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yes-associated protein promotes endothelial-tomesenchymal transition of endothelial cells in choroidal neovascularization fibrosis

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International Journal of Ophthalmology(English edition) 2022年第5期15卷 701-710页

作者： Rong Zou Yi-Fan Feng Ya-Hui Xu Min-Qian Shen Xi Zhang Yuan-Zhi Yuan Department of Ophthalmology Zhongshan HospitalFudan UniversityShanghaiChina Department of Ophthalmology Xiamen BranchZhongshan HospitalFudan UniversityXiamenFujian ProvinceChina

AIM:To reveal whether and how yes-associated protein(YAP)promotes the occurrence of subretinal fibrosis in agerelated macular degeneration(AMD).METHODS:Cobalt chloride(Co Cl2)was used in primary human umbilical vein endothelial cells(HUVECs)to induce hypoxia in ***-week-old male C57 BL/6 J mice weighing 19-25 g were used for a choroidal neovascularization(CNV)model induced by laser photocoagulation in *** levels of YAP,phosphorylated YAP,mesenchymal markers[αsmooth muscle actin(α-SMA),vimentin,and Snail],and endothelial cell markers(CD31 and zonula occludens 1)were measured by Western blotting,quantitative real-time PCR,and immunofluorescence *** molecules YC-1(Lificiguat,a specific inhibitor of hypoxia-inducible factor 1α),CA3(CIL56,an inhibitor of YAP),and XMU-MP-1(an inhibitor of Hippo kinase MST1/2,which activates YAP)were used to explore the underlying ***:Co Cl2 increased expression of mesenchymal markers,decreased expression of endothelial cell markers,and enhanced the ability of primary HUVECs to proliferate and ***-1 suppressed hypoxia-induced endothelialto-mesenchymal transition(End MT).Moreover,hypoxia promoted total expression,inhibited phosphorylation,and enhanced the transcriptional activity of ***-MP-1 enhanced hypoxia-induced End MT,whereas CA3 elicited the opposite *** of YAP,α-SMA,and vimentin were upregulated in the laser-induced CNV ***,silencing of YAP by vitreous injection of small interfering RNA targeting YAP could reverse these ***:The findings reveal a critical role of the hypoxia-inducible factor-1α(HIF-1α)/YAP signaling axis in End MT and provide a new therapeutic target for treatment of subretinal fibrosis in AMD.

关键词： endothelial-to-mesenchymal transition yes-associated protein hypoxia-inducible factor-1α choroidal neovascularization age-related macular degeneration

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yes-associated protein contributes to magnesium alloy-derivedinflammation in endothelial cells

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Regenerative Biomaterials 2022年第1期9卷 130-142页

作者： Hongchi Yu Zhe Hou Nuoya Chen Rifang Luo Li Yang Michael Miao Xiaoyi Ma Lifeng Zhou Fugui He Yang Shen Xiaoheng Liu Yunbing Wang National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610065China Institute of Biomedical Engineering West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China Division of Oral&Craniofacial Health Sciences University of North Carolina Adams School of DentistryChapel HillNC 27599USA Beijing Key Laboratory of Cardiac Drug Device Technology and Evidence Based Medicine Beijing 100021China

Magnesium alloy(Mg alloy)has attracted massive attention in the potential applications of cardiovascular stents because of its good biocompatibility and ***,whether and how the Mg alloy induces inflammation in endothelial cells remains *** the present work,we investigated the activation of yes-associated protein(YAP)upon Mg alloy stimuli and unveiled the transcriptional function in Mg alloy-induced *** RT–PCR,western blotting and immunofluorescence staining showed that Mg alloy inhibited the Hippo pathway to facilitate nuclear shuttling and activation of YAP in human coronary artery endothelial cells(HCAECs).Chromatin immunoprecipitation followed sequencing was carried out to explore the transcriptional function of YAP in Mg alloy-derived *** led to the observation that nuclear YAP further bonded to the promoter region of inflammation transcription factors and co-transcription *** binding event activated their transcription and modified mRNA methylation of inflammation-related genes through regulating the expression of N6-methyladenosine modulators(METTL3,METTL14,FTO and WTAP).This then promoted inflammation-related gene expression and aggravated inflammation in *** YAP deficiency cells,Mg alloy-induced inflammation was ***,our data suggest that YAP contributes to the Mg alloy-derived inflammation in HCAECs and may provide a potential therapeutic target that alleviates inflammation after Mg alloy stent implantation.

