Science's STKEPub Date : 2002-02-12DOI: 10.1126/scisignal.1192002tw67
{"title":"Hypermethylation and Carcinogenesis","authors":"","doi":"10.1126/scisignal.1192002tw67","DOIUrl":"https://doi.org/10.1126/scisignal.1192002tw67","url":null,"abstract":"In cancer cells, abnormal methylation patterns of DNA sequences are often present. By examining the role of the PML-RAR fusion gene, a well-studied translocation in leukemia, Di Croce et al. demonstrate that transcriptional silencing in cancer cells can occur through the recruitment of a DNA methyltransferase (Dnmt) by the PML-RAR fusion protein. Recruitment of Dnmts results in the hypermethylation of a PML-RAR target gene, RARβ2. In the presence of PML-RAR and Dnmt, cell differentiation was blocked, but this block could be overcome by administration of retinoic acid. Hence, transcription factors associated with neoplasia can function in methylation-linked silencing of genes important for growth and differentiation. Furthermore, the work shows that a genetic change in cancer can induce epigenetic gene silencing. L. Di Croce, V. A. Raker, M. Corsaro, F. Fazi, M. Fanelli, M. