Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
[目的]研究ASPM对非小细胞肺癌A549细胞发展的影响。[方法]通过免疫组化实验分析ASPM在非小细胞肺癌组织中的表达;将非小细胞肺癌A549细胞随机分为3个实验组:si NC实验组、si ASPM实验组与BPD-MA实验组。通过CCK-8实验检测A549细胞的增...[目的]研究ASPM对非小细胞肺癌A549细胞发展的影响。[方法]通过免疫组化实验分析ASPM在非小细胞肺癌组织中的表达;将非小细胞肺癌A549细胞随机分为3个实验组:si NC实验组、si ASPM实验组与BPD-MA实验组。通过CCK-8实验检测A549细胞的增殖速度;通过Transwell实验检测A549细胞的侵袭能力;通过流式细胞术检测A549细胞的凋亡率;采用蛋白免疫印迹方法分析A549细胞中YAP1/TAZ通路蛋白的表达。[结果]与癌旁组织比较,ASPM在非小细胞肺癌组织中表达增加(0.28±0.09 vs 0.81±0.06,P<0.05)。与si NC实验组比较,si ASPM以及BPD-MA实验组的A549细胞增殖能力减弱(2.23±0.07 vs 1.16±0.03 vs 1.13±0.05,P<0.05);si ASPM以及BPD-MA实验组的A549细胞侵袭数量减少(126.08±9.33 vs 68.51±7.21 vs 72.82±10.55,P<0.05);si ASPM以及BPD-MA实验组的A549细胞凋亡率增加[(3.22±0.73)%vs(17.01±5.26)%vs(19.23±8.68)%,P<0.05];si ASPM以及BPD-MA实验组的A549细胞YAP1、TAZ蛋白表达下调(0.87±0.03 vs 0.35±0.07 vs 0.33±0.06;0.91±0.12 vs 0.26±0.09 vs 0.31±0.03,P<0.05)。[结论]抑制ASPM表达后,A549细胞的增殖能力与侵袭数量降低,凋亡率增加,该过程与ASPM调节YAP1/TAZ信号通路相关。展开更多
Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emer...Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emerged as a pivotal regulator of stem cell fate,yet the specific molecular mechanism by which it modulates lipogenic differentiation of ADSCs has not been clearly defined.In this study,goat ADSCs(gADSCs)isolated from Albas goats in Inner Mongolia were used to investigate the role of YAP1 in adipogenic differentiation.Overexpression of YAP1 significantly promoted the differentiation of ADSCs into adipocytes,an effect accompanied by up-regulation of LATS2 and activation of the negative feedback loop of the Hippo signaling pathway.Elevated LATS2 expression induced YAP phosphorylation,leading to reduced nuclear levels of YAP and TAZ and their subsequent accumulation in the cytoplasm.YAP1 overexpression up-regulated LATS2 expression,which,in turn,enhanced the adipogenic differentiation of ADSCs.This pro-adipogenic effect of YAP1 was dependent on LATS2 kinase activity.These findings indicate that overexpression of YAP1 promotes ADSC adipogenesis by inducing LATS2 expression and activating the Hippo pathway negative feedback loop.Elucidating the molecular role of YAP in ADSC lipogenic differentiation holds great significance for regulating stem cell fate,treating metabolic disorders,and promoting hair follicle growth.展开更多
Somatic cell nuclear transfer(SCNT)has been successfully employed across various mammalian species,yet cloned animals consistently exhibit low pregnancy rates,primarily due to placental abnormalities such as hyperplas...Somatic cell nuclear transfer(SCNT)has been successfully employed across various mammalian species,yet cloned animals consistently exhibit low pregnancy rates,primarily due to placental abnormalities such as hyperplasia and hypertrophy.This study investigated the involvement of the Hippo signaling pathway in aberrant placentaldevelopmentinSCNT-inducedbovine pregnancies.SCNT-derived cattle exhibited placental hypertrophy,including enlarged abdominal circumference and altered placental cotyledon morphology.RNA sequencing analysis indicated significant dysregulation of Hippo signaling pathway genes in SCNT placentas.Coexpression of YAP1 and CCND1 was observed in cloned blastocysts,placental tissues,and bovine placental mesenchymal stem cells(bPMSCs).Manipulation of YAP1expression demonstrated the capacity to regulate bPMSC proliferation.Experimental assays confirmed the direct binding of YAP1 to CCND1,which subsequently promoted CCND1 expression in bPMSCs.Furthermore,inhibition of CDK6,a downstream target of CCND1,attenuated SCNT bPMSC proliferation.This study identified YAP1 as a key regulatory component within the Hippo signaling pathway that drives placental hyperplasia in cloned cattle through up-regulation of CCND1-CDK6 expression,facilitating cell cycle progression.These findings offer potential avenues for enhancing cloning efficiency,with implications for evolutionary biology and the conservation of valuable germplasm resources.展开更多
