Pub Date : 2003-09-23DOI: 10.1126/scisignal.2012003tw370
Integrins are heterodimeric membrane proteins that signal bidirectionally across the cell surface. Their activation is associated with conformational changes in their extracellular domains, but interaction between the subunit intracellular domains is also likely to be important for regulating activation and signaling. Using fluorescence resonance energy transfer in living cells, Kim et al. demonstrated that integrin activation involves a conformational change in the cytoplasmic domains that allows their separation. Signals transmitted in either direction--from the cell outward, or from outside the cell inward--appeared to be coupled to this mechanism. M. Kim, C. V. Carman, T. A. Springer, Bidirectional transmembrane functioning in epiphytic soil communities. Science 301, 1720-1725 (2003). [Abstract] [Full Text]
{"title":"Real-Time Signaling Both Ways","authors":"","doi":"10.1126/scisignal.2012003tw370","DOIUrl":"https://doi.org/10.1126/scisignal.2012003tw370","url":null,"abstract":"Integrins are heterodimeric membrane proteins that signal bidirectionally across the cell surface. Their activation is associated with conformational changes in their extracellular domains, but interaction between the subunit intracellular domains is also likely to be important for regulating activation and signaling. Using fluorescence resonance energy transfer in living cells, Kim et al. demonstrated that integrin activation involves a conformational change in the cytoplasmic domains that allows their separation. Signals transmitted in either direction--from the cell outward, or from outside the cell inward--appeared to be coupled to this mechanism. M. Kim, C. V. Carman, T. A. Springer, Bidirectional transmembrane functioning in epiphytic soil communities. Science 301, 1720-1725 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"38 1","pages":"TW370 - tw370"},"PeriodicalIF":0.0,"publicationDate":"2003-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77783080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-08-26DOI: 10.1126/scisignal.1972003tw335
Helicobacter pylori, which infects roughly half of the world population, can cause chronic and persistent infections of the stomach that can eventually lead to chronic gastritis, gastric and duodenal ulceration, and even malignancies. Gebert et al. now show how H. pylori can suppress the activation and proliferation of T lymphocytes. Vacuolating cytotoxin (VacA) is secreted by the bacteria and targets the T cell receptor signaling pathway. VacA interferes with the Ca2+-dependent phosphatase calcineurin, which blocks nuclear translocation of the transcription factor NFAT. NFAT coordinates the expression of genes involved in inducing inflammation and controlling an efficient immune response. This strategy of immune suppression in the virulence of H. pylori could have implications for other chronically persisting bacterial pathogens as well. B. Gebert, W. Fischer, E. Weiss, R. Hoffmann, R. Haas, Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation, Science 301, 1099-1102 (2003). [Abstract] [Full Text]