关键词： magnesium alloy yes-associated protein inflammation

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yes-associated protein-mediated melatonin regulates the function of periodontal ligament stem cells under oxidative stress conditions

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World Journal of Stem Cells 2024年第11期16卷 926-943页

作者： Ke Gu Xiao-Mei Feng Shao-Qing Sun Xing-Yao Hao Yong Wen Department of Implantology School and Hospital of StomatologyCheeloo College of MedicineShandong University&Shandong Key Laboratory of Oral Tissue Regeneration&Shandong Engineering Research Center of Dental Materials and Oral Tissueegeneration&Shandong Provincial Clinical Research Center for Oral DiseasesNo.44-1 Wenhua Road WestJinan 250012Shandong ProvinceChina Stomatological Hospital School of MedicineNankai UniversityTianjin Key Laboratory of Oral and Maxillofacial Function ReconstructionTianjin 300041China

BACKGROUND Human periodontal ligament stem cells(PDLSCs)regenerate oral *** vitro expansion causes replicative senescence in stem *** causes intracellular reactive oxygen species(ROS)accumulation,which can impair stem cell *** engineering efficiency is reduced by exogenous ROS stimulation,which causes premature senescence under oxidative ***(MT),a powerful free radical scavenger,can delay PDLSCs senescence but may not maintain stemness under oxidative *** experiment examined the effects of hydrogen peroxide-induced oxidative stress on PDLSCs’apoptosis,senescence,and *** To determine if MT can reverse the above effects along with the underlying molecular mechanisms *** PDLSCs were isolated from human premolars and cultured in different *** cytometry was used to characterize the cell surface markers of BACKGROUND Human periodontal ligament stem cells(PDLSCs)regenerate oral *** vitro expansion causes replicative senescence in stem *** causes intracellular reactive oxygen species(ROS)accumulation,which can impair stem cell *** engineering efficiency is reduced by exogenous ROS stimulation,which causes premature senescence under oxidative ***(MT),a powerful free radical scavenger,can delay PDLSCs senescence but may not maintain stemness under oxidative *** experiment examined the effects of hydrogen peroxide-induced oxidative stress on PDLSCs’apoptosis,senescence,and *** To determine if MT can reverse the above effects along with the underlying molecular mechanisms *** PDLSCs were isolated from human premolars and cultured in different *** cytometry was used to characterize the cell surface markers of differentiation,ROS,and senescence-associatedβ-galactosidase activity were assessed by various *** transcription-polymerase chain reaction and western blot were used to measure the expression of genes and

关键词： Human periodontal ligament stem cells Melatonin Reactive oxygen species Senescence yes-associated protein

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Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation

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Acta Pharmaceutica Sinica B 2021年第3期11卷 727-737页

作者： Yue Gao Shicheng Fan Hua Li Yiming Jiang Xinpeng Yao Shuguang Zhu Xiao Yang Ruimin Wang Jianing Tian Frank JGonzalez Min Huang Huichang Bi Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Hepatic Surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNIHBethesdaMD 20892USA

The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor *** was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver ***-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx *** enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

关键词： Constitutive androstane receptor Nuclear receptors Hepatomegaly Liver enlargement Liver regeneration yes-associated protein proteineprotein interaction Partial hepatectomy

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Significance and relationship between yes-associated protein and survivin expression in gastric carcinoma and precancerous lesions

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World Journal of Gastroenterology 2009年第32期15卷 4055-4061页

作者： Chun-Li Da Yan Xin Jing Zhao Xiang-Dong Luo The Fourth Laboratory of Cancer Institute Department of Tumor Pathology of General Surgery Institute the First Hospital of China Medical University Shenyang 11000 1 Liaoning Province China

