Hippo signaling pathway in liver tissue homeostasis

肝脏是人体最重要的器官之一,乙肝等病毒性与酒精等非病毒性因素诱发的肝损伤引起肝脏功能衰竭、再生重塑障碍、肝癌等疾病是我国重大社会健康问题,因此,; 研究肝脏稳态的调控机制对肝病的预防和临床治疗至关重要。Hippo信号通路参与了哺乳动物多种细胞和器官的稳态调控。最近研究表明,Hippo信号通路; 在肝脏发育、肝细胞命运决定、肝脏再生和癌症发生发展等过程中都发挥了非常重要的作用。因此,Hippo信号通路可成为肝脏相关疾病的治疗提供了新的靶点; 。本文综述了Hippo信号通路与肝脏稳态调控的相关研究及最新进展,以期为研究肝脏发育和肝脏相关疾病的治疗提供新的思路和策略。Liver cancer and diseases have become the leading cause of deaths in; China. Liver diseases including liver failure and liver cancer can be; genetic or caused by a variety of factors that damage the liver, such as; viruses and alcohol overdose. However, the underlying mechanisms that; maintain liver homeostasis remain unclear. Recent studies show that the; Hippo signaling pathway plays a critical role in maintaining liver; tissue homeostasis. Dysregulation of the Hippo signaling pathway impairs; liver regeneration and remarkly enhances liver overgrowth and; tumorigenesis. In this review, we summarize recent progresses on the; roles and regulation mechanisms of the Hippo signaling pathway in liver; development and diseases.国家自然科学基金项

Mammalian STE20-like kinase 2, not kinase 1, mediates photoreceptor cell death during retinal detachment

Photoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1−/− and MST2−/− mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2−/− mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2−/− mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2−/− mice post-RD. Retinas of MST2−/− mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2−/− mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target

Hippo信号通路:器官大小与组织稳态调控器

复杂机体如何控制器官大小是发育生物学最基本问题之一,其调控机制的解析也是生命科学领域长期存在的一大难题。Hippo信号通路是21世纪初利用果蝇遗; 传学研究发现并命名的,它可以通过调控细胞增殖、凋亡和干细胞的自我更新与分化,在器官大小决定、组织稳态维持与重塑等生命活动过程中发挥关键作用。由于; Hippo信号通路在物种间高度保守,它的发现为人们研究生物个体器官发育大小及再生的调控机制提供了可能,这是利用果蝇遗传学研究解决重大科学问题的又; 一个经典范例。在过去的十几年中,针对Hippo信号通路的研究逐渐成为国际上又一新兴的研究热点

The transcriptional coactivator TAZ regulates reciprocal differentiation of T(h)17 cells and T(reg) cells

自身免疫性疾病是一类机体对自身抗原发生免疫反应而导致自身多器官、组织受累的慢性炎症性疾病。目前大量研究表明机体内促炎症的TH17细胞和抑制炎症Treg细胞在类群数量和活化状态的失衡是造成自身免疫疾病的主要致病因素。陈兰芬教授和周大旺教授团队的前期研究发现小鼠中Hippo信号通路中激酶Mst1/2缺失导致免疫缺陷，机体易受病原体感染并伴随着严重自身免疫疾病。该研究揭示了Hippo 信号通路转录共激活因子TAZ在决定CD4+初始T细胞分化为促进炎症的TH17效应细胞和抑制免疫反应的Treg调节性细胞过程中发挥着关键作用，拓展了当前对于Hippo信号通路的相关研究内容。 陈兰芬，博士，厦门大学生命科学学院教授。【Abstraact】An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under T H17 cell–inducing conditions and was required for TH17 differentiation and TH17 cell–mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under T regcell–skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.J. Avruch for comments on the manuscript.Supported by the National Basic Research Program (973) of China (2015CB910502 to L.C.), the National Natural Science Foundation of China (81422018 to L.C.; 31625010 and U1505224 to D.Z.; U1405225 and 81372617 to L.C.; J1310027 to D.Z.; 81472229 to L.H.; and 31600698 to J. Geng), the 111 Projects (B12001 and B06016), China's 1000 Young Talents Program (D.Z., and L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720160071 to D.Z. and 20720160054 to L.H.) and Major disease research projects of Xiamen (3502Z20149029 to L.C.)

生物化学实验课教学改革及本科生基本科研素质培养

生物化学实验课是生物学及相关专业的一门学科类通修课程,其教学目的是让学生学习和掌握生物化学实验基本操作技能的同时,注重学生基本科研素质培养。我们根据这个理念将生物化学实验课内容设计成三个模块:基本生物化学实验技术训练模块,综合实验训练模块,以及自主设计实验模块,并在课程开展中注重学生基本科研素质的培养,达到了实验教学培养学生科研实践能力和综合素质的目的

