【专题讨论】Notch信号大家谈

把最近的Seminar in cancer biology 里面Notch专辑作了全部编译，共8个 主要是和癌症相关的，欢迎大家来拍 啊！1、Notch signaling in development and disease疾病和发育中的Notch信号Emil M. Hansson, Urban Lendahl∗, Gavin ChapmanDepartment of Cell and Molecular Biology, Karolinska Institute, Stockholm SE-171 77, SwedenAbstractCells in multicellular organisms need to decipher extracellular cues into appropriate responses including correct differentiation choices. A considerable portion of this information is relayed through a surprisingly small number of signaling pathways, which are highly evolutionarily conserved and used in many different cell types. This “ivy league” of signaling mechanisms comprises the Wnt/wingless, BMP/TGF-beta, Sonic Hedgehog, receptor tyrosine kinases, nuclear receptors, JAK/STAT and, the subject of this review, the Notch signaling pathway. The aim of this article is to provide an overview of the Notch signaling pathway. The role of Notch in various types of cancers is discussed in the accompanying articles in this issue of SCBI.© 2004 Elsevier Ltd. All rights reserved.Keywords: Cell–cell communication; Endocytosis; CSL; Numb; BMP多细胞生物必需对外界的信号作出适当的反应，比如说细胞对其分化的选择。大部分这种信息的传递都是通过一种在进化上保守的细胞小分子来完成的。这一类“常春藤联盟”（老美的比喻而已，“核心集团”）包括Wnt/wingless, BMP/TGF-beta, Hedgehog,受体酪氨酸激酶, 核受体, JAK/STAT 信号通路以及我们将要展开论述的Notch信号通路。这篇文章对Notch信号通路作了概括，而其在各种癌症中的作用将在以下的文章进行具体讨论，这篇文章不再做进一步展开。主要包括：1、简述Notch通路的研究史2、具体化Notch信号通路3、Notch相作用或相修饰的蛋白4、Notch与其他信号通路的“对话”5、Notch信号通路与疾病的关系6、Notch信号通路和癌症的关系对首次接触这条通路的新手来说是份不错的参考资料。[color=black][/color] screen.width-333)this.width=screen.width-333" width=640 height=393 title="Click to view full 未命名2.JPG (760 X 467)" border=0 align=absmiddle>2、Notch信号与乳腺癌Notch in mammary gland development and breast cancerKaterina Politi a,1, Nikki Feirt b, Jan Kitajewski AbstractNotch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the mouse mammary tumor virus and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer© 2004 Elsevier Ltd. All rights reserved.Keywords: Notch; Mammary gland; Breast cancer; Signaling pathwaysNotch信号已经被证明和许多的生命过程相关，比如细胞的死亡和癌发生。小鼠Notch1和Notch2是其本身乳腺瘤病毒（mtv病毒）插入和重组的靶位点，该位点的突变可以促进上皮乳瘤的发生。另外，乳房上皮细胞持续激活Notch4的表达能抑制上皮细胞分化从而导致该组织处肿瘤的产生。这些数据都说明了Notch信号通路的确在乳癌的发生过程中起作用，但是我们还需要进一步的实验来阐明其具体的作用。这篇文章总结了小鼠体内及体外细胞培养模型中Notch诱导肿瘤发生的一些研究，从而来说明在人乳腺癌中Notch的激活是一个必然因素。（From animal model to human）Notch1和Notch4是有所不同的，其还通过Notch4/int-3通路激活下游的h-int3sh而作用。从图就可以看出来，其介导的下游通路而致乳癌的通路缺失，这就是尚待展开的工作。Notch and T cell malignancy3、Notch信号与T细胞恶性肿瘤Patrick A. Zweidler-McKay a,b, Warren S. Pear b,c,d,∗AbstractNotch signaling is required for normal T cell development. However, Notch expression must be precisely regulated as constitutive Notch signaling leads to T cell lymphomas. Recent evidence has provided insights into potential mechanisms of Notch-mediated lymphomagenesis and its relationship to T cell development. The evidence suggests that Notch likely interacts with several important cellular pathways and can cooperate with other oncogenes during lymphomagenesis. In particular, Notch appears to modulate pre-TCR signaling, inhibit the E2A pathway, and in murine leukemia models, frequently cooperates with Myc, E2A-PBX and dominant negative Ikaros dysregulation. This review will present current knowledge in these areas and explore theories on Notch-mediated T cell lymphomagenesis.© 2004 Elsevier Ltd. All rights reserved.  Keywords: CSL; Leukemia; Oncogene; Hematopoiesis; DevelopmentNotch信号是正常T细胞发育所必需的。但是，Notch信号必需被精确调控否则就会导致T细胞淋巴瘤的形成。目前的实验证据可让我们进一步探求Notch所介导的淋巴瘤生成以及其在T细胞发育中的潜在机制。而这些证据都说明在淋巴瘤形成过程中，Notch可能与其他的重要的胞内信号相互作用，此外，Notch也可能和其他癌基因协同作用。具体的来说，Notch可能参与了前-TCR信号的调节、抑制了E2A通路。在鼠非白血性白血病模型中，其更可能与Myc，E2A-PBX和显性负相Ikaros失调等协同作用。这篇文章里我们总结了这些相关领域的最近研究成果并且对Notch介导的淋巴瘤形成进行深入的探究。善待解决的问题：1、Notch失调到何种程度就能介导了淋巴瘤的形成？2、Notch在淋巴瘤形成中具体的作用是什么呢？