AIM:To analyze the differences and relevance of yes-associated protein (YAP) and survivin, and to explore the correlation and signifi cance of their expression in gastric carcinoma and precancerous ***: The PV9000 immunohistochemical method was used to detect the expression of YAP and survivin in 98 cases of normal gastric mucosa, 58 intestinal metaplasia (IM), 32 dysplasia and 98 gastric ***: The positive rates of YAP in dysplasia (37.5%) and gastric carcinoma (48.0%) were significantly higher than that in normal gastric mucosa (13.3%), P<0.01. The positive rates of survivin in IM (53.4%), dysplasia (59.4%) and gastric carcinoma (65.3%) were significantly higher than in normal gastric mucosa (11.2%), P<0.01. Survivin expression gradually increased from 41.7% in well differentiated adenocarcinoma through 58.3% in moderately differentiated adenocarcinoma to 75.6% in poorly differentiated adenocarcinoma, with significant Rank correlation, rk=0.279, P<0.01. The positive rate of survivin in gastric carcinoma of diffused type (74.6%) was significantly higher than that in intestinal type (51.3%), P<0.05. In gastric carcinoma with lymph node metastasis (76.9%), the positive rate of survivin was signifi cantly higher than that in the group without lymph node metastasis (41.2%), P<0.01. In 98 cases of gastric carcinoma, the expression of YAP and of survivin were positively correlated, rk=0.246, P<***: YAP may play an important role as a carcinogenic factor and may induce survivin expression. Detecting both markers together may help in early diagnosis of gastric carcinoma.

关键词： Apoptosis Cell proliferation Gastric cancer Immunohistochemistry Neoplastic processes Survivinprotein yes-associated protein

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Chinese Medical Journal 2021年第17期134卷 2054-2065页

作者： Bin Chen Bin Liu Tao Yu Yun-Feng Han Chao Wu Zhen-Yu Wang Department of Neurosurgery Peking University Third HospitalBeijing 100191China

Background:The Nuclear Dbf2-related(NDR1)kinase is a member of the NDR/LATS family,which was a supplementary of Hippo ***,whether NDR1 could inhibit glioblastoma(GBM)growth by phosphorylating yes-associated protein(YAP)remains ***,the role of NDR1 in GBM was not *** study aimed to investigate the role of NDR1-YAP pathway in ***:Bioinformation analysis and immunohistochemistry(IHC)were performed to identify the expression of NDR1 in *** effect of NDR1 on cell proliferation and cell cycle was analyzed utilizing CCK-8,clone formation,immunofluorescence and flow cytometry,*** addition,the xenograft tumor model was established as *** interaction was examined by Coimmunoprecipitation and immunofluorescence to observe ***:Bioinformation analysis and IHC of our patients’tumor tissues showed that expression of NDR1 in tumor tissue was relatively lower than that in normal tissues and was positively related to a lower survival ***1 could markedly reduce the proliferation and colony formation of U87 and ***,the results of flow cytometry showed that NDR1 led to cell cycle arrest at the G1 *** growth was also inhibited in xenograft nude mouse models in NDR1-overexpression *** blotting and immunofluorescence showed that NDR1 could integrate with and phosphorylate YAP at S127 ***,NDR1 could mediate apoptosis ***:In summary,our findings point out that NDR1 functions as a tumor suppressor in ***1 is identified as a novel regulator of YAP,which gives us an in-depth comprehension of the Hippo signaling pathway.

关键词： Glioblastoma Hippo signaling pathway Nuclear Dbf2-related yes-associated protein

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Survivin和yes-associated protein在宫颈癌组织中的表达及临床意义

Survivin和Yes-associated protein在宫颈癌组织中的表达及临床意...

