Science's STKEPub Date : 2002-12-03DOI: 10.1126/scisignal.1612002tw449
{"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}
Science's STKEPub Date : 2002-11-26DOI: 10.1126/scisignal.1602002tw446
{"title":"Pulled Sideways","authors":"","doi":"10.1126/scisignal.1602002tw446","DOIUrl":"https://doi.org/10.1126/scisignal.1602002tw446","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"45 1","pages":"TW446 - tw446"},"PeriodicalIF":0.0,"publicationDate":"2002-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77798499","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}
Science's STKEPub Date : 2002-11-12DOI: 10.1126/scisignal.1582002tw417
{"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}
Science's STKEPub Date : 2002-11-05DOI: 10.1126/scisignal.1572002tw405
Mark T. Nelson
{"title":"Protecting the Heart","authors":"Mark T. Nelson","doi":"10.1126/scisignal.1572002tw405","DOIUrl":"https://doi.org/10.1126/scisignal.1572002tw405","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"84 1","pages":"TW405 - tw405"},"PeriodicalIF":0.0,"publicationDate":"2002-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85455717","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}
Science's STKEPub Date : 2002-10-29DOI: 10.1126/scisignal.1562002tw397
{"title":"Strong Bones via Tailored Hormones","authors":"","doi":"10.1126/scisignal.1562002tw397","DOIUrl":"https://doi.org/10.1126/scisignal.1562002tw397","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"24 1","pages":"TW397 - tw397"},"PeriodicalIF":0.0,"publicationDate":"2002-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72892016","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}
Science's STKEPub Date : 2002-10-29DOI: 10.1126/scisignal.1562002tw395
{"title":"Live Long and Reproduce","authors":"","doi":"10.1126/scisignal.1562002tw395","DOIUrl":"https://doi.org/10.1126/scisignal.1562002tw395","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"375 1","pages":"TW395 - tw395"},"PeriodicalIF":0.0,"publicationDate":"2002-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80089238","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}
Science's STKEPub Date : 2002-10-15DOI: 10.1126/scisignal.1542002tw374
{"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}
Science's STKEPub Date : 2002-09-24DOI: 10.1126/scisignal.1512002tw353
{"title":"Direct Assistance","authors":"","doi":"10.1126/scisignal.1512002tw353","DOIUrl":"https://doi.org/10.1126/scisignal.1512002tw353","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"43 1","pages":"tw353 - tw353"},"PeriodicalIF":0.0,"publicationDate":"2002-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80953911","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}
Science's STKEPub Date : 2002-09-03DOI: 10.1126/scisignal.1482002tw326
{"title":"Making New Ties","authors":"","doi":"10.1126/scisignal.1482002tw326","DOIUrl":"https://doi.org/10.1126/scisignal.1482002tw326","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"6 1","pages":"tw326 - tw326"},"PeriodicalIF":0.0,"publicationDate":"2002-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88407356","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}
Science's STKEPub Date : 2002-08-27DOI: 10.1126/scisignal.1472002tw316
{"title":"Interfering with Receptors","authors":"","doi":"10.1126/scisignal.1472002tw316","DOIUrl":"https://doi.org/10.1126/scisignal.1472002tw316","url":null,"abstract":"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]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"70 1","pages":"TW316 - tw316"},"PeriodicalIF":0.0,"publicationDate":"2002-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79395992","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}
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