Wnt基因/Wnt信号通路与乳腺癌

Wnt蛋白是一组调控胚胎形成期间细胞间信号传导的高度保守的分泌信号分子.在过去的几年里,由Wnt蛋白触发的不同信号通路已经得到了详尽的研究.Wnt基因与Wnt信号通路组成分子的突变可引起发育缺陷,异常的Wnt信号传导可导致人类疾病包括肿瘤的发生.许多证据都表明,Wnt信号通路的失调与乳腺癌的发生发展密切相关.micro...     

Multi-lineage differentiation of mesenchymal stem cells – To Wnt,or not Wnt

Mesenchymal stem cells (MSCs) are multipotent precursor cells originating from several adult connective tissues. MSCs possess the ability to self-renew and differentiate into several lineages, and are recognized by the expression of unique cell surface markers. Several lines of evidence suggest that various signal transduction pathways and their interplay regulate MSC differentiation. To that end, a critical player in regulating MSC differentiation is a group of proteins encoded by the Wnt gene family, which was previously known for influencing various stages of embryonic development and cell fate determination. As MSCs have gained significant clinical attention for their potential applications in regenerative medicine, it is imperative to unravel the mechanisms by which molecular regulators control differentiation of MSCs for designing cell-based therapeutics. It is rather coincidental that the functional outcome(s) of Wnt-induced signals share similarities with cellular redox-mediated networks from the standpoint of MSC biology. Furthermore, there is evidence for a crosstalk between Wnt and redox signalling, which begs the question whether Wnt-mediated differentiation signals involve the intermediary role of reactive oxygen species. In this review, we summarize the impact of Wnt signalling on multi-lineage differentiation of MSCs, and attempt to unravel the intricate interplay between Wnt and redox signals.     

Wnt基因族的进化

Ｗｎｔ基因族的进化马德如（南开大学分子生物学研究所,天津３０００７１）关键词Ｗｎｔ基因,分子进化一八十年代以来大量证据表明,原癌基因（ｐｒｏｔｏｏｎｃｏｇｅｎｅｓ）在细胞分化和胚胎发育中有重要作用。其中突出的例证是１９８２年由Ｎｕｓｓｅ和Ｖａｒｍｕｓ...     

Wnt信号转导及其生物效应

 Wnt蛋白与其下游效应物构成一组重要的信号转导通路 .信号转导过程包括 :Wnt首先激活细胞表面受体佛力子 (FZ) ,活化的FZ将通过Dvl、CKIε抑制糖原合成酶激酶 3β ,继而拮抗 β 链结素( β cat)催毁器的作用 ,使胞浆中 β cat积聚并进入核内 .β cat在核内与转录因子LEF TCF协作 ,激活控制胚胎发育和细胞命运的靶基因 ;活化的FZ还经激活JNK及Flamingo来影响细胞骨架的聚合 ,以决定细胞的平面极性及纺缍体定位     

Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用探究

目的：研究WntSa对Wnt3a处理过的melan—a细胞分泌黑色素的影响。方法：体外培养黑色素细胞（melan-a细胞）,分别进行GFP、Wnt3a、Wnt3a＋WntSa处理,比较细胞的突起,酪氨酸酶的活性以及黑素合成相关基因（TYR、TRP2、MITF）表达情况。结果：Wnt3a促进黑色素细胞突起的生长和TYR、TRP2、MITF的表达,而Wnt5a逆转了Wnt3a对黑色素细胞的作用。结论：Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用,表明在melan．a黑素细胞中Wnt5a可有效抑制wnt经典通路。     

Wnt信号通路与神经干细胞

神经干细胞增殖、分化机制的研究为神经系统疾病治疗提供了新的途径,具有巨大的潜在应用价值和理论研究意义。业已发现,Wnt信号通路对神经干细胞的增殖发挥着决定性作用,但新近的研究却表明Wnt信号能够明显促进神经干细胞向神经元分化,这种不同的表现可能与神经干细胞的内在特点、周围环境及靶基因的不同有关。本文试从Wnt信号通路及其在调控神经干细胞的增殖、分化中的作用加以综述。     

Wnt基因的类别及功能

Wnt是一类癌基因,在动物发育过程中具有广泛的作用。该文介绍哺乳动物基因组中19个Wnt基因的功能。     

Wnt信号通路与哺乳动物生殖

Wnt蛋白及其受体、调节蛋白等一起组成了复杂的信号通路,调控细胞的分化,参与发育的多个重要过程.近来的研究表明：Wnt信号通路也是调节哺乳动物生殖系统正常发育所必需.它主要参与了缪勒氏管及其派生器官的形成,调控卵泡的发育、排卵及黄体化,另外与正常妊娠的建立以及妊娠过程中乳腺的变化也有关.     

LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/β-catenin signaling

LGR5, a seven-transmembrane domain receptor of the rhodopsin family, is a Wnt target gene and a bona fide marker of adult stem cells in the gastrointestinal tract and hair follicle bulge. Recently, we and others demonstrated that LGR5 and its homologues function as receptors of the R-spondin family of stem cell factors to potentiate Wnt/β-catenin signaling. However, the mechanism of how LGR5 enhances the signaling output remains unclear. Here we report that following costimulation with the ligands R-spondin1 and Wnt3a, LGR5 interacts and forms a supercomplex with the Wnt coreceptors LRP6 and Fzd5 which is rapidly internalized and then degraded. Internalization of LGR5 is mediated through a dynamin- and clathrin-dependent pathway. Inhibition of this endocytic process has no effect on LGR5 signaling. Deletion of the C-terminal tail of LGR5 maintains its ability to interact with LRP6, yet this LGR5 mutant exhibits increased signaling activity and a decreased rate of endocytosis in response to R-spondin1 compared to the wild-type receptor. This study provides direct evidence that LGR5 becomes part of the Wnt signaling complex at the membrane level to enhance Wnt/β-catenin signaling. However, internalization of LGR5 does not appear to be essential for potentiating the canonical Wnt signaling pathway.     

绵羊Wnt2蛋白生物信息学分析

Wnt2蛋白是Wnts蛋白家族的重要成员,参与卵巢的发育。本研究以NCBI蛋白质数据库中发布的Wnt2蛋白氨基酸序列为研究对象,采用生物信息学软件对Wnt2蛋白的理化性质、信号肽及跨膜结构域、糖基化和磷酸化位点、二级结构和功能结构域、亚细胞定位和功能结构分类、序列相似比对及聚类、三级结构进行预测分析。结果发现,绵羊Wnt2由360个氨基酸组成,其等电点为9.21,有糖基化位点和磷酸化位点,是一个有信号肽的稳定的蛋白;二级结构与三级结构一致,均显示Wnt2由α-螺旋、延伸链、无规则卷曲构成;绵羊Wnt2蛋白是细胞外蛋白,主要参与信号转导和转录调控。研究结果为深入探讨Wnt2基因及其编码蛋白的结构和功能提供相关依据。     

Wnt信号途径及其作用机制

Ｗｎｔ信号途径的重要性近年来逐渐为人们所认识。在胚胎发育过程中 ,Ｗｎｔ途径不但参与了胚胎背腹轴的形成 ,而且与细胞极性建立、细胞命运决定等多个发育事件有关。一旦阻断Ｗｎｔ信号途径 ,动物胚胎会因为形态建成过程遭到破坏而产生非常明显的突变表型 ,例如果蝇的异常表皮、小鼠腹侧化肢体、线虫ＥＭＳ细胞丧失不对称分裂[1] 等等。此外 ,科学家也发现 ,许多肿瘤的发生与Ｗｎｔ途径成员的突变相关[2 ] 。本文通过对近年来所发表的结果综合整理 ,从Ｗｎｔ信号在细胞内外作用位点的决定、关键信号途径成员Ａｒｍ/β 连环蛋白 ( β ｃａ…     