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作者：谢颖芳大连医科大学

学位级别：硕士

目的: 检测正常宫颈、宫颈上皮内瘤样病变及宫颈癌组织中Survivin和yes-associated protein的表达水平,分析二者表达的差异性和相关性,探讨Survivin和yes-associated protein的表达与宫颈癌发生、发展的关系和临床意义。方法: ... 详细信息

目的: 检测正常宫颈、宫颈上皮内瘤样病变及宫颈癌组织中Survivin和yes-associated protein的表达水平,分析二者表达的差异性和相关性,探讨Survivin和yes-associated protein的表达与宫颈癌发生、发展的关系和临床意义。方法: 临床病理资料收集:收集大连医科大学附属第一医院妇产科手术切除宫颈上皮内瘤样病变及宫颈癌标本83例。其中宫颈上皮内瘤样病变（Cervical intraepithelial neoplasia,CIN）21例,浸润癌62例。浸润癌按FIGO分期:Ia期10例、Ib期31例、IIa期17例、IIb期4例;按WHO组织病理学分类:鳞癌49例,腺癌13例。同时选取子宫肌瘤患者子宫全切的正常宫颈组织15例作为对照。免疫组化染色与结果判定:采用免疫组织化学PV-6000-G二步法染色。Survivin阳性表达定位于细胞浆,偶见于细胞核,以细胞浆或胞核出现淡黄色、棕黄色或棕褐色颗粒为阳性信号;YAP阳性表达以在胞核或细胞浆出现淡黄色、棕黄色或棕褐色免疫反应颗粒为阳性信号。每例均随机观察5个高倍视野（×400）,用半定量积分法判断结果。染色阳性细胞所占比例按以下标准计分:阳性细胞≤5%为0分,6%～25%为1分,26%～50%为2分,51%～75%为3分,＞75%为4分;染色强度计分以细胞显色反应程度计分:无着色0分,淡黄色为1分,棕黄色为2分,棕褐色为3分;最后将阳性细胞所占的百分比分值和染色强度分值相乘为结果:0分为阴性（-）,1～4分为弱阳性（+）,5～8分为中度阳性（++）,9～l2分为强阳性（+++）。结果: 本研究实验结果表明Survivin在CIN和宫颈浸润癌中的阳性表达率显著高于正常宫颈组织,P＜0.01;在CIN和宫颈浸润癌之间Survivin的阳性表达率也有显著差异,P＜0.05,而且随着宫颈浸润癌临床分期的增高和组织分化程度的降低,Survivin的阳性表达率也增高,P＜0.05。宫颈腺癌中Survivin的阳性表达率显著高于鳞癌,P＜0.05。Survivin的阳性表达与患者的年龄无关,P＞0.05。 YAP在CIN和宫颈浸润癌中的阳性表达率显著高于正常宫颈组织,P＜0.05;但在CIN和宫颈浸润癌之间YAP的阳性表达率无显著差异,P＞0.05,随着宫颈癌临床分期的增高,YAP的阳性表达率也增高,但差别无统计学意义,P＞0.05。YAP的阳性表达与患者的年龄、组织类型以及分化程度无关,P＞0.05。 Survivin和YAP在宫颈癌组织中的表达呈正相关,r=0.323,P＜0.05。结论: Survivin的表达在CIN和宫颈浸润癌中显著高于正常宫颈组织,与宫颈癌的临床分期、组织类型和分化程度有关,与患者的年龄无关。提示Survivin在宫颈癌的发生、发展和组织侵袭中起了重要作用。 YAP在CIN和宫颈浸润癌中的阳性表达率显著高于正常宫颈组织,但与患者的年龄、临床分期、组织类型以及分化程度无关。推测YAP表达增高可能是宫颈上皮发生癌变的早期因素,应用免疫组化技术检测YAP蛋白在宫颈上皮的表达,有可能成为临床早期评价宫颈癌形成的重要分子生物学指标。 Survivin和YAP在宫颈癌组织中表达成正相关,YAP可能诱导凋亡抑制因子Survivin等的高表达,Survivin通过抑制宫颈癌中细胞凋亡、调节细胞有丝分裂和促进肿瘤血管形成等机制参与宫颈癌的发生、发展及转移。进一步研究Survivin和YAP之间关系与宫颈癌的形成机制,对指导宫颈癌的诊断、治疗和判断预后可提供更有效的理论依据。

关键词：宫颈癌 Survivin yes-associated protein 免疫组化

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YAP regulates the liver size during the fasting-refeeding transition in mice