3、在那么多以之协同作用的因子中哪些是必需的呢？这些都是需要我们进一步去研究和解答的。图片 在白血病转化中Notch潜在的信号通路 screen.width-333)this.width=screen.width-333" width=420 height=361 title="Click to view full 未命名1.JPG (420 X 361)" border=0 align=absmiddle>Modulation of Notch signaling by mastermind-like (MAML)transcriptional co-activators and their involvement in tumorigenesis4、Notch信号转录辅助激活蛋白基因MAML的致癌性Lizi Wu a,b, James D. Griffina,b,∗AbstractNotch signaling is mediated by cell–cell interactions and is critical for cell fate determination in many species. Recently, a family of mastermind-like (MAML) transcriptional co-activator genes was identified that encode proteins that cooperate with Notch and CSL to activate transcription. Here, we review our current understanding of the roles of the MAML proteins in Notch signaling, and their involvement in certain human cancers. The mounting biochemical and functional evidence indicate that the MAML genes are critical components of the Notch signaling pathway, likely regulating cellular events involved in both normal development and oncogenesis.目前一个称为mastermind-like (MAML)[类主导？]的转录辅助激活蛋白的基因已被鉴定而且发现其编码的蛋白能够与Notch 和CSL协同作用而激活转录。这篇文章主要是总结了目前关于mastermind-like (MAML) 蛋白在Notch信号及其在肿瘤中的作用。大量的生化和功能方面的实验证据都说明了MAML基因是Notch信号的一个关键的组件，该组件对细胞内的正常发育以及癌发生具有调节作用。Notch对上皮细胞癌有抑制，这似乎提供了一个新的治疗靶点，但是还需进一步研究来证实。Notch in lung development and lung cancer5、Notch和肺发育及肺癌Brendan J. Collins a,b, Wolfram Kleeberger a,c, Douglas W. Ball a,d,∗AbstractAlthough data regarding the role of the Notch pathway in human lung cancer are still limited, fetal lung developmental studies suggest that Notch signaling plays a critical role in regulating airway epithelial development. The moderate hypotrophic phenotype of lungs from animals bearing a Hes1 mutation, and the expression of Notch components in the distal lung bud during branching morphogenesis, together suggest that Notch may play a role in normal lung growth, especially in Clara cell precursors. Non-small cell lung cancers, including adenocarcinoma, appear to actively utilize this conserved developmental pathway. Pharmacologic inhibition of the Notch pathway is a potential experimental approach to lung cancer treatment.© 2004 Elsevier Ltd. All rights reserved.Keywords: Notch; Hes1; Lung development; Lung cancer; Mash1虽然目前对于Notch信号通路在肺癌中的作用知之甚少，但是对于胎儿肺发育的研究表明Notch信号通路对于气道上皮细胞的发育起到关键作用。Hes1的突变导致肺营养缺陷表型的出现，而Notch在肺分支的远侧肺芽也表达，都说明了Notch肺的正常生长中也起作用，特别是在Clara细胞前体中。非小细胞性肺癌，包括腺癌，都有效的利用了保守发育途径。药物抑制Notch信号途径可能是非癌治疗的一个潜在靶点。Notch signaling in neuroblastoma6、Notch与成神经细胞瘤（神经母细胞瘤）Sven Påhlman, Marie-Thérése Stockhausen, Erik Fredlund, Håkan Axelson∗Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS,Entrance 78, 3rd Floor, SE-205 02 Malmö, SwedenAbstractNeuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system that have discontinued their normal differentiation program. This review is focused on involvement of the Notch signaling cascade in the process of differentiation in neuroblastoma cells and normal cells of the sympathetic nervous system. Hypoxia induces dedifferentiation of neuroblastoma cells in vivo and in vitro, and under oxygen-compromised conditions the Notch cascade is activated. This activation might promote development of the dedifferentiated phenotype. The implications of these observations for tumor biology are also discussed.© 2004 Elsevier Ltd. All rights reserved.Keywords: Neuroblastoma; Notch; Hes; Differentiation; Normoxia; Hypoxia成神经细胞瘤是一种儿科肿瘤，来源于交感神经系统非正常分化的前体细胞。这篇文章集中于Notch级联信号在交感神经中的成神经细胞瘤分化和正常细胞分化的作用。在体内和体外缺氧可诱生成神经细胞瘤的去分化，而氧妥协的情况下，Notch信号则被激活。这种激活作用会导致去分化表型的发育。接下来文章主要是讨论这些结果的肿瘤生物学意义。Notch signaling in the integrated control of keratinocytegrowth/differentiation and tumor suppression7、Notch与角质化细胞和皮肤癌Karine Lefort a, G. Paolo Dotto a,b,∗a Department of Biochemistry, Lausanne University, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerlandb Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USAAbstractOncogenesis is closely linked to abnormalities in cell differentiation. Notch signaling provides an important form of intercellular communication involved in cell fate determination, stem cell potential and differentiation. Here we review the role of this pathway in the integrated growth/differentiation control of the keratinocyte cell type, and the maintenance of normal skin homeostasis. In parallel with the pro-differentiation function of Notch1 in keratinocytes, we discuss recent evidence pointing to a tumor suppressor function of this gene in both mouse skin and human cervical carcinogenesis. The possibility that Notch signaling elicits signals with a duality of growth positive and negative function will be discussed.© 2004 Elsevier Ltd. All rights reserved.Keywords: Notch1; Keratinocyte; Differentiation; Tumorigenesis肿瘤的生成和细胞分裂的异常密切相关。Notch信号是决定细胞命运、干细胞分化的一个重要的胞内通讯系统的信号。这篇综述总结了Notch信号在控制角质化细胞的整合生长和分化中的作用，另外也综述了Notch信号维持皮肤稳态的作用。与Notch信号在角质化细胞中的作用相同的是一个目前发现的与之类似的抑癌基因，该基因存在于小鼠皮肤爱和人颈部癌中。而Notch信号可能引发了此基因从而具有了控制生长的双重属性。Viral interactions with the Notch pathway8、Notch与病毒感染S. Diane Hayward∗Viral Oncology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,School of Medicine, CRB 308, 1650 Orleans Street, Baltimore, MD 21231, USAAbstractThe Notch signaling pathway influences cell fate decisions, proliferation versus differentiation and cell survival. Viruses both utilize and manipulate the differentiation state of infected cells, promote or block cell cycling and employ a variety of mechanisms to evade innate cellular anti-viral responses and promote cell survival. In light of these commonalities, it is perhaps not surprising that several viruses have tapped into the Notch pathway to advance their own life cycles. This first became apparent from studies showing targeting of Epstein-Barr virus proteins to the nuclear effector of Notch signaling CSL (CBF1/RBPJk). More recently the Kaposi’s sarcoma-associated herpesvirus RTA protein has been found to bind CSL. Notch pathway interactions have also been described for adenovirus SV40 and human papilloma virus. This review focuses on the herpesvirus protein interactions with the Notch pathway and the insights that these interactions have provided.© 2004 Elsevier Ltd. All rights reserved.病毒可以利用和控制被感染细胞的分化状态，可以促进或阻断细胞周期并且具有多种机制逃避宿主细胞的抗病毒反应，最终加速细胞的死亡。这就不奇怪为什么能够插入到Notch信号途径中来加速其生长。比如说EB病毒蛋白的靶点就是Notch信号CSL (CBF1/RBPJk)的核效应子。目前有发现Kaposi’s肉瘤相关疱疹病毒蛋白RTA也能够结合到CSL上。这篇综述主要研究了疱疹病毒蛋白和Notch信号途径的相互作用并探究其进一步的机制。我这人有个不好就是说话直——我觉得，看过您的翻译后，感觉您没有用太多时间，可能时间较忙吧。另外，也可见ahge斑竹的翻译功底还有待进一步提高。尤其是细胞分裂和细胞分化还没分清楚，还有读您的翻译语句别扭，反正不怎么地道。（得罪斑竹的地方尽情海涵）欢迎vetchj战友拍砖！摘要编译的目的主要有2个，一是为战友提供信息，二是通过锻炼提高自己的翻译水平。 vetchj战友认为哪些翻译不对的地方请具体指出，以便大家共同提高。谢谢！真是不好意思啊!由于上网时间不多,先修了第一篇,请各位战友批评指正.1、Notch signaling in development and disease疾病和发育中的Notch信号Cells in multicellular organisms need to decipher extracellular cues into appropriate responses including correct differentiation choices. A considerable portion of this information is relayed through a surprisingly small number of signaling pathways, which are highly evolutionarily conserved and used in many different cell types. This “ivy league” of signaling mechanisms comprises the Wnt/wingless, BMP/TGF-beta, Sonic Hedgehog, receptor tyrosine kinases, nuclear receptors, JAK/STAT and, the subject of this review, the Notch signaling pathway. The aim of this article is to provide an overview of the Notch signaling pathway. The role of Notch in various types of cancers is discussed in the accompanying articles in this issue of SCBI.多细胞生物的细胞需将外界的信息解密/转变成相应的/适当的反应，比如正确的细胞分化选择。令人惊奇的是,大部分这类信息仅通过一小部分信号传导途径传递.它们在进化上高度保守,存在多种不同类型的细胞内。这类“常春藤联盟”（老美的比喻而已，“核心集团”,美国有八大著名高校联盟）包括Wnt/wingless, BMP/TGF-beta, 声波环状蛋白(Sonic Hedgehog,SHH),酪氨酸激酶受体, 核受体, JAK/STAT 以及本综述提到的Notch信号通路。(这篇文章)本文旨在总结Notch信号通路,而Notch在各种癌症中的作用在会SCBI这期刊物的相应文章里深入论述(下面的文章才提及)，这里不在赘述(略过)。主要包括：1、(简述了下)Notch的概述2、Notch信号通路3、Notch关联蛋白或修饰蛋白4、Notch与其他信号通路的联系/对话5、Notch信号通路与疾病的关系6、Notch信号通路和癌症的关系感谢vetchj 的拍砖，. 你改得不错，很详细、很全面。我当初译得比较仓促，就说个大概意思，当时想如需进一步领会的还需看原文。欢迎你继续指出其他的文章有误之处。 刚才利用做试验的间隙弄好两篇：再请批评指正！谢谢两位版主的肯定。2。Notch在乳腺发育和乳癌发生中的作用Notch in mammary gland development and breast cancerNotch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer Notch信号已经被证实（证明和许多生命过程相关）存在于多种生命过程中，如细胞生死和癌变（发生）。小鼠Notch1和Notch2基因是鼠乳腺瘤病毒（mouse mammary tumor virus，MMTV）插入和重组的靶位，该些突变则促进乳腺上皮肿瘤的发生。再者（另外），乳腺上皮细胞中一种持续活化形式Notch4的表达也能抑制上皮细胞的分化，从而导致肿瘤形成。这些数据说明：Notch信号通路参与乳腺的癌变过程，但是，我们还需要进一步的实验研究来阐明Notch在人乳腺癌形成中的作用。本文主要总结了Notch在小鼠体内（及体）外细胞培养模型中诱导乳腺癌变（肿瘤发生）的一些研究，指出（从而来说明）Notch的激活是人乳腺癌的致病因素之一（一个必然因素）。[（From animal model to human）.Notch1和Notch4是有所不同的，其还通过Notch4/int-3通路激活下游的h-int3sh而作用。从图就可以看出来，其介导的下游通路而致乳癌的通路缺失，这就是尚待展开的工作。]Notch and T cell malignancy3、Notch信号与T细胞恶性肿瘤Notch signaling is required for normal T cell development. However, Notch expression must be precisely regulated as constitutive Notch signaling leads to T cell lymphomas. Recent evidence has provided insights into potential mechanisms of Notch-mediated lymphomagenesis and its relationship to T cell development. The evidence suggests that Notch likely interacts with several important cellular pathways and can cooperate with other oncogenes during lymphomagenesis. In particular, Notch appears to modulate pre-TCR signaling, inhibit the E2A pathway, and in murine leukemia models, frequently cooperates with Myc, E2A-PBX and dominant negative Ikaros dysregulation. This review will present current knowledge in these areas and explore theories on Notch-mediated T cell lymphomagenesis.T细胞正常发育需要Notch信号（是所必需的）。但是，Notch蛋白必须在精确而持续的Notch信号调控下才能表达，但这会导致T细胞淋巴瘤。目前的实验研究结果已提出一些有关（进一步探求）Notch介导淋巴瘤形成的可能（潜在）机制以及Notch与T细胞发育关系的观点。这（而这些证据都说明）表明：在淋巴瘤形成过程中，Notch可能与（其他的）几种重要的胞内信号相互作用，并（此外，Notch也可能）与其他癌基因协同作用。特别是（具体的来说，）Notch可能参与了前-TCR信号的调节，并抑制E2A通路。在鼠非白血性白血病模型中，该蛋白常（其更可能）与Myc，E2A-PBX和显性负相Ikaros失调因子等协同作用。本综述（这篇文章里）中主要提供在这些领域的最新研究动态，并探讨Notch介导的淋巴瘤形成机理。亟待解决（善待解决）的问题：1、介导（了）淋巴瘤的形成时，Notch失调程度？2、Notch在淋巴瘤形成中具体的作用（是什么呢）？3、（在那么多以之）协同（作用的）因子中哪些是必需的（呢）？vetchj 的修正很不错，这份工作能更加完善对于Notch与癌症相作用的准确理解。支持！等待看你的续篇。今天刚搞定的其余几篇:一起传上来,还是请各位指教[拍的不好,再跟吧]:其实说心里话,摘要比全文还难翻译,很怕理解错,再者翻译需要全局考虑,不能斟酌字句的.这是这些年的体会.拍砖的来吧:Modulation of Notch signaling by mastermind-like (MAML)transcriptional co-activators and their involvement in tumorigenesis4、MAML样转录辅助激活蛋白对Notch信号的调节与肿瘤形成Notch signaling is mediated by cell–cell interactions and is critical for cell fate determination in many species. Recently, a family of mastermind-like (MAML) transcriptional co-activator genes was identified that encode proteins that cooperate with Notch and CSL to activate transcription. Here, we review our current understanding of the roles of the MAML proteins in Notch signaling, and their involvement in certain human cancers. The mounting biochemical and functional evidence indicate that the MAML genes are critical components of the Notch signaling pathway, likely regulating cellular events involved in both normal development and oncogenesis.Notch信号受到细胞间相互作用的调节，对许多物种体的生死存亡至关重要。最近，研究者鉴定出一个被称为mastermind-like (MAML)[ 注：mastermind本意是具有极大才智，但翻译出来不对味，可以不翻译，反而意境更美]样转录辅助激活蛋白的多基因家族，（已被鉴定而且发现）其编码的蛋白能够与Notch 和CSL协同（作用而）激活转录。本文（这篇文章主要是）总结了MAML蛋白在Notch信号及其在特定癌症（肿瘤）中的作用。大量（的）生化和功能研究证实（方面的实验证据都说明了）MAML多基因家族是Notch信号途径的（一个）关键组分（的组件），并且（该组件）对细胞（内的）正常发育以及癌症的发生可能具有调节作用。[Notch对上皮细胞癌有抑制，这似乎提供了一个新的治疗靶点，但是还需进一步研究来证实。]