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
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
Objective:Yes associated protein 1(YAP1)is a member of the Hippo pathway,acting as a transcriptional coactivator.To elucidate the role of YAP1 and phosphorylated(p)YAP1 in prostate cancer(PCa)tumorigenesis,we investig...Objective:Yes associated protein 1(YAP1)is a member of the Hippo pathway,acting as a transcriptional coactivator.To elucidate the role of YAP1 and phosphorylated(p)YAP1 in prostate cancer(PCa)tumorigenesis,we investigated their expression in clinical samples of PCa and cell lines.Methods:Fifty-four tumor,adjacent nontumor,and prostate intraepithelial neoplasia(PIN)tissues from patients with PCa after radical prostatectomy were selected from a retrospective cohort and studied using immunohistochemistry(IHC).Protein and m RNA expression levels of YAP1 were evaluated by Western blot analysis and quantitative real-time reverse transcription PCR,respectively,in cancer cell lines.Publicly available gene expression datasets were downloaded to analyze YAP1 m RNA and protein levels in PCa tissue samples.Results:IHC analysis of PCa tissues revealed that YAP1 staining intensities were moderate to weak in the nucleus and cytoplasm of tumor cells,whereas adjacent normal epithelia showed strong staining.We observed that benign prostates were characterized by higher expression levels of both nuclear(P=0.004)and cytosolic(P=0.005)YAP1.p YAP1 staining was weak in the cytoplasm and absent in the nucleus of all the tissues investigated.YAP1 expression was an indicator of extraprostatic extension(EPE).The level of YAP1 was negatively correlated with the level of the androgen receptor(AR)in The Cancer Genome Atlas dataset and Western blot analysis of cell lines.Conclusions:Our study suggested that YAP1 expression is heterogeneous in PCa tissue samples;therefore,YAP1 might play different roles in different aspects of PCa progression.This might involve AR–YAP1 interplay in PCa.展开更多
Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes （T2D...Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes （T2D）. Despite the physiological importance of β-cells, the viability of β-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect β-cell viability is high concentration of free fatty acids （FFAs） such as palmitate. In this work, we demonstrated that Yes-associated protein （Yap1） is activated when β-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in β-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor （CTGF）. Our gain-offunction analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.展开更多
As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and pl...As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.展开更多
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.
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。
基金financially supported by the The Scientific and Technological Research Council of Turkey(TUBITAK,Grant No.114S419)Istanbul Medeniyet University Scientific Research Grants(Grant No.FBA-2014-293)
文摘Objective:Yes associated protein 1(YAP1)is a member of the Hippo pathway,acting as a transcriptional coactivator.To elucidate the role of YAP1 and phosphorylated(p)YAP1 in prostate cancer(PCa)tumorigenesis,we investigated their expression in clinical samples of PCa and cell lines.Methods:Fifty-four tumor,adjacent nontumor,and prostate intraepithelial neoplasia(PIN)tissues from patients with PCa after radical prostatectomy were selected from a retrospective cohort and studied using immunohistochemistry(IHC).Protein and m RNA expression levels of YAP1 were evaluated by Western blot analysis and quantitative real-time reverse transcription PCR,respectively,in cancer cell lines.Publicly available gene expression datasets were downloaded to analyze YAP1 m RNA and protein levels in PCa tissue samples.Results:IHC analysis of PCa tissues revealed that YAP1 staining intensities were moderate to weak in the nucleus and cytoplasm of tumor cells,whereas adjacent normal epithelia showed strong staining.We observed that benign prostates were characterized by higher expression levels of both nuclear(P=0.004)and cytosolic(P=0.005)YAP1.p YAP1 staining was weak in the cytoplasm and absent in the nucleus of all the tissues investigated.YAP1 expression was an indicator of extraprostatic extension(EPE).The level of YAP1 was negatively correlated with the level of the androgen receptor(AR)in The Cancer Genome Atlas dataset and Western blot analysis of cell lines.Conclusions:Our study suggested that YAP1 expression is heterogeneous in PCa tissue samples;therefore,YAP1 might play different roles in different aspects of PCa progression.This might involve AR–YAP1 interplay in PCa.
文摘Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes （T2D）. Despite the physiological importance of β-cells, the viability of β-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect β-cell viability is high concentration of free fatty acids （FFAs） such as palmitate. In this work, we demonstrated that Yes-associated protein （Yap1） is activated when β-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in β-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor （CTGF）. Our gain-offunction analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.
基金supported by grants from the National Natural Science Foundation of China (81872860, 81803521, 81673433)National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104, China)+5 种基金Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093, China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province, 2017B090903004,China)Natural Science Foundation of Guangdong Province(2019A1515010273, China)Foundation from Guangdong Traditional Medicine Bureau (20191060, China)Fundamental Research Funds for the Central Universities (19ykpy131, China)Research and Industrialization team of Taxus chinensis var.mairel (2014YT02S044, China)。
文摘As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.