Objectives:Although Yes-associated protein 1(YAP1)is an important oncogene in hepatocellular carcinoma(HCC)progression,its nuclear localization prevents it from being considered a potential therapeutic target.Recently...Objectives:Although Yes-associated protein 1(YAP1)is an important oncogene in hepatocellular carcinoma(HCC)progression,its nuclear localization prevents it from being considered a potential therapeutic target.Recently,studies have reported that coatomer protein complex subunit beta 2(COPB2)also plays a critical role in HCC development;however its mechanism of action is unclear.This study aimed to investigate the role of COPB2 and YAP1 in the progression of HCC and to elucidate the underlying mechanisms.Methods:COPB2 and YAP1 expression in HCC tissues were first analyzed by database searches and immunohistochemistry.Nomogram and artificial neural network models were established based on COPB2 and YAP1 expression.Cell proliferation was detected by cell counting kit-8 and clone formation assay,while cell migration and invasion were assessed using Transwell assays.Finally,the potential mechanisms underlying COPB2 regulation of YAP1 nuclear translocation were explored by immunofluorescence assay and Western blot.Results:COPB2 combined with YAP1 expression was associated with overall postoperative survival in HCC patients and was an independent prognostic factor.High expression of both COPB2 and YAP1 in patients may reduce the efficacy of postoperative transarterial chemoembolization therapy.In vitro experiments revealed that COPB2 affected the sensitivity of HCC cells to Cisplatin(DDP)by regulating YAP1 nuclear translocation.Conclusions:Our findings suggest that COPB2/YAP1 affects the drug sensitivity of HCC cells to DDP and that targeting COPB2/YAP1 may be a promising strategy for the precision treatment of HCC.展开更多
目的探讨Yes相关蛋白1(Yes-associated protein 1,YAP1)和β-连环蛋白(β-catenin)在大肠癌组织中的表达及其与肠癌患者临床病理因素间的关系。方法应用免疫组织化学Envision二步法检测YAP1和β-catenin在99例人大肠癌组织及30例正常肠...目的探讨Yes相关蛋白1(Yes-associated protein 1,YAP1)和β-连环蛋白(β-catenin)在大肠癌组织中的表达及其与肠癌患者临床病理因素间的关系。方法应用免疫组织化学Envision二步法检测YAP1和β-catenin在99例人大肠癌组织及30例正常肠黏膜组织中的表达状况。结果YAP1蛋白在大肠癌组织中的阳性表达率为56.57%(56/99),显著高于正常肠黏膜组织16.67%(5/30)(χ2=14.704,P<0.01);β-catenin蛋白在大肠癌组织中的异位(细胞质/核)表达率为51.52%(51/99),明显高于正常肠黏膜组织0%(0/30)(χ2=25.559,P<0.01)。YAP1蛋白的表达与患者性别、年龄、肿瘤的分化程度、浸润深度、淋巴结转移及临床Duke's分期均无关;β-catenin蛋白的细胞核表达与大肠癌的分化程度及浸润深度相关(χ2=6.641、4.229,P<0.05);β-catenin蛋白的细胞质表达水平与大肠癌的分化程度相关(χ2=6.761,P<0.05);β-catenin蛋白的细胞膜表达水平与临床病理因素均无关。β-catenin蛋白细胞质、细胞核的表达与YAP1细胞核、细胞质/核的表达呈正相关性(P<0.05);β-catenin蛋白细胞核表达与YAP1细胞质的表达呈正相关性(P<0.05)。结论 YAP1和β-catenin在大肠癌的发生发展中均具有重要作用,β-catenin细胞的核表达可能有助于大肠癌的预后判断。展开更多
Yes相关蛋白1(Yes-associated protein 1,YAP1)是Hippo信号通路(Hippo pathway)中的一个分子.早期研究人员发现,在Hippo信号通路正常的情况下,YAP1处于非激活状态;当Hippo信号通路中的某些分子出现突变时,YAP1处于超激活状态.此时,超激...Yes相关蛋白1(Yes-associated protein 1,YAP1)是Hippo信号通路(Hippo pathway)中的一个分子.早期研究人员发现,在Hippo信号通路正常的情况下,YAP1处于非激活状态;当Hippo信号通路中的某些分子出现突变时,YAP1处于超激活状态.此时,超激活状态下的YAP1可以促进细胞增殖、转移、生存(survival)以及维持干细胞活性.由于YAP1的超激活可以促进肿瘤的发生与发展,因此,YAP1被定义为一个癌蛋白.近期,研究者发现,YAP1的突变体与小细胞肺癌病人的存活率有一定关系,YAP1与链蛋白(catenin)、Kras相互作用,调节肿瘤细胞的转移侵袭能力,此外,部分micro RNA也与YAP1有相互作用.基于YAP1的功能,可以制定一些抗癌策略,寻找一些抗癌靶点.本文对当前YAP1的研究进行综述,为肿瘤治疗的基础及临床研究提供一些依据.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
文摘[目的]研究ASPM对非小细胞肺癌A549细胞发展的影响。[方法]通过免疫组化实验分析ASPM在非小细胞肺癌组织中的表达;将非小细胞肺癌A549细胞随机分为3个实验组:si NC实验组、si ASPM实验组与BPD-MA实验组。通过CCK-8实验检测A549细胞的增殖速度;通过Transwell实验检测A549细胞的侵袭能力;通过流式细胞术检测A549细胞的凋亡率;采用蛋白免疫印迹方法分析A549细胞中YAP1/TAZ通路蛋白的表达。[结果]与癌旁组织比较,ASPM在非小细胞肺癌组织中表达增加(0.28±0.09 vs 0.81±0.06,P<0.05)。与si NC实验组比较,si ASPM以及BPD-MA实验组的A549细胞增殖能力减弱(2.23±0.07 vs 1.16±0.03 vs 1.13±0.05,P<0.05);si ASPM以及BPD-MA实验组的A549细胞侵袭数量减少(126.08±9.33 vs 68.51±7.21 vs 72.82±10.55,P<0.05);si ASPM以及BPD-MA实验组的A549细胞凋亡率增加[(3.22±0.73)%vs(17.01±5.26)%vs(19.23±8.68)%,P<0.05];si ASPM以及BPD-MA实验组的A549细胞YAP1、TAZ蛋白表达下调(0.87±0.03 vs 0.35±0.07 vs 0.33±0.06;0.91±0.12 vs 0.26±0.09 vs 0.31±0.03,P<0.05)。[结论]抑制ASPM表达后,A549细胞的增殖能力与侵袭数量降低,凋亡率增加,该过程与ASPM调节YAP1/TAZ信号通路相关。
基金supported by the Joint Fund for Regional Innovation and Development of the National Natural Science Foundation of China(U23A20226)Science and Technology Planning Project of Inner Mongolia Autonomous Region(2023KYPT0014)。
文摘Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emerged as a pivotal regulator of stem cell fate,yet the specific molecular mechanism by which it modulates lipogenic differentiation of ADSCs has not been clearly defined.In this study,goat ADSCs(gADSCs)isolated from Albas goats in Inner Mongolia were used to investigate the role of YAP1 in adipogenic differentiation.Overexpression of YAP1 significantly promoted the differentiation of ADSCs into adipocytes,an effect accompanied by up-regulation of LATS2 and activation of the negative feedback loop of the Hippo signaling pathway.Elevated LATS2 expression induced YAP phosphorylation,leading to reduced nuclear levels of YAP and TAZ and their subsequent accumulation in the cytoplasm.YAP1 overexpression up-regulated LATS2 expression,which,in turn,enhanced the adipogenic differentiation of ADSCs.This pro-adipogenic effect of YAP1 was dependent on LATS2 kinase activity.These findings indicate that overexpression of YAP1 promotes ADSC adipogenesis by inducing LATS2 expression and activating the Hippo pathway negative feedback loop.Elucidating the molecular role of YAP in ADSC lipogenic differentiation holds great significance for regulating stem cell fate,treating metabolic disorders,and promoting hair follicle growth.
基金supported by the National Natural Science Foundation of China (32060755)Natural Science Foundation of Inner Mongolia (2024MS03001)+7 种基金Inner Mongolia Autonomous Region Open Competition Projects (2022JBGS0018)Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NJYT23090)Inner Mongolia Autonomous Region Science and Technology Leading Team (2022LJRC0006)Inner Mongolia Autonomous Region Science and Technology Major Project (2021ZD0009)Major Agricultural Science and Technology Project of the Ministry of Agriculture and Rural Affairs (NK2022130203)Central Government Guides Local Science and Technology Development Funds (2022ZY0212)Inner Mongolia Autonomous Region High-level Talent Support ProgramInner Mongolia University Chief Scientist Program。
文摘Somatic cell nuclear transfer(SCNT)has been successfully employed across various mammalian species,yet cloned animals consistently exhibit low pregnancy rates,primarily due to placental abnormalities such as hyperplasia and hypertrophy.This study investigated the involvement of the Hippo signaling pathway in aberrant placentaldevelopmentinSCNT-inducedbovine pregnancies.SCNT-derived cattle exhibited placental hypertrophy,including enlarged abdominal circumference and altered placental cotyledon morphology.RNA sequencing analysis indicated significant dysregulation of Hippo signaling pathway genes in SCNT placentas.Coexpression of YAP1 and CCND1 was observed in cloned blastocysts,placental tissues,and bovine placental mesenchymal stem cells(bPMSCs).Manipulation of YAP1expression demonstrated the capacity to regulate bPMSC proliferation.Experimental assays confirmed the direct binding of YAP1 to CCND1,which subsequently promoted CCND1 expression in bPMSCs.Furthermore,inhibition of CDK6,a downstream target of CCND1,attenuated SCNT bPMSC proliferation.This study identified YAP1 as a key regulatory component within the Hippo signaling pathway that drives placental hyperplasia in cloned cattle through up-regulation of CCND1-CDK6 expression,facilitating cell cycle progression.These findings offer potential avenues for enhancing cloning efficiency,with implications for evolutionary biology and the conservation of valuable germplasm resources.