Notch in lung development and lung cancer5、Notch在肺发育及肺癌中的作用Although data regarding the role of the Notch pathway in human lung cancer are still limited, fetal lung developmental studies suggest that Notch signaling plays a critical role in regulating airway epithelial development. The moderate hypotrophic phenotype of lungs from animals bearing a Hes1 mutation, and the expression of Notch components in the distal lung bud during branching morphogenesis, together suggest that Notch may play a role in normal lung growth, especially in Clara cell precursors. Non-small cell lung cancers, including adenocarcinoma, appear to actively utilize this conserved developmental pathway. Pharmacologic inhibition of the Notch pathway is a potential experimental approach to lung cancer treatment.虽然目前对于Notch信号通路在肺癌中的作用知之甚少，但是对（于）胎儿肺发育的研究表明：Notch信号通路对于气道上皮细胞的发育起到关键作用。动物发生温和性肺营养缺陷表型时，Hes1发生突变，且在肺分支成形过程（branching morphogenesi）中，Notch在末梢肺芽中表达。这都说明：Notch对肺的正常生长（中也）起到一定作用，特别是在Clara细胞前体中。非小细胞性肺癌，如腺癌，似乎都能（有效的）利用（了）这一保守的发育途径。通过药物抑制Notch信号途径可能是（对）肺（非）癌治疗的途径之一（一个潜在靶点）。Notch signaling in neuroblastoma6、Notch信号与神经母细胞瘤Neuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system that have discontinued their normal differentiation program. This review is focused on involvement of the Notch signaling cascade in the process of differentiation in neuroblastoma cells and normal cells of the sympathetic nervous system. Hypoxia induces dedifferentiation of neuroblastoma cells in vivo and in vitro, and under oxygen-compromised conditions the Notch cascade is activated. This activation might promote development of the dedifferentiated phenotype. The implications of these observations for tumor biology are also discussed.成神经细胞瘤是一种儿科肿瘤，来源于交感神经系统非正常分化的前体细胞。本文（这篇文章）主要关注（集中于）Notch级联信号在交感神经中的成神经细胞瘤分化和正常细胞分化的作用（Good！）。体内（和体）外缺氧可诱导成神经细胞瘤的去分化作用（加作用二字，可缓和语气—本人认为），而在氧充分时（妥协的情况下），Notch信号则被激活。这种激活作用会促进（导致）去分化表型的产生。本文还讨论了（接下来文章主要是讨论）这些发现（结果）的肿瘤生物学意义。Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression7、在角质细胞生长/分化共同控制下的Notch信号和肿瘤抑制（皮肤癌）Oncogenesis is closely linked to abnormalities in cell differentiation. Notch signaling provides an important form of intercellular communication involved in cell fate determination, stem cell potential and differentiation. Here we review the role of this pathway in the integrated growth/differentiation control of the keratinocyte cell type, and the maintenance of normal skin homeostasis. In parallel with the pro-differentiation function of Notch1 in keratinocytes, we discuss recent evidence pointing to a tumor suppressor function of this gene in both mouse skin and human cervical carcinogenesis. The possibility that Notch signaling elicits signals with a duality of growth positive and negative function will be discussed.肿瘤的形成与细胞分化（分裂）的异常有极为（closely）密切的联系。Notch信号是决定细胞命运、干细胞分化的胞内通讯系统的一个重要组成部分。这篇综述总结了Notch信号通路在角质细胞的整合型生长/分化控制（在控制角质化细胞的整合生长和分化中的作用）和维持皮肤稳态过程中的作用。与Notch1信号在角质细胞中的前分化作用类似（相同）的是：在鼠皮肤癌和人类宫颈癌形成时，（这一基因）Notch最近被发发现具有（个目前发现的与之类似的）抑癌基因的特性（该基因存在于小鼠皮肤爱和人颈部癌中）。这可能是由于Notch信号（可能）引发（了此基因从而具有了）具有控制生长/生长抑制双重属性的信号通路。Viral interactions with the Notch pathway8、Notch与病毒感染Viruses both utilize and manipulate the differentiation state of infected cells, promote or block cell cycling and employ a variety of mechanisms to evade innate cellular anti-viral responses and promote cell survival. In light of these commonalities, it is perhaps not surprising that several viruses have tapped into the Notch pathway to advance their own life cycles. This first became apparent from studies showing targeting of Epstein-Barr virus proteins to the nuclear effector of Notch signaling CSL (CBF1/RBPJk). More recently the Kaposi’s sarcoma-associated herpesvirus RTA protein has been found to bind CSL. Notch pathway interactions have also been described for adenovirus SV40 and human papilloma virus. This review focuses on the herpesvirus protein interactions with the Notch pathway and the insights that these interactions have provided.