHRF1)在恶性胸膜间皮瘤(MPM)中的表达水平及临床意义。基于TCGA数据库和GTEx数据库差异表达分析UHRF1 m RNA在MPM组织和正常肺组织中的表达水平;使用R软件分析UHRF1 mRNA表达量与临床病理参数的相关性;构建Kaplan-Meier模型和单因素多因素COX回归模型分析UHRF1基因在MPM中的预后;利用TIMER2.0数据库分析UHRF1基因与免疫细胞浸润的关系;GSEA分析UHRF1基因发挥功能的主要富集通路。选取8例MPM组织及4例非MPM胸膜组织,通过RT-q PCR的方法验证UHRF1在MPM与非MPM胸膜组织的表达情况。数据库分析结果表明,与正常肺组织相比,UHRF1 m RNA在MPM组织中高表达;UHRF1高表达患者提示MPM患者预后不良;UHRF1基因表达量与CD4^(+)辅助型T细胞2、CD4^(+)效应记忆性T细胞、巨噬细胞等多种免疫细胞浸润水平具有显著的相关性(P<0.01),且显著影响MPM患者的预后。功能富集分析显示,UHRF1主要在DNA复制、蛋白酶体、同源重组等通路中起作用。在收集到的病例样本中,与非MPM胸膜组织相比,UHRF1 mRNA在MPM组织中的表达显著增高(P<0.001)。UHRF1在MPM组织中高表达,可能通过调节DNA甲基化和免疫细胞浸润来影响MPM患者预后,有望成为MPM治疗和预后评估的潜在靶点。