控制肝脏组织发育、再生重塑与大小的关键蛋白质机器

肝脏损伤、功能衰竭及肝癌等疾病是我国重大健康问题,它们的发生发展与肝脏再生重塑及大小调控异常密切相关。针对肝脏发育、再生及大小控制机理的基础研究对于解决上述重大肝脏疾病的临床需求具有重要意义。前期研究发现Hippo信号通路在调控细胞增殖及分化、干细胞命运等方面起着关键作用,而Hippo通路的失调可导致肝脏等器官发育和大小异常,严重影响受损组织再生与重塑,或导致肿瘤迅速发生。本项目拟以肝脏为研究对象,聚焦Hippo相关信号网络如何感知器官大小并适时调控细胞生长、分化与死亡以实现器官发育、再生重塑和器官大小控制这一关键科学问题,整合基础、临床、药学领域的先进研究技术,拟通过基因编辑、内胚层干细胞肝向分化、肝细胞移植和肝脏重建、肝脏损伤修复等模型、临床病理分析、蛋白结构解析和靶向药物设计等方法,深入探讨该通路失控导致肝脏发育异常、再生重塑障碍、癌症发生的致病机理,并提出靶向干预新策略。控制肝脏组织发育、再生重塑与大小的关键蛋白质机器(2017YFA0504500

国家级实验教学示范中心综合育人功能

厦门大学生命科学国家级实验教学示范中心秉承\"以学生为本,知识、能力和素质全面协调发展\"的育人理念,强化实验教学综合育人职能,在创新实验室管理模式和运行机制、促进优质教学资源整合与共享、优化实验实践教学体系、改革教学方法以及人才培养模式等方面进行了有益的探索与实践。厦门大学本科教学改革研究项目(JG20170233);;教育部基础学科拔尖学生培养试验计划研究课题(20170402

免疫细胞代谢及其功能调节研究进展

免疫系统是维持机体正常生长发育和生存的重要组分之一,而物质和能量代谢在种类多样的免疫细胞维持自身和机体稳态过程中是不可或缺的。不同代谢物对免疫细胞会产生不同的生物学效应,同时代谢组失衡也与免疫细胞功能紊乱互为因果,从代谢组学视角深入研究免疫细胞失调的内在机制已经成为近些年免疫学研究的新热点。该文将从不同代谢物对免疫细胞的增殖、分化或功能影响的角度进行阐述,希望能找到相关代谢通路或分子来调控免疫细胞增殖、分化或功能,这将有助于我们更加深刻理解免疫学现象和分子机制,并对免疫系统相关疾病的治疗或预防发挥潜在的指导作用

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

大多数真核生物的体细胞是二倍体，即仅含有两组染色体，分别遗传自父本和母本。而一些特定组织如心脏、肝脏等就含有多倍体细胞，特别是肝脏组织含有较高比例的四、八倍体等多倍体细胞。肝脏是人体的重要解毒器官，同时酒精、肝炎病毒等毒性物质或毒性代谢物容易诱发肝细胞的基因突变，多倍体被认为有利于提供代偿性的正常基因来维持肝脏稳态。然而肝脏受损后，多倍体细胞将会受胁迫进行增殖，再生修复受损的肝组织。因此研究机体调控多倍体细胞产生及多倍体细胞进行细胞分裂的调控机理对于理解肝癌的发病机理和肝癌的治疗至关重要。Hippo信号通路在调节组织成体干细胞的分化和增殖，调控器官再生与尺寸大小中具有重要作用。深入研究发现, Hippo信号通路下游效应分子YAP通过AKT-SKP2信号促进二倍体细胞向多倍体转化及多倍体细胞的生长增殖。本项研究阐明了Hippo缺失及YAP激活促进多倍体细胞产生及增殖作为肝癌发生发展中的一个重要机制，为肝癌诊疗提供了新的策略。 周大旺，博士，厦门大学生命科学学院教授、副院长、国家杰出青年基金获得者。【Abstract】Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.该研究工作获得了国家自然科学基金委、国家重点基础研究发展计划(973)项目、青年千人计划和中央高校基本科研基金的资助。 The Yap (S127A) transgenic mice were kindly provided by Dr. Fernando Camargo from Harvard Medical School, Boston, MA. D.Z. and L.C. were supported by the National Natural Science Foundation of China (31625010,U1505224, and J1310027 to D.Z.; 81422018, U1405225, and 81372617 to L.C.; 81472229 to L.H.), the National Basic Research Program (973) of China (2015CB910502 to L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720140551 to L.C. and 2013121034 and 20720140537 to D.Z.)

“双一流”背景下对生命科学领域拔尖人才培养体系的探索

本文针对如何在国内创建国际一流的办学条件,培养生命科学领域拔尖人才的问题,总结了厦门大学生命科学学院近几年在师资、教材、培养平台和培养方式等方面所开展的改革探索。为了在国内培养国际一流的科研创新人才,我院成立了由诺贝尔奖获得者亲自负责的博伊特勒书院,建设了一支由国内外著名科学大师组成的多层次、交互共融的强大师资队伍,打造了一个多层次、多平台、多学科交叉、符合人才成长规律、高效运转的拔尖人才培养体系,从科研训练、课题研究和国际交流三个层次全面提升学生的科研创新能力,在国内本土培养了一批优秀的生命科学领域拔尖人才,符合\"双一流\"建设中关于师资建设和人才培养的要求。教育部基础学科拔尖学生培养试验计划研究课题(课题编号:20160803,20170606,20170402