病毒可以利用和控制被感染细胞的分化状态，可以促进或阻断细胞周期并且具有多种逃避宿主细胞的抗病毒反应机制，最终加速细胞的死亡[OK！]。了解了这一共性，我们就不奇怪一些病毒干扰（为什么能够插入到）Notch信号途径来加速病毒自身的生长。最初的研究来源于（比如说）EB病毒蛋白，研究发现这些蛋白的靶点就是Notch信号CSL (CBF1/RBPJk)的核效应子。目前有研究发现Kaposi’s肉瘤相关疱疹病毒蛋白RTA也能够结合（到）CSL（上）。本文（这篇综述）主要（研究了，没有研究！）探讨疱疹病毒蛋白和Notch信号途径的相互关系，（作用）并进一步探究这些关系的机制[可不翻译出来的]。有关Notch的文献,可以参考战友的文章,还不错.>三人行必有吾师楼上几位佩服佩服！有没有关于说notch1-4结构的文章，主要的几个胞内damain,有的话和我们分享！！谢谢Notch的信号通路图片 （缩略图，点击图片链接看原图）　Notch是一类穿膜受体，广泛存在于所有已知动物细胞中。Notch介导细胞与细胞间的局部信号传递及相应的信号级联反应。Notch信号对多种组织、细胞的命运起重要作用，包括表皮、神经、血液、肌肉等组织。其信号异常导致个体严重的发育缺陷及病理情况。为此CMBI特准备了关于Notch signaling的特别报道，供实践参考,更多文献,请用相关关键词通过CMBI文献查询获取。以下是关于该蛋白的大量文献，链接见>-------------------------------------------------------------------------------- Impaired Vascular Mechanotransduction in a Transgenic Mouse Model of CADASIL ArteriopathyViral interactions with the Notch pathwayThe Tat protein of the human immunodeficiency virus type 1 (HIV-1) interacts with the EGF-like repeats of the Notch proteins and the EGF precursorRegulation of Notch signaling genes during BMP2-induced differentiation of osteoblast precursor cellsNotch signalling in hematopoiesisNotch signaling in development and diseaseNotch promotes survival of neural precursor cells via mechanisms distinct from those regulating neurogenesisNestin expression is lost in a neural stem cell line through a mechanism involving the proteasome and Notch signallingMouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signalingThe Notch and Sonic hedgehog signalling pathways in immunityRegulation of B cell development by Notch-RBP-J signalingNotch3, another Notch in T cell developmentNotch signalling in the regulation of peripheral T-cell functionNotch signalling at the crossroads of T cell development and leukemogenesisNotch signaling in lymphopoiesisNotch and T cell malignancyNotch and lymphopoiesisMicroenvironmental regulation of Notch signalling in T cell developmentIdentification of c-Kit receptor as a regulator of adult neural stem cells in the mammalian eye-interactions with Notch signalingFGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ developmentEXPRESSION OF NOTCH AND NOTCH LIGANDS DURING FOLLICULOGENESIS AND CORPUS LUTEUM FORMATION MARKS A SUBSET OF OVARIAN VESSELSDifferentiation of bone marrow cells into cells that express liver-specific genes in vitro-implication of the Notch signals in differentiationTHE ROLE OF NOTCH SIGNALING IN VASCULAR SMOOTH MUSCLE CELL MIGRATIONNotch signaling in primary endothelial cellsCHARACTERIZATION OF NOTCH SIGNALING FUNCTIONS DURING ANGIOGENESIS USING A NOVEL IN VITRO TUBE FORMING ASSAY.Notch signaling in the integrated control of keratinocyte growth-differentiation and tumor suppressionNotch signaling in neuroblastomaNotch in mammary gland development and breast cancerNotch in lung development and lung cancerNotch activation induces apoptosis in neural progenitor cells through a p53-dependent pathwayModulation of Notch signaling by mastermind-like (MAML) transcriptional co-activators and their involvement in tumorigenesisNotch signaling and cancer-emerging complexityRegulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cellsNotch-1 Regulates Cell Death IndependentlyNotch1 competes with the amyloid precursor protein for gamma-secretase and down-regulates presenilin-1 gene expressionNotch signaling regulates left-right asymmetry determination by inducing Nodal expressionNotch Signaling Induces Multilineage Myeloid DifferentiationNotch signaling in development and diseaseNotch signaling controls multiple steps of pancreatic differentiationNotch signaling and inherited disease syndromesNotch oncoproteins depend on gamma-secretase-presenilin activity for processing and functionMODULATION OF NOTCH SIGNALING DURING SOMITOGENESISThe anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt-PKB-mediated