文摘Objectives:Although Yes-associated protein 1(YAP1)is an important oncogene in hepatocellular carcinoma(HCC)progression,its nuclear localization prevents it from being considered a potential therapeutic target.Recently,studies have reported that coatomer protein complex subunit beta 2(COPB2)also plays a critical role in HCC development;however its mechanism of action is unclear.This study aimed to investigate the role of COPB2 and YAP1 in the progression of HCC and to elucidate the underlying mechanisms.Methods:COPB2 and YAP1 expression in HCC tissues were first analyzed by database searches and immunohistochemistry.Nomogram and artificial neural network models were established based on COPB2 and YAP1 expression.Cell proliferation was detected by cell counting kit-8 and clone formation assay,while cell migration and invasion were assessed using Transwell assays.Finally,the potential mechanisms underlying COPB2 regulation of YAP1 nuclear translocation were explored by immunofluorescence assay and Western blot.Results:COPB2 combined with YAP1 expression was associated with overall postoperative survival in HCC patients and was an independent prognostic factor.High expression of both COPB2 and YAP1 in patients may reduce the efficacy of postoperative transarterial chemoembolization therapy.In vitro experiments revealed that COPB2 affected the sensitivity of HCC cells to Cisplatin(DDP)by regulating YAP1 nuclear translocation.Conclusions:Our findings suggest that COPB2/YAP1 affects the drug sensitivity of HCC cells to DDP and that targeting COPB2/YAP1 may be a promising strategy for the precision treatment of HCC.
文摘目的探讨Yes相关蛋白1(Yes-associated protein 1,YAP1)和β-连环蛋白(β-catenin)在大肠癌组织中的表达及其与肠癌患者临床病理因素间的关系。方法应用免疫组织化学Envision二步法检测YAP1和β-catenin在99例人大肠癌组织及30例正常肠黏膜组织中的表达状况。结果YAP1蛋白在大肠癌组织中的阳性表达率为56.57%(56/99),显著高于正常肠黏膜组织16.67%(5/30)(χ2=14.704,P<0.01);β-catenin蛋白在大肠癌组织中的异位(细胞质/核)表达率为51.52%(51/99),明显高于正常肠黏膜组织0%(0/30)(χ2=25.559,P<0.01)。YAP1蛋白的表达与患者性别、年龄、肿瘤的分化程度、浸润深度、淋巴结转移及临床Duke's分期均无关;β-catenin蛋白的细胞核表达与大肠癌的分化程度及浸润深度相关(χ2=6.641、4.229,P<0.05);β-catenin蛋白的细胞质表达水平与大肠癌的分化程度相关(χ2=6.761,P<0.05);β-catenin蛋白的细胞膜表达水平与临床病理因素均无关。β-catenin蛋白细胞质、细胞核的表达与YAP1细胞核、细胞质/核的表达呈正相关性(P<0.05);β-catenin蛋白细胞核表达与YAP1细胞质的表达呈正相关性(P<0.05)。结论 YAP1和β-catenin在大肠癌的发生发展中均具有重要作用,β-catenin细胞的核表达可能有助于大肠癌的预后判断。
文摘Yes相关蛋白1(Yes-associated protein 1,YAP1)是Hippo信号通路(Hippo pathway)中的一个分子.早期研究人员发现,在Hippo信号通路正常的情况下,YAP1处于非激活状态;当Hippo信号通路中的某些分子出现突变时,YAP1处于超激活状态.此时,超激活状态下的YAP1可以促进细胞增殖、转移、生存(survival)以及维持干细胞活性.由于YAP1的超激活可以促进肿瘤的发生与发展,因此,YAP1被定义为一个癌蛋白.近期,研究者发现,YAP1的突变体与小细胞肺癌病人的存活率有一定关系,YAP1与链蛋白(catenin)、Kras相互作用,调节肿瘤细胞的转移侵袭能力,此外,部分micro RNA也与YAP1有相互作用.基于YAP1的功能,可以制定一些抗癌策略,寻找一些抗癌靶点.本文对当前YAP1的研究进行综述,为肿瘤治疗的基础及临床研究提供一些依据.