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1588-1599页

作者： Xuan Li Shicheng Fan Chenghui Cai Yue Gao Xinhui Wang Yifei Zhang Hangfei Liang Huilin Li Jie Yang Min Huang Huichang Bi Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518000China

Liver is the central hub regulating energy metabolism during feeding-fasting *** suggests that fasting and refeeding induce dynamic changes in liver size,but the underlying mechanisms remain ***-associated protein(YAP)is a key regulator of organ *** study aims to explore the role of YAP in fasting-and refeeding-induced changes in liver ***,fasting significantly reduced liver size,which was recovered to the normal level after ***,hepatocyte size was decreased and hepatocyte proliferation was inhibited after ***,refeeding promoted hepatocyte enlargement and proliferation compared to fasted ***,fasting or refeeding regulated the expression of YAP and its downstream targets,as well as the proliferation-related protein cyclin D1(CCND1).Furthermore,fasting significantly reduced the liver size in AAV-control mice,which was mitigated in AAV Yap(5SA)*** overexpression also prevented the effect of fasting on hepatocyte size and ***,the recovery of liver size after refeeding was delayed in AAV Yap shRNA *** knockdown attenuated refeeding-induced hepatocyte enlargement and *** summary,this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition,which provides new evidence for YAP in regulating liver size under energy stress.

关键词： Liver Fasting Refeeding yes-associated protein Hepatocyte size Hepatocyte proliferation β-Catenin Cyclin D1

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GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1222-1240页

作者： Paipai Guo Ji Jiang Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu Wei Wei Shihao Zhang Qingtong Wang Institute of Clinical Pharmacology Anhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune MedicineMinistry of EducationCollaborative Innovation Center of Anti-inflammatory and Immune MedicinesHefei 230032China School of Pharmacy Bengbu Medical CollegeBengbu 233030China The Third Affiliated Hospital of Anhui Medical University(the First People’s Hospital of Hefei) Hefei 230061China

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint *** yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream *** Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA ***,SAV1 protein expression is extremely ***,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in *** process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs *** depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and ***,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical ***,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

关键词： Rheumatoid arthritis Fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 yes-associated protein

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Hippo-YAP/TAZ signaling in breast cancer:Reciprocal regulation of microRNAs and implications in precision medicine

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Genes & Diseases 2024年第2期11卷 760-771页

作者： Farzad Sadri Seyede fatemeh Hosseini Zohreh Rezaei Mohammad Fereidouni Student Research Committee Birjand University of Medical SciencesBirjand ***Iran Tabas School of Nursing Birjand University of Medical SciencesBirjand ***Iran Department of Biology University of Sistan and BaluchestanZahedan ***Iran Cellular and Molecular Research Center Birjand University of Medical SciencesBirjand ***Iran

Breast cancer is a molecularly heterogeneous disease and the most common female *** recent years,therapy approaches have evolved to accommodate molecular diversity,with a focus on more biologically based therapies to minimize negative *** regulate cell fate in human breast cells,the Hippo signaling pathway has been associated with the alpha subtype of estrogen *** pathway regulates tissue size,regeneration,and healing,as well as the survival of tissue-specific stem cells,proliferation,and apoptosis in a variety of organs,allowing for cell *** signaling is mediated by the kinases MST1,MST2,LATS1,and LATS2,as well as the adaptor proteins SAV1 and *** kinases phosphorylate the downstream effectors of the Hippo pathway,yes-associated protein(YAP),and transcriptional coactivator with PDZ-binding motif(TAZ),suppressing the expression of their downstream target *** Hippo signaling pathway kinase cascade plays a significant role in all *** the principles of this kinase cascade would prevent the occurrence of breast *** recent years,small noncoding RNAs,or microRNAs,have been implicated in the development of several malignancies,including breast *** interconnections between miRNAs and Hippo signaling pathway core proteins in the breast,on the other hand,remain poorly *** this review,we focused on highlighting the Hippo signaling system,its key parts,its importance in breast cancer,and its regulation by miRNAs and other related pathways.

关键词： Breast cancer Hippo signaling Large tumor suppressor kinase 1 microRNAs PDZ-binding motif yes-associated protein

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