signaling in T cellsTCR-Mediated Notch Signaling Regulates Proliferation and IFN-Production in Peripheral T CellsT cell lineage commitment and peripheral T cell responses by Notch-RBP-JSurface expression of Notch1 on thymocytesNotch signaling is necessary but not sufficient for differentiation of dendritic cellsNotch signaling in T-and B-cell developmentNotch 1 signaling regulates peripheral T cell activationInhibition of Notch signaling biases rat thymocyte development towards the NK cell lineageGrowth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch SignalingCombined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloidHES and HERP families-multiple effectors of the Notch signaling pathwayEvidence that C promoter-binding factor 1 binding is required for Notch-1-mediated repression of activator protein-1Direct regulation of the Nrarp gene promoter by the Notch signaling pathwayDelta-Notch signaling regulates oligodendrocyte specificationDelta-Notch signaling controls the generation of neurons-glia from neural stem cellsVascular expression of Notch pathway receptors and ligands is restricted to arterial vesselsNotch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and-independent pathwaysNotch Signaling in Vascular DevelopmentNotch function in the vasculatureNotch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformationNotch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migrationMouse Fbw7-Sel-10-Cdc4 is required for notch degradation during vascular developmentMolecular control of arterial-venous blood vessel identityDefective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box proteinCalcineurin signaling and NFAT activation in cardiovascularCrystal structure of the nuclear effector of Notch signaling, CSL, bound to DNAcontrol of cell communication and cell fateCoexpression of Cux-1 and notch signaling pathway components during kidney developmentThe Notch signaling cascade in neuroblastomaNotch signaling as a therapeutic targetNotch signaling as a therapeutic targeNotch signaling as a therapeutic targettMultiple niches for Notch in cancerjohnson88 wrote:有没有关于说notch1-4结构的文章，主要的几个胞内damain,有的话和我们分享！！谢谢下面这张图是人的notch1-4受体的结构 （缩略图，点击图片链接看原图）这张是对应的基因 （缩略图，点击图片链接看原图）在动物的发育过程中涉及极其复杂的信号转导过程，除了前面几节提到的信号途径以外，还有可控性蛋白水解相关的信号途径，如Wnt、Hedgehog、Notch、NF-κB等信号途径，这些信号途径往往影响相邻细胞的分化，称为侧向信号发放（lateral signaling）。一、Wnt信号途径Wnt是一类分泌型糖蛋白，通过自分泌或旁分泌发挥作用。在小鼠中，肿瘤病毒整合在Wnt之后而导致乳腺癌，命名为Int1，它与果蝇的无翅基因（Wingless，wg）有高度同源性。Wnt信号途径能引起胞内β-连锁蛋白（β-catenin）积累。β-catenin（在果蝇中叫做犰狳蛋白Armadillo）是一种多功能的蛋白质，在细胞连接处它与钙粘素相互作用，参与形成粘合带，而游离的β-catenin可进入细胞核，调节基因表达。Wnt信号在动物发育中起重要作用，其异常表达或激活能引起肿瘤。Wnt的受体是卷曲蛋白（frizzled，Frz），为7次跨膜蛋白，结构类似于G蛋白偶联型受体，Frz胞外N端具有富含半胱氨酸的结构域（cysteine rich domain，CRD），能与Wnt结合。Frz作用于胞质内的蓬乱蛋白（Dishevelled，Dsh或Dvl），Dsh能切断β-catenin的降解途径，从而使β-catenin在细胞质中积累，并进入细胞核，与T细胞因子（T cell factor / lymphoid enhancer factor，TCF/LEF）相互作用，调节靶基因的表达，TCF/ LEF是一类具有双向调节功能的转录因子，它与Groucho结合抑制基因转录，而与结合β-catenin则促进基因转录。Wnt还需要另外一个受体（co-receptor），即LRP5/6，属于低密度脂蛋白受体相关蛋白（LDL-receptor-related protein，LRP），但至今还不清楚它如何与Frz一起活化Dsh。 图8-34 Wnt信号途径 引自Johan H. van ES 2003Wnt信号途径可概括为（图8-34）：Wnt→Frz→Dsh→β-catenin的降解复合体解散→β-catenin积累，进入细胞核→TCF/LEF→基因转录（如c-myc、cyclinD1）。β-catenin的降解复合体：主要由APC、Axin、GSK-3β、CK1等构成。GSK-3β：是一种蛋白激酶，在没有Wnt信号时，GSK-3β能将磷酸基团加到β-catenin氨基端的丝氨酸/苏氨酸残基上，磷酸化的β-catenin再结合到β-TRCP蛋白上[7]，受泛素[8]的共价修饰，被蛋白酶体（proteasome）降解。β-catenin中被GSK3磷酸化的氨基酸序列称为破坏盒（destruction box），此序列发生变异可能引起某些癌症。CK1：酪蛋白激酶（casein kinase 1），能将β-catenin的Ser45磷酸化，随后GSK-3β将β-catenin的Thr41、Ser37、Ser33磷酸化（图8-35）。 图8-35 β-catenin的磷酸化 引自Johan H. van ES 2003APC：是一种抑癌基因，其突变引起良性肿瘤——结肠腺瘤样息肉（adenomatous polyposis coli），但随着时间的推移，可能发生恶变。APC蛋白的作用是增强降解复合体与β-catenin的亲和力。Axin：是一种支架蛋白，具有多个与其它蛋白作用的位点，能将APC、GSK-3β、β-catenin、CK1结合在一起。此外它还能与Dishevelled、PP2A（protein phosphatase 2A）等成分结合，其中Dsh与Axin结合能使降解复合体解体。