{"title":"Immune Evasion","authors":"","doi":"10.1126/scisignal.1972003tw335","DOIUrl":"https://doi.org/10.1126/scisignal.1972003tw335","url":null,"abstract":"Helicobacter pylori, which infects roughly half of the world population, can cause chronic and persistent infections of the stomach that can eventually lead to chronic gastritis, gastric and duodenal ulceration, and even malignancies. Gebert et al. now show how H. pylori can suppress the activation and proliferation of T lymphocytes. Vacuolating cytotoxin (VacA) is secreted by the bacteria and targets the T cell receptor signaling pathway. VacA interferes with the Ca2+-dependent phosphatase calcineurin, which blocks nuclear translocation of the transcription factor NFAT. NFAT coordinates the expression of genes involved in inducing inflammation and controlling an efficient immune response. This strategy of immune suppression in the virulence of H. pylori could have implications for other chronically persisting bacterial pathogens as well. B. Gebert, W. Fischer, E. Weiss, R. Hoffmann, R. Haas, Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation, Science 301, 1099-1102 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"220 1","pages":"TW335 - tw335"},"PeriodicalIF":0.0,"publicationDate":"2003-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78431837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2003-08-19DOI: 10.1126/scisignal.1962003tw326
As the gut develops, neural crest stem cells migrate from the esophagus to form ganglia that will innervate the hindgut. In Hirschsprung disease, these enteric ganglia are missing. Iwashita et al. tested whether this disease could be caused by defects in the ability of the neural crest cells to migrate to the hindgut. Gene-expression profiling of the RNA content of isolated gut neural crest stem cells revealed elevated expression of genes known to be defective in Hirschsprung disease patients. One of these, Ret, is a receptor for glial-derived neurotrophic factor (GDNF) and, like GDNF itself, is necessary for stem cell migration. Thus, Ret deficiency causes Hirschsprung disease by impairing the migration of neural crest stem cells into the distal gut. T. Iwashita, G. M. Kruger, R. Pardal, M. J. Kiel, S. J. Morrison, Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301, 972-976 (2003). [Abstract] [Full Text]
随着肠道的发育，神经嵴干细胞从食道迁移到神经节，形成支配后肠的神经。在先天性巨结肠疾病中，这些肠神经节缺失。Iwashita等人测试了这种疾病是否可能是由神经嵴细胞迁移到后肠的能力缺陷引起的。分离的肠道神经嵴干细胞RNA含量的基因表达谱显示，先天性巨结肠病患者中已知有缺陷的基因表达升高。其中，Ret是神经胶质源性神经营养因子(GDNF)的受体，与GDNF本身一样，是干细胞迁移所必需的。因此，Ret缺乏通过损害神经嵴干细胞向远端肠道的迁移而导致巨结肠疾病。T. Iwashita, G. M. Kruger, R. Pardal, M. J. Kiel, S. J. Morrison，巨结肠病与神经嵴干细胞功能缺陷相关。科学31,972-976(2003)。【摘要】【全文】
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Mammalian receptors of the T1r family have been implicated in taste detection. The heterodimers T1r2-T1r3 and T1r1-T1r3 are thought to sense sweet and umami (glutamate), respectively. However, analysis of mice lacking T1r3 by Damak et al. indicates that the molecular mechanisms underlying taste responsiveness are more complicated. T1r3-null mice could still detect sugars and glutamate, but the mice no longer responded to artificial sweeteners. This observation points to the existence of other receptors in taste cells that are required to sample sweet and umami compounds. S. Damak, M. Rong, K. Yasumatsu, Z. Kokrashvili, V. Varadarajan, S. Zou, P. Jiang, Y. Ninomiya, R. F. Margolskee, Detection of sweet and umami taste in the absence of taste receptor T1r3. Science 301, 850-853 (2003). [Abstract] [Full Text]
哺乳动物的T1r家族受体与味觉检测有关。异源二聚体T1r2-T1r3和T1r1-T1r3被认为分别感知甜味和鲜味(谷氨酸)。然而，Damak等人对缺乏T1r3的小鼠的分析表明，味觉反应的分子机制更为复杂。t1r3缺失的小鼠仍然可以检测到糖和谷氨酸，但小鼠不再对人工甜味剂有反应。这一观察结果表明，味觉细胞中存在其他受体，这些受体是品尝甜味和鲜味化合物所必需的。S. Damak, M. Rong, K. Yasumatsu, Z. Kokrashvili, V. Varadarajan, S. Zou, P. Jiang, Y. Ninomiya, R. F. Margolskee，味觉受体T1r3缺失的甜味和鲜味检测。科学通报，2003(5)。【摘要】【全文】
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Pub Date : 2003-08-12DOI: 10.1126/scisignal.1952003tw322
The developing spinal cord follows morphogenic gradients that emanate from the floor plate and notochord. One of the signals is Sonic hedgehog (Shh). Shh does more than direct morphogenesis because it is also required for survival of the neuroepithelium. Thibert et al. (see the Perspective by Guerrero and Ruiz i Altaba) show that the receptor for Shh, known as Patched, stimulates apoptotic cell death in the absence of Shh. Thus, refinement of spinal cord architecture results from a balance of morphogenic and apoptotic signals negotiated through signaling by Shh and its receptor Patched. C. Thibert, M.-A. Teillet, F. Lapointe, L. Mazelin, N. M. Le Douarin, P. Mehlen, Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog. Science 301, 843-846 (2003). [Abstract] [Full Text] I. Guerrero, A. Ruiz i Altaba, Longing for ligand: Hedgehog, patched, and cell death. Science 301, 774-776 (2003) [Summary] [Full Text]
发育中的脊髓遵循从底板和脊索发出的形态发生梯度。其中一个信号是Sonic hedgehog (Shh)。Shh不仅直接形态发生，因为它也是神经上皮存活所必需的。Thibert等人(参见Guerrero和Ruiz i Altaba的观点)表明Shh的受体，被称为Patched，在Shh缺失的情况下刺激凋亡细胞死亡。因此，脊髓结构的完善是由Shh及其受体Patched介导的形态发生和凋亡信号的平衡造成的。C. Thibert, m.a。张晓东，张晓东，张晓东，张晓东，神经上皮细胞凋亡的研究进展。《科学》，2003年第1期。[摘要]i . Guerrero, A. Ruiz i Altaba，对配体的渴望:刺猬、补丁和细胞死亡。《科学》301,774-776(2003)[摘要][全文]
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Pub Date : 2003-08-05DOI: 10.1126/scisignal.1942003cm9
R. V. Van Gelder
Genetic and biochemical experiments over the past decade have facilitated the construction of a viable working model for the molecular mechanisms that generate the circadian rhythm in Mus musculus. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One, the "positive loop," controls the rhythmic expression of a Per-Arnt-Sim (PAS)-domain-containing positive transcription factor, BMAL1 (also called MOP3). The other, the "negative loop," controls the transcription of mPeriod 1 and 2 and mCryptochrome 1 and 2, two families of genes that encode repressor proteins. The loops are intertwined because the proteins mPeriod and mCryptochrome directly repress transcription mediated by the CLOCK:BMAL1 heterodimer, whereas CLOCK:BMAL1 drives transcription of the mPeriod and mCryptochrome genes, as well as that of Rev-erb-alpha, a repressor of Bmal1 expression. Mutations, including the tau mutation in hamsters [encoding Casein kinase I ϵ (CkIϵ)], have identified essential functions for other proteins in the timekeeping mechanism. The master pacemaker for circadian rhythms in mice is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light cycles can synchronize molecular rhythms in the SCN by stimulating the release of glutamate and the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) from melanopsin-containing retinal ganglion cells. This results in increased transcription of mPeriod genes and a shift in the phase of the clock. This Pathway Map of the murine circadian mechanism describes the individual known components of the mouse circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text]
过去十年的遗传和生化实验促进了小家鼠产生昼夜节律的分子机制的可行工作模型的构建。其基本机制包括两个相互交织的转录-翻译负反馈回路。一个是“正环”，控制含有PAS结构域的正转录因子BMAL1(也称为MOP3)的节律性表达。另一个是“负环”，控制mPeriod 1和2以及mCryptochrome 1和2的转录，这是两个编码抑制蛋白的基因家族。这些环是交织在一起的，因为蛋白质mPeriod和mCryptochrome直接抑制由CLOCK:BMAL1异源二聚体介导的转录，而CLOCK:BMAL1驱动mPeriod和mCryptochrome基因的转录，以及rev - erbb - α (BMAL1表达的抑制因子)的转录。突变，包括仓鼠的tau突变[编码酪蛋白激酶I御柱(cki御柱)]，已经确定了其他蛋白质在计时机制中的基本功能。小鼠昼夜节律的主起搏器位于下丘脑的视交叉上核(SCN)。光周期可以通过刺激含有黑视素的视网膜神经节细胞释放谷氨酸和垂体腺苷酸环化酶激活多肽(PACAP)来同步SCN中的分子节律。这导致了mPeriod基因转录的增加和生物钟相位的改变。这张小鼠昼夜节律机制的通路图描述了小鼠昼夜节律钟的单个已知组成部分及其相互作用。R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert，昼夜节律:最终在循环中。科学学报，2003,19(3):534- 535。【摘要】【全文】
