Pub Date : 2002-12-03DOI: 10.1126/scisignal.1612002tw449
Rapizzi et al. have demonstrated that the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane plays an important role in transmitting Ca2+ signals from the endoplasmic reticulum (ER) to the mitochondria. Recent research indicates that mitochondria respond to localized increases in the concentration of free intracellular Ca2+ ([Ca2+]i) near release sites in the ER by increasing mitochondrial Ca2+ concentrations ([Ca2+]m), a response that may be important in limiting bulk changes in [Ca2+]i and in eliciting changes in mitochondrial function. The specific mechanisms whereby localized Ca2+ signaling between ER and mitochondria occurs, however, and the identity of the molecules involved, have remained unclear. Using aequorin derivatives and Ca2+-sensitive green fluorescent protein (GFP) derivatives specifically targeted to the mitochondria or ER, Rapizzi et al. showed that overexpression of tagged VDACs enhanced histamine-stimulated increases in [Ca2+]m in HeLa cells and carbachol-stimulated increases in [Ca2+]m in skeletal myotubes dependent on Ca2+ release from ER stores, without changing Ca2+ handling by the ER or mitochondrial Ca2+ uptake in HeLa cells permeabilized with digitonin. Experiments with targeted aequorin derivatives with different Ca2+ binding affinities, together with immunocytochemical analyses of the spatial relationship among ER, VDAC, and mitochondria, suggested that VDAC overexpression enhanced mitochondrial Ca2+ permeability at ER-mitochondrial contact sites without expanding the area of contact. HeLa cells overexpressing VDACs showed increased sensitivity to ceramide-induced alterations in mitochondrial morphology and cell death, which suggests an important functional role for VDAC-mediated increases in [Ca2+]m in apoptosis. E. Rapizzi, P. Pinton, G. Szabadkai, M. R. Wieckowski, G. Vandecasteele, G. Baird, R. A. Tuft, K. E. Fogarty, R. Rizzuto, Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J. Cell Biol. 159, 613-624 (2002). [Abstract] [Full Text]
Rapizzi等人已经证明，线粒体外膜的电压依赖性阴离子通道(VDAC)在将Ca2+信号从内质网(ER)传递到线粒体中起着重要作用。最近的研究表明，线粒体通过增加线粒体Ca2+浓度([Ca2+]m)来响应内质网释放位点附近游离细胞内Ca2+ ([Ca2+]i)浓度的局部增加，这一反应可能对限制[Ca2+]i的大量变化和引发线粒体功能的变化很重要。然而，内质网和线粒体之间发生局部Ca2+信号的具体机制以及所涉及的分子的身份仍不清楚。Rapizzi等人利用aequorin衍生物和专门针对线粒体或内质网的Ca2+敏感绿色荧光蛋白(GFP)衍生物表明，标记的VDACs过表达增强了HeLa细胞中组胺刺激的[Ca2+]m的增加，以及依赖于内质网Ca2+释放的骨骼肌管中碳水酚刺激的[Ca2+]m的增加，而不改变内质网对Ca2+的处理或线粒体对洋地黄苷渗透的HeLa细胞中Ca2+摄取。利用具有不同Ca2+结合亲和力的靶向aqorin衍生物进行的实验，以及对ER、VDAC和线粒体之间空间关系的免疫细胞化学分析表明，VDAC过表达增强了ER-线粒体接触部位的线粒体Ca2+通透性，而不会扩大接触面积。过表达vdac的HeLa细胞对神经酰胺诱导的线粒体形态改变和细胞死亡的敏感性增加，这表明vdac介导的[Ca2+]m增加在细胞凋亡中起重要的功能作用。E. Rapizzi, P. Pinton, G. Szabadkai, M. R. Wieckowski, G. Vandecasteele, G. Baird, R. A. Tuft, K. E. Fogarty, R. Rizzuto，电压依赖性阴离子通道的重组表达增强Ca2+微域向线粒体的转移。中国生物医学工程学报，2009,32(2):481 - 481。【摘要】【全文】
{"title":"Mitochondrial Voltage-Dependent Anion Channels Implicated in Ca2+ Signaling","authors":"","doi":"10.1126/scisignal.1612002tw449","DOIUrl":"https://doi.org/10.1126/scisignal.1612002tw449","url":null,"abstract":"Rapizzi et al. have demonstrated that the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane plays an important role in transmitting Ca2+ signals from the endoplasmic reticulum (ER) to the mitochondria. Recent research indicates that mitochondria respond to localized increases in the concentration of free intracellular Ca2+ ([Ca2+]i) near release sites in the ER by increasing mitochondrial Ca2+ concentrations ([Ca2+]m), a response that may be important in limiting bulk changes in [Ca2+]i and in eliciting changes in mitochondrial function. The specific mechanisms whereby localized Ca2+ signaling between ER and mitochondria occurs, however, and the identity of the molecules involved, have remained unclear. Using aequorin derivatives and Ca2+-sensitive green fluorescent protein (GFP) derivatives specifically targeted to the mitochondria or ER, Rapizzi et al. showed that overexpression of tagged VDACs enhanced histamine-stimulated increases in [Ca2+]m in HeLa cells and carbachol-stimulated increases in [Ca2+]m in skeletal myotubes dependent on Ca2+ release from ER stores, without changing Ca2+ handling by the ER or mitochondrial Ca2+ uptake in HeLa cells permeabilized with digitonin. Experiments with targeted aequorin derivatives with different Ca2+ binding affinities, together with immunocytochemical analyses of the spatial relationship among ER, VDAC, and mitochondria, suggested that VDAC overexpression enhanced mitochondrial Ca2+ permeability at ER-mitochondrial contact sites without expanding the area of contact. HeLa cells overexpressing VDACs showed increased sensitivity to ceramide-induced alterations in mitochondrial morphology and cell death, which suggests an important functional role for VDAC-mediated increases in [Ca2+]m in apoptosis. E. Rapizzi, P. Pinton, G. Szabadkai, M. R. Wieckowski, G. Vandecasteele, G. Baird, R. A. Tuft, K. E. Fogarty, R. Rizzuto, Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J. Cell Biol. 159, 613-624 (2002). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"47 1","pages":"tw449 - tw449"},"PeriodicalIF":0.0,"publicationDate":"2002-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87451692","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 : 2002-11-26DOI: 10.1126/scisignal.1602002tw446
Bacteria lack rigid cell walls and must respond rapidly to salt-induced gradients in osmotic pressure. In Escherichia coli, the mechanosensitive channel proteins MscL and MscS open in response to pressure applied perpendicularly to the membrane, which has the effect of pulling laterally on the membrane-embedded proteins. Bass et al. (see the Perspective by Bezanilla and Perozo) provide the crystal structure of MscS and describe how the transmembrane helices might reorient themselves as a result of being pulled sideways. The authors also propose how changes in transmembrane electrical potential might trigger movement of positively charged arginines and voltage-gate the osmolyte flux. R. B. Bass, P. Strop, M. Barclay, D. C. Rees, Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel. Science 298, 1582-1587 (2002). [Abstract] [Full Text] F. Bezanilla, E. Perozo, Force and voltage sensors in one structure. Science 298, 1562-1563 (2002). [Summary] [Full Text]
细菌缺乏坚硬的细胞壁，必须对盐引起的渗透压梯度迅速作出反应。在大肠杆菌中，机械敏感通道蛋白MscL和MscS在垂直施加于膜的压力下打开，这对膜上的蛋白具有横向拉力的作用。Bass等人(见Bezanilla和Perozo的观点)提供了MscS的晶体结构，并描述了跨膜螺旋如何在被拉向一侧时重新定位自己。作者还提出了跨膜电位的变化如何触发带正电的精氨酸的运动和渗透液通量的电压闸。R. B. Bass, P. Strop, M. Barclay, D. C. Rees，大肠杆菌MscS的晶体结构，电压调制和机械敏感通道。科学通报，29(2002)。[摘要]F. Bezanilla, E. Perozo，一种结构的力和电压传感器。科学29,1562-1563(2002)。【摘要】【全文】
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Pub Date : 2002-11-12DOI: 10.1126/scisignal.1582002tw417
How is specificity gained when numerous genes are regulated by a single transcription factor in response to diverse stimuli? Hoffman et al. (see the Perspective by Ting and Endy) examined how a transcription factor called nuclear factor-κB (NF-κB) is differentially controlled by three different isoforms of an inhibitor protein called IκB. They combined computational modeling with biochemical data that they obtained from genetically engineered cells that express only one IκB isoform. During the cell's exposure to a stimulus, a bimodal and temporal signal processing mechanism determines which IκB-NF-κB pathway and downstream target genes get activated. A. Hoffmann, A. Levchenko, M. L. Scott, D. Baltimore, The IκB-NF-κB signaling module: Temporal control and selective gene activation. Science 298, 1241-1245 (2002). [Abstract] [Full Text] A. Y. Ting, D. Endy, Decoding NF-κB signaling. Science 298, 1189-1190 (2002). [Summary] [Full Text]