PP2A可能引起Axin去磷酸化，而使降解复合体解体，因此属于Wnt途径的正调控因子，但PP2A至少由催化亚基和调节亚基两部分构成，其调节亚基仍算作是抑癌基因。Wnt信号途径的其它成分：GBP：GSK-3β结合蛋白（Frat基因的产物），对Wnt信号途径起正调控作用，GBP/Frat抑制GSK3-β的活性。Dickkopf1（DKK1）：是一种分泌蛋白，其与Wnt受体LRP5/6及另一类穿膜蛋白Kremen1/2结合，形成三聚体，诱导快速的细胞内吞，减少细胞膜上的LRP5/6，由此阻断了Wnt信号向胞内的传递。sFRP：分泌型Frz相关蛋白（secreted frizzled-related proteins），含有一个CRD结构域，但缺少七次跨膜域，它可能与Frz竞争结合Wnt蛋白。其他的抑制蛋白还有Sizzled、WIF-1和Cerberus，它们也直接与Wnt蛋白结合，从而拮抗Wnt信号。二、Notch信号途径Notch基因最早发现于果蝇，部分功能缺失导致翅缘缺刻（notches，图8-36）。在胚胎发育中，当上皮组织的前体细胞中分化出神经元细胞后，其细胞表面Notch配体Delta与相邻细胞膜上的Notch结合，启动信号途径，防止其它细胞发生同样的分化，这种现象叫作侧向抑制（lateral inhibition）。Notch突变的半合子[9]或纯合子在胚胎期死亡，其胚胎中神经组织取代了上皮组织从而使神经组织异常丰富。 图8-36 Notch缺陷引起果蝇翅缘缺刻Notch信号途径由Notch、Notch配体（DSL蛋白）和CSL（一类DNA结合蛋白）等组成。Notch及其配体均为单次跨膜蛋白，当配体（如Delta）和相邻细胞的Notch结合后，Notch被蛋白酶体切割，释放出具有核定位信号的胞质区ICN（intracellular domain of Notch），进入细胞核与CLS结合，调节基因表达。可概括为（图8-37）：Delta→Notch→酶切→ICN→进入细胞核→CLS-ICN复合体→基因转录。Notch：为分子量约300KD的蛋白质，果蝇只有1个Notch基因，人类4个（Notch1-4）。Notch的胞外区是结合配体的区域，具有不同数量的EGF样重复序列（EGF-R）和3个LNR（Lin/Notch repeats）。胞内区由RAM（RBP-J kappa associated molecular）结构域、6个锚蛋白（cdc10/ankyrin，ANK）重复序列、2个核定位信号[10]（NLS）和PEST结构域。RAM结构域是与CSL结合的区域，PEST结构域与Notch的降解有关。Notch蛋白要经过三次切割，第一次在高尔基体内被furin切割为2个片断，转运到细胞膜形成异二聚体。当配体结合到胞外区，Notch蛋白又发生两次断裂，先是被肿瘤坏死因子-α-转化酶（TNF-α-converting enzyme，TACE）切割，然后被γ-促分泌酶（γ-secretase）切割，后者需要早老蛋白（presenilin，PS）参与。酶切以后释放Notch胞内区ICN，进入细胞核发挥生物学作用。Notch配体：在果蝇中Notch个配体为Delta和Serrate，线虫为Lag-2，取首写字母，Notch的配体又被称为DSL蛋白（在哺乳动物中叫做Jagged），都是单次跨膜糖蛋白，其胞外区含有数量不等的EGF样重复区，N端有一个结合Notch体必需的DSL基序。CSL：为转录因子，在哺乳动物中叫做CBF1，在果蝇中叫做Suppressor of Hairless，在线虫中叫做Lag-1，故名。CSL能识别并结合特定的DNA序列（GTGGGAA），这个序列位于Notch诱导基因的启动子上。ICN不存在时，CSL为转录抑制因子。当结合ICN时，CSL能诱导相关基因的表达。Notch信号的靶基因多为碱性螺旋-环-螺旋类转录因子（basic helix-loop-helix，bHLH），它们又调节其它与细胞分化直接相关的基因的转录。如哺乳动物中的HES（hairy/ enhancer of split）、果蝇中的E（spl） （enhancer of split）及非洲爪蟾中的XHey-1等。 图8-37 Notch信号途径三、Hedgehog信号途径Hedgehog是一种共价结合胆固醇的分泌性蛋白，在动物发育中起重要作用。果蝇的该基因突变导致幼虫体表出现许多刺突，形似刺猬，故名Hedgehog。脊椎动物中至少有3个基因编码Hedgehog蛋白，即：Shh（Sonic hedgehog）、Ihh（Indian hedgehog）和Dhh（desert hedgehog），其中Shh是根据电子游戏中的角色命名的，后两者是用刺猬的两个种命名的。两个跨膜蛋白Patched（Ptc）和Smoothened（Smo）介导Hedgehog信号向胞内传递。Ptc是12次跨膜蛋白，能与Hedgehog结合；Smo为7次跨膜蛋白，与G蛋白偶联型受体同源。在无Hedgehog的情况下，Ptc抑制Smo。当Hedgehog与Ptc结合时，则解除了Ptc对Smo的抑制作用，引发下游事件（图8-38）。Hedgehog信号途径的转录因子是Ci（Cubitus interruptus，在脊椎动物中为Gli），具有锌指结构，分子量155KD。在胞质中Ci与其它蛋白形成复合体，这些蛋白包括：Fu（Fused，一种丝氨酸/苏氨酸激酶）、Cos（Costal，一种能将复合体锚定在微管上的蛋白）和Su（suppressor of Fused，适配蛋白）。在没有Hedgehog信号时，Ci被水解为75KD的片段，进入细胞核，抑制Hedgehog信号响应基因。当Hedgehog与Ptc结合时，Ci的降解被抑制，从复合体中释放出来，全长的Ci进入细胞核中，启动相关基因表达，这些基因包括Wnt和Ptc。Ptc的表达，又会抑制Smo，从而抑制Hedgehog信号，是一种反馈调节。 图8-38 Hedgehog信号途径 引自Kent Nybakken、Norbert Perrimon 2002四、NF-κB信号途径NF-κB是属于Rel家族的转录因子，参与调节与机体免疫、炎症反应、细胞分化有关的基因转录。哺乳动物细胞中有五种NF-κB/Rel：RelA(P65)，RelB，C-Rel，NF-κB1(P50)、NF-κB2(P52)，都具有Rel同源区(Rel homology domain，RHD)，能形成同或异二聚体，启动不同的基因转录。静息状态下，NF-κB二聚体与抑制蛋白IκB结合成三聚体而被隐蔽于细胞质，胞外刺激可激活IκB的泛素化降解途径，而使NF–κB二聚体进入胞核，调节基因转录。IκB家族成员有IκBα，IκBβ，IκBγ，IκBδ，IκBε，Bcl-3等，都具有与Rel蛋白相互作用的锚蛋白重复序列和与降解有关的C端PEST序列。IKK(IκB kinases)是NF-κB信号传导通路的关键性激酶。胞外信号如：肿瘤坏死因子α（tumor necrosis factor，TNF）、白介素1(interleukin-1，IL-1)等可以激活IKK，使IκB磷酸化，随后被泛素化途径降解。________________________________________[7]泛素连接酶E3的组成成分。[8] 由76个氨基酸组成，高度保守。共价结合泛素的蛋白质能被蛋白酶体识别和降解，这是细胞内短寿命蛋白和一些异常蛋白降解的普遍途径。[9]半合子（hemizygote），虽然是二倍体，但一个或多个基因是单价的，没有与之相对应的等位基因。[10] Nuclear localization signal，一段信号序列，可引导蛋白质进入细胞核。大家都是牛人啊===佩服佩服!!!!!!!收益非浅高手云集！Notch信号通路作用复杂，同样是在Nature系列杂志2003年分别证实Notch1是癌基因和抑癌基因。纵观现在关于Notch和肿瘤的文章，大多倾向于是癌基因，但也有一些文章相继报道发挥抑癌基因的作用，其在特定的组织中发挥作用是由组织自身决定的Notch在神经干细胞中的作用研究也很多，上传一篇综述 Notch信号通路与神经干细胞的增殖分化.part1.rar (195.31k)Notch信号通路与神经干细胞的增殖分化.part2 Notch信号通路与神经干细胞的增殖分化.part2.rar (174.99k)传统上大家认为Notch信号具有抑制神经干细胞分化的作用，近来研究表明其在神经干细胞向胶质细胞分化也发挥作用。 Notch signalling You make me feel so glial.pdf (58.02k)转Notch基因造血干细胞FTOC器官培养定向诱导分化对T淋巴细胞命运的决定及其机制 （曾经做的一个ppt) 新建 Microsoft PowerPoint 演示文稿.ppt (81.0k)