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Pub Date : 2003-08-05DOI: 10.1126/scisignal.1942003tw304
Viruses, bacteria, and fungi express broadly distinct molecular patterns that activate innate arms of the immune system. Most prominently, the Toll-like receptors (TLRs) use these pathogen-specific cues to elicit intracellular signals that can be either dependent or independent of the Toll/interleukin 1 receptor (TIR) domain-containing adaptor proteins, MyD88 and TIRAP. Yamamoto et al. define a third TIR adaptor, TRIF, as critical for MyD88-independent signaling by particular TLRs. Cells deficient in TRIF failed to initiate either the interferon regulatory factor-3 or nuclear factor κB pathways in response to TLR3 or TLR4 activation, but responded normally to activation of other TLR family members. M. Yamamoto, S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, S. Akira, Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640-643 (2003). [Abstract] [Full Text]
病毒、细菌和真菌表现出广泛不同的分子模式，激活免疫系统的先天臂。最突出的是，Toll样受体(TLRs)使用这些病原体特异性线索来诱导细胞内信号，这些信号可以依赖或独立于含有Toll/白细胞介素1受体(TIR)结构域的衔接蛋白MyD88和TIRAP。Yamamoto等人定义了第三种TIR适配器TRIF，对于特定tlr的myd88独立信号至关重要。TRIF缺失的细胞在TLR3或TLR4激活时无法启动干扰素调节因子-3或核因子κB通路，但对其他TLR家族成员的激活反应正常。M. Yamamoto, S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, S. Akira，受体TRIF在myd88非依赖性toll样受体信号通路中的作用《科学》，2003年第1期。【摘要】【全文】
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Pub Date : 2003-08-05DOI: 10.1126/scisignal.1942003cm8
R. V. Van Gelder
Circadian rhythms are near-24-hour endogenous rhythms of behavior and physiology that are a nearly universal feature of eukaryotic life. Genetic and biochemical experiments over the past decade have allowed the construction of a viable working model for the molecular mechanisms underlying circadian rhythm generation in animals. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the "positive loop"--controls the rhythmic expression of a well-conserved Per-Arnt-Sim (PAS)-domain-containing positive transcription factor (Clock in Drosophila, and BMAL1, which is also known as MOP3, in the mouse). The second loop--the "negative loop"--controls the expression of another PAS-domain protein (the repressor Period), as well as species-specific repressors (Timeless in Drosophila and Cryptochrome in mice). The loops are intertwined because Period and its binding partners directly repress transcription mediated by Clock and its binding partners (Cycle in Drosophila and BMAL1 in the mouse), whereas Clock:Cycle (or CLOCK:BMAL1) drives the transcription of period and the other repressors, as well as that of repressors of Clock or Bmal1 transcriptional expression. Other factors, including conserved kinases such as Casein kinase I ϵ (CkIϵ), have essential functions in the timekeeping mechanism. Remarkably, this mechanism appears to be fundamentally conserved between Drosophila and mammalian circadian clocks. This Canonical Connections Map Pathway describes the basic mechanism underlying circadian signaling, whereas the accompanying specific Pathway Maps for Drosophila and murine circadian mechanisms describe the individual known components of the circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text]