{"title":"Picking a Signaling Pathway","authors":"","doi":"10.1126/scisignal.1582002tw417","DOIUrl":"https://doi.org/10.1126/scisignal.1582002tw417","url":null,"abstract":"How is specificity gained when numerous genes are regulated by a single transcription factor in response to diverse stimuli? Hoffman et al. (see the Perspective by Ting and Endy) examined how a transcription factor called nuclear factor-κB (NF-κB) is differentially controlled by three different isoforms of an inhibitor protein called IκB. They combined computational modeling with biochemical data that they obtained from genetically engineered cells that express only one IκB isoform. During the cell's exposure to a stimulus, a bimodal and temporal signal processing mechanism determines which IκB-NF-κB pathway and downstream target genes get activated. A. Hoffmann, A. Levchenko, M. L. Scott, D. Baltimore, The IκB-NF-κB signaling module: Temporal control and selective gene activation. Science 298, 1241-1245 (2002). [Abstract] [Full Text] A. Y. Ting, D. Endy, Decoding NF-κB signaling. Science 298, 1189-1190 (2002). [Summary] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"155 1","pages":"tw417 - tw417"},"PeriodicalIF":0.0,"publicationDate":"2002-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88292059","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 : 2002-11-05DOI: 10.1126/scisignal.1572002tw405
Mark T. Nelson
Within the mitochondria of heart cells, ion channels control the flux of different ions and change the physiological status of the mitochondria, which in turn affect the relative health of the heart cell. Xu et al. now describe the role of a calcium-activated potassium channel in the inner mitochondrial membrane of guinea-pig heart cells in protecting the cells from ischemia. A drug that opened the channel could protect the heart from infarction. W. Xu, Y. Liu, S. Wang, T. McDonald, J. E. Van Eyk, A. Sidor, B. O'Rourke, Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science 298, 1029-1033 (2002). [Abstract] [Full Text]
在心脏细胞的线粒体内，离子通道控制不同离子的通量，改变线粒体的生理状态，进而影响心脏细胞的相对健康。Xu等人现在描述了豚鼠心脏细胞线粒体内膜中钙活化的钾通道在保护细胞免受缺血中的作用。一种打开通道的药物可以防止心脏梗塞。徐伟，刘玉英，王淑娟，王志强，王志强，王志强，王志强，J. E. Van Eyk, A. Sidor, B. O'Rourke，钙离子激活的K+通道在心肌线粒体内膜的细胞保护作用。科学29,1029-1033(2002)。【摘要】【全文】
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Pub Date : 2002-10-29DOI: 10.1126/scisignal.1562002tw397
Interest in alternative preventive strategies against bone loss has intensified in light of the recent announcement of risks associated with hormone replacement therapy. Previous cell culture studies showed that estrogen and androgen protect bone through a mechanism distinct from the DNA-mediated mechanism underlying their effects on reproductive organs. Kousteni et al. now show that a synthetic compound (estren) that mimics these "nongenotropic" effects can increase bone mass in estrogen- or androgen-deficient mice without adverse effects on reproductive organs. S. Kousteni, J.-R. Chen, T. Bellido, L. Han, A. A. Ali, C. A. O'Brien, L. Plotkin, Q. Fu, A. T. Mancino, Y. Wen, A. M. Vertino, C. C. Powers, S. A. Stewart, R. Ebert, A. M. Parfitt, R. S. Weinstein, R. L. Jilka, S. C. Manolagas, Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298, 843-846 (2002). [Abstract] [Full Text]
鉴于最近公布的激素替代疗法的相关风险，对骨质流失的替代预防策略的兴趣已经增强。先前的细胞培养研究表明，雌激素和雄激素通过一种不同于dna介导的机制保护骨骼，这是它们对生殖器官的影响。Kousteni等人现在表明，一种模拟这些“非基因致型”效应的合成化合物(estren)可以增加雌激素或雄激素缺乏小鼠的骨量，而不会对生殖器官产生不利影响。S. Kousteni, j.r。Chen, T. Bellido, L. Han, A. A. Ali, C. A. O'Brien, L. Plotkin, Q. Fu, A. T. Mancino, Y. Wen, A. M. Vertino, C. C. Powers, S. A. Stewart, R. Ebert, A. M. Parfitt, R. S. Weinstein, R. L. Jilka, S. C. Manolagas，性类固醇非基因性信号逆转小鼠骨质流失。科学298,843-846(2002)。【摘要】【全文】
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Pub Date : 2002-10-29DOI: 10.1126/scisignal.1562002tw395
Insulin and other insulin-like growth factors signal through a pathway that involves phosphatidylinositol 3-kinase and the forkhead transcription factors. This pathway is a critical regulator of life-span and reproduction in many organisms. Dillin et al. have now determined that in the nematode Caenorhabditis elegans, life-span can be regulated through this pathway only in the adult and reproduction only in the developmental phases. Thus, the long-standing notion that life-span can be lengthened only at the expense of reproductive fitness is almost certainly false. A. Dillin, D. K. Crawford, C. Kenyon, Timing requirements for Insulin/IGF-1 signaling in C. elegans. Science 298, 830-834 (2002). [Abstract] [Full Text]
胰岛素和其他胰岛素样生长因子通过一条涉及磷脂酰肌醇3-激酶和叉头转录因子的途径发出信号。这一途径是许多生物寿命和繁殖的关键调节因子。Dillin等人现在已经确定，在秀丽隐杆线虫中，只有在成虫中才能通过这一途径调节寿命，只有在发育阶段才能进行繁殖。因此，长期以来认为只有牺牲生殖健康才能延长寿命的观念几乎肯定是错误的。A. Dillin, D. K. Crawford, C. Kenyon，线虫胰岛素/IGF-1信号的时间要求。科学29,830-834(2002)。【摘要】【全文】
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Pub Date : 2002-10-15DOI: 10.1126/scisignal.1542002tw374
A single gene can give rise to more than one gene product through the differential splicing of messenger RNA. There has been growing evidence that this processing event may be functionally linked to RNA transcription. Auboeuf et al. report that in the case of nuclear receptors for steroid hormones, receptor-ligand interactions coordinate these processes at specific gene promoters through the recruitment of receptor coregulators that can both control gene transcription and splicing. This double-duty may ensure that the appropriate gene product is generated in response to a steroid hormone signal. D. Auboeuf, A. Hönig, S. M. Berget, B. W. O'Malley, Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298, 416-419 (2002). [Abstract] [Full Text]
{"title":"Regulating Both Splicing and Transcription","authors":"","doi":"10.1126/scisignal.1542002tw374","DOIUrl":"https://doi.org/10.1126/scisignal.1542002tw374","url":null,"abstract":"A single gene can give rise to more than one gene product through the differential splicing of messenger RNA. There has been growing evidence that this processing event may be functionally linked to RNA transcription. Auboeuf et al. report that in the case of nuclear receptors for steroid hormones, receptor-ligand interactions coordinate these processes at specific gene promoters through the recruitment of receptor coregulators that can both control gene transcription and splicing. This double-duty may ensure that the appropriate gene product is generated in response to a steroid hormone signal. D. Auboeuf, A. Hönig, S. M. Berget, B. W. O'Malley, Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298, 416-419 (2002). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"34 1","pages":"TW374 - tw374"},"PeriodicalIF":0.0,"publicationDate":"2002-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85765340","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 : 2002-09-24DOI: 10.1126/scisignal.1512002tw353