谷氨酰胺合成酶与Wnt信号转导通路

GS（glutamine synthetase）或GLuL（glutamate-ammonia ligase）,即谷氨酰胺合成酶,为人体内重要的功能酶,催化谷氨酸与氨生成谷氨酰胺。在体内氮的代谢中,尤其在维持氨离子和谷氨酰胺的稳定中发挥着重要的作用。GS表达和活性的异常常会导致人体很多疾病的发生。近年来研究发现GS表达和活性的异常与Wnt信号通路的异常密切相关。     

Wnt5a can both activate and repress Wnt/β-catenin signaling during mouse embryonic development

Embryonic development is controlled by a small set of signal transduction pathways, with vastly different phenotypic outcomes depending on the time and place of their recruitment. How the same molecular machinery can elicit such specific and distinct responses, remains one of the outstanding questions in developmental biology. Part of the answer may lie in the high inherent genetic complexity of these signaling cascades, as observed for the Wnt-pathway. The mammalian genome encodes multiple Wnt proteins and receptors, each of which show dynamic and tightly controlled expression patterns in the embryo. Yet how these components interact in the context of the whole organism remains unknown. Here we report the generation of a novel, inducible transgenic mouse model that allows spatiotemporal control over the expression of Wnt5a, a protein implicated in many developmental processes and multiple Wnt-signaling responses. We show that ectopic Wnt5a expression from E10.5 onwards results in a variety of developmental defects, including loss of hair follicles and reduced bone formation in the skull. Moreover, we find that Wnt5a can have dual signaling activities during mouse embryonic development. Specifically, Wnt5a is capable of both inducing and repressing β-catenin/TCF signaling in vivo, depending on the time and site of expression and the receptors expressed by receiving cells. These experiments show for the first time that a single mammalian Wnt protein can have multiple signaling activities in vivo, thereby furthering our understanding of how signaling specificity is achieved in a complex developmental context.     

棉铃虫Wnt1基因启动子活性研究

经典的Wnt信号通路是一条与生长发育密切相关的信号通路,经典Wnt信号通路在棉铃虫滞育蛹脑中受到抑制。本研究以棉铃虫Wnt1基因的转录调控为研究目标,对Wnt1启动子的活性进行了分析。首先,运用染色体步移的技术成功克隆了一段长为1566 bp的Wnt1启动子。然后,通过PCR扩增不同长度的启动子片段,构建到报告质粒,转染棉铃虫Hz Am1细胞并进行启动子活性分析,结果表明-1077~-1120以及-1120~-1140这两个区域对Wnt1基因的转录起着明显的激活作用。最后对这两个区域潜在的转录因子结合位点进行了预测。本研究从根本上了解棉铃虫滞育蛹脑中经典Wnt信号通路的调节机制打下了基础。     

Wnt信号膜质转导的机制

Wnt信号通路是一条高度保守的信号转导通路,在生物体多个发育过程以及一系列疾病发生中发挥重要作用。Wnt信号通路重要的生物学功能和复杂的信号转导调控网络引起了人们广泛和持续的研究兴趣。介绍了经典Wnt信号通路信号转导的分子框架,结合自身实验室新的研究发现,重点阐述Wnt信号由细胞膜上向细胞质内转导的机制。     

Wnt signalling: pathway or network?

Members of the Wnt family of secreted glycoproteins participate in many signalling events during development. Recent findings suggest that Wnt signals can sometimes play a permissive role during cell-fate assignment. Wnt proteins have been shown to interact with a number of extracellular and cell-surface proteins, whereas many intracellular components of the Wnt-signalling pathway are also involved in other cellular functions. The consequences of Wnt signalling can be affected by members of the MAP kinase family. These observations suggest that the future understanding of Wnt signalling may require models that are based on a signalling network rather than a single linear pathway.     