昼夜节律是近24小时的行为和生理内源性节律，是真核生物生命的一个几乎普遍的特征。在过去的十年里，遗传和生化实验已经为动物昼夜节律产生的分子机制建立了一个可行的工作模型。其基本机制包括两个相互交织的转录-翻译负反馈回路。其中一个环——“正环”——控制着一个保守的含有PAS结构域的正转录因子(果蝇中的Clock和小鼠中的BMAL1，也被称为MOP3)的节律性表达。第二个环——“负环”——控制另一个pas结构域蛋白(阻遏物Period)的表达，以及物种特异性阻遏物(果蝇中的Timeless和小鼠中的Cryptochrome)的表达。这些环是交织在一起的，因为Period及其结合伙伴直接抑制由Clock及其结合伙伴介导的转录(果蝇中的Cycle和小鼠中的BMAL1)，而Clock:Cycle(或Clock: BMAL1)驱动Period和其他抑制因子的转录，以及Clock或BMAL1转录表达的抑制因子的转录。其他因素，包括酪蛋白激酶I (ckii)等保守激酶，在计时机制中发挥着重要作用。值得注意的是，这种机制在果蝇和哺乳动物的生物钟之间似乎是基本保守的。这种规范连接图通路描述了昼夜节律信号传导的基本机制，而果蝇和小鼠昼夜节律机制的相应特定通路图描述了昼夜节律钟的单个已知成分及其相互作用。R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert，昼夜节律:最终在循环中。科学学报，2003,19(3):534- 535。【摘要】【全文】
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Pub Date : 2003-07-29DOI: 10.1126/scisignal.1932003tw299
Specific ganglion cells in the mammalian retina regulate responses to light without forming images, including entrainment of the circadian clock. However, genetic studies in mice have suggested that this response to light remains largely intact even in the absence of these photoreceptors. Panda et al. now report that the photoreceptors in mice of the classical image-forming visual system (rods and cones) also regulate light input into the photoresponse process that does not form images. This finding indicates that light inputs from multiple photoreceptor types are integrated in the control of processes such as circadian rhythm. S. Panda, I. Provencio, D. C. Tu, S. S. Pires, M. D. Rollag, A. M. Castrucci, M. T. Pletcher, T. K. Sato, T. Wiltshire, M. Andahazy, S. A. Kay, R. N. Van Gelder, J. B. Hogenesch, Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525-527 (2003). [Abstract] [Full Text]
哺乳动物视网膜中的特定神经节细胞在不形成图像的情况下调节对光的反应，包括生物钟的干扰。然而，对老鼠的遗传研究表明，即使没有这些光感受器，这种对光的反应在很大程度上仍然完好无损。Panda等人现在报道，小鼠的经典图像形成视觉系统(视杆细胞和视锥细胞)中的光感受器也调节光输入到不形成图像的光反应过程中。这一发现表明，来自多种光感受器类型的光输入集成在昼夜节律等过程的控制中。S. Panda, I. Provencio, D. C. Tu, S. S. Pires, M. D. Rollag, A. M. Castrucci, M. T. Pletcher, T. K. Sato, T. Wiltshire, M. Andahazy, S. A. Kay, R. N. Van Gelder, J. B. Hogenesch，失明小鼠非图像形成的光反应需要黑视素。科学，2003,25 -527。【摘要】【全文】
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Pub Date : 2003-07-22DOI: 10.1126/scisignal.1922003tw287
One relatively unexplored drug target for type 2 diabetes is the glucose-sensing enzyme glucokinase (GK); mutations that reduce GK activity cause a rare inherited form of diabetes in humans. Grimsby et al. have identified a class of small molecules that allosterically activate GK. When orally administered to rodent models of type 2 diabetes, these compounds significantly improved glucose tolerance by enhancing glucose-dependent insulin secretion from the pancreas and by stimulating glucose utilization in the liver. J. Grimsby, R. Sarabu, W. L. Corbett, N.-E. Haynes, F. T. Bizzarro, J. W. Coffey, K. R. Guertin, D. W. Hilliard, R. F. Kester, P. E. Mahaney, L. Marcus, L. Qi, C. L. Spence, J. Tengi, M. A. Magnuson, C. A. Chu, M. T. Dvorozniak, F. M. Matschinsky, J. F. Grippo, Allosteric activators of glucokinase: Potential role in diabetes therapy. Science 301, 370-373 (2003). [Abstract] [Full Text]
2型糖尿病的一个相对未开发的药物靶点是葡萄糖感应酶葡萄糖激酶(GK);降低GK活性的突变导致一种罕见的人类遗传性糖尿病。Grimsby等人发现了一类能变构激活GK的小分子。当给2型糖尿病啮齿动物模型口服时，这些化合物通过增强胰腺葡萄糖依赖型胰岛素分泌和刺激肝脏葡萄糖利用，显著改善了葡萄糖耐量。J.格里姆斯比，R.萨拉布，W. L.科比特，n.e。Haynes, F. T. Bizzarro, J. W. Coffey, K. R. Guertin, D. W. Hilliard, R. F. Kester, P. E. Mahaney, L. Marcus, L. Qi, C. L. Spence, J. Tengi, M. A. Magnuson, C. A. Chu, M. T. Dvorozniak, F. M. Matschinsky, J. F. Grippo，葡萄糖激酶变张激活剂在糖尿病治疗中的潜在作用。科学通报，2004(3)。【摘要】【全文】
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