Both B and T lymphocyte responses require support from specialized helper T lymphocytes, which mediate their effects via the cell-surface protein CD40. For B cells, this support involves direct interaction with helper T cells expressing CD40-ligand (CD40-L). For CD8+ T cells, such help has been assumed to depend on signals generated via CD40 on third-party antigen-presenting cells (APCs). Bourgeois et al. developed an in vivo system for priming CD8 responses in which CD40 was present on CD8+ T cells, but absent on APCs. As expected, CD4+ cells were required to supply help via CD40-L but could generate CD8+ T cell memory without the need for CD40 on APCs. The role for CD40 on CD8+ T cells, rather than on the APCs, indicates a direct form of help paralleling that used in B cell memory formation. C. Bourgeois, B. Rocha, C. Tanchot, A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297, 2060-2063 (2002). [Abstract] [Full Text]
B淋巴细胞和T淋巴细胞的反应都需要专门的辅助T淋巴细胞的支持，T淋巴细胞通过细胞表面蛋白CD40介导它们的作用。对于B细胞，这种支持包括与表达cd40配体(CD40-L)的辅助性T细胞的直接相互作用。对于CD8+ T细胞，这种帮助被认为依赖于通过CD40在第三方抗原呈递细胞(apc)上产生的信号。Bourgeois等人开发了一种启动CD8反应的体内系统，其中CD40存在于CD8+ T细胞上，但不存在于apc上。正如预期的那样，CD4+细胞需要通过CD40- l提供帮助，但可以在apc上不需要CD40的情况下产生CD8+ T细胞记忆。CD40在CD8+ T细胞上的作用，而不是在apc上的作用，表明了在B细胞记忆形成中使用的一种直接的帮助并行形式。C. Bourgeois, B. Rocha, C. Tanchot, CD8+ T细胞中CD40表达在CD8+ T细胞记忆生成中的作用。科学297,2060-2063(2002)。【摘要】【全文】
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Pub Date : 2002-09-03DOI: 10.1126/scisignal.1482002tw326
Neurons communicate with one another through specialized junctions called synapses that are so robust that they survive homogenization. Although several cell-surface receptor-ligand pairs have been proposed to participate in forming and maintaining synapses, one of the best families of candidates--the immunoglobulin-domain proteins--have only been found in invertebrates. Biederer et al. report that IGSF4 is a homophilic protein that can induce the formation of fully functional glutamatergic synapses when cotransfected into nonneural, vertebrate human embryonic kidney (HEK) cells along with glutamate receptors. T. Biederer, Y. Sara, M. Mozhayeva, D. Atasoy, X. Liu, E. T. Kavalali, T. C. Südhof, SynCAM, a synaptic adhesion molecule that drives synapse assembly, Science 297, 1525-1531 (2002). [Abstract] [Full Text]
神经元通过称为突触的特殊连接相互交流，突触非常坚固，可以在同质化过程中存活下来。虽然已经提出了几种细胞表面受体配体对参与突触的形成和维持，但最好的候选家族之一-免疫球蛋白结构域蛋白-仅在无脊椎动物中被发现。Biederer等人报道，IGSF4是一种同源蛋白，当与谷氨酸受体一起共转染到非神经、脊椎动物人胚胎肾(HEK)细胞时，可以诱导形成全功能的谷氨酸能突触。T. Biederer, Y. Sara, M. Mozhayeva, D. Atasoy, X. Liu, E. T. Kavalali, T. C. s dhof, SynCAM:驱动突触组装的突触粘附分子，Science, 297, 1525-1531(2002)。【摘要】【全文】
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Pub Date : 2002-08-27DOI: 10.1126/scisignal.1472002tw316
The family of receptors for epidermal growth factor (EGF) transmits signals critical for growth and differentiation of cells in a wide variety of tissues during development. Inappropriate expression of these receptors occurs in many human cancers, and Herceptin, an antibody against one of these receptors (HER2), is used in the treatment of breast cancer. Cho and Leahy present the 2.6 angstrom crystal structure of the entire extracellular portion of one member of this receptor family, HER3. One of the L-shaped halves sits atop the other and assumes a toroidal shape with a protruding spur. Previously mapped regions of the EGF binding site, on the spur and the torus, must be brought together in order to interact productively with the ligand. Interference with this large-scale conformational change might offer a promising route to therapeutics. H.-S. Cho, D. J. Leahy, Structure of the extracellular region of HER3 reveals an interdomain tether, Science 297, 1330-1333 (2002). [Abstract] [Full Text]
表皮生长因子(EGF)受体家族在多种组织发育过程中传递对细胞生长和分化至关重要的信号。这些受体的不适当表达发生在许多人类癌症中，赫赛汀是一种针对这些受体之一(HER2)的抗体，用于治疗乳腺癌。Cho和Leahy展示了该受体家族成员HER3的整个细胞外部分的2.6埃晶体结构。其中一个l形的一半位于另一个的顶部，呈环形，有一个突出的马刺。先前绘制的EGF结合位点区域，在骨刺和环面上，必须聚集在一起，以便与配体有效地相互作用。干扰这种大规模的构象变化可能为治疗提供一条有希望的途径。H.-S。Cho, D. J. Leahy, HER3的胞外区结构揭示了一个域间链，科学297,1330-1333(2002)。【摘要】【全文】
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