经典Wnt信号通路与人类肿瘤

近年来,随着对肿瘤的深入研究,Wnt信号的研究也受到了高度的关注．Wnt信号通路是一条在进化上保守的信号途径,在控制胚胎发育,调节细胞生长、迁移、分化,调控正常组织重建等生命活动中发挥重要的作用,其异常活化与众多人类肿瘤的发生、发展密切相关．Wnt信号途径异常的核心是β-catenin在细胞内累积,并通过其下游途径引起特异靶基因的转录．本文着重介绍Wnt/β-catenin信号转导通路的研究进展及其与肿瘤的关系,了解该通路在肿瘤发生过程中的具体分子机制有助于为临床诊断提供依据,为早期干预治疗提供方法．     

Wnt/��-catenin signaling in hepatic organogenesis

Wnt/β-catenin signaling has come to the forefront of liver biology in recent years. This pathway regulates key pathophysiological events inherent to the liver including development, regeneration and cancer, by dictating several biological processes such as proliferation, apoptosis, differentiation, adhesion, zonation and metabolism in various cells of the liver. This review will examine the studies that have uncovered the relevant roles of Wnt/β-catenin signaling during the process of liver development. We will discuss the potential roles of Wnt/β-catenin signaling during the phases of development, including competence, hepatic induction, expansion and morphogenesis. In addition, we will discuss the role of negative and positive regulation of this pathway and how the temporal expression of Wnt/β-catenin can direct key processes during hepatic development. We will also identify some of the major deficits in the current understanding of the role of Wnt/β-catenin signaling in liver development in order to provide a perspective for future studies. Thus, this review will provide a contextual overview of the role of Wnt/β-catenin signaling during hepatic organogenesis.Key words: liver development, liver cancer, liver regeneration, Wnt signaling, proliferation, differentiationThe Wnt/β-catenin pathway is an evolutionarily well-conserved pathway that has proven to be essential to normal cellular processes such as development, growth, survival, regeneration and self-renewal.^1–5 Its diverse functions also include the initiation and progression of cancer.⁶ In fact, one area in which this pathway has been extensively studied is in liver cancer.Mutations of Wnt/β-catenin pathway members in hepatocarcinogenesis are common. For example, 90–100% of hepatoblastomas contain mutations in adenomatous polyposis coli (APC), CTNNB1 and/or Axin1/2, which causes cytoplasmic and nuclear localization of β-catenin.^7–9 Axin1 and β-catenin mutations have also been identified in approximately 25% of hepatocellular carcinomas,^10–12 while overexpression of the frizzled-7 receptor¹³ and glycogen synthase kinase-3 (GSK-3) inactivation¹⁴ can also lead to aberrant β-catenin pathway activation. The dysregulation of this pathway in hepatic cancers makes it an attractive target for potential therapies, and experimental treatment in vivo has shown promising results. For example, inhibiting β-catenin expression by siRNA or R-Etodolac decreases proliferation and survival of human hepatoma cell lines.^15,16 Since cancer recapitulates development, determining the timing of β-catenin activation during hepatogenesis will help us to better understand the inappropriate activation of this pathway in hepatocarcinogenesis.Recent work has elucidated the role of β-catenin signaling in the liver, and has highlighted its essential role in liver health and disease.¹⁷ In addition, emerging evidence suggests that this pathway plays a key role in liver organogenesis.     

Wnt蛋白：从合成到分泌

Wnt信号通路是细胞发育和调节生长的一个关键途径,通过Wnt基因编码的Wnt蛋白与膜上相应受体结合引起细胞浆内β-catenin转入细胞核,激活相关基因转录。在正常情况下对胚胎发育和成人的部分组织形成和功能发挥起着重要作用。当该途径异常时,会导致多种疾病的发生。Wnt蛋白结构及其修饰对Wnt信号转导具有很重要的影响,本文就Wnt蛋白的合成和分泌等予以综述。     

Which way does the Wnt blow? Exploring the duality of canonical Wnt signaling on cellular aging

Critical cellular functions, including stem cell maintenance, fate determination, and cellular behavior, are governed by canonical Wnt signaling, an evolutionarily conserved pathway whose intracellular signal is transduced by beta-catentin. Emerging evidence suggests that canonical Wnt signaling influences cellular aging, indicating that increases in Wnt signaling delay age-related deficits.1 However, recent Science papers suggest that Wnt signaling accelerates the onset of aging.2,3 In an attempt to resolve this paradox and clarify how Wnt signaling affects aging, we provide a selective review of research relevant to Wnt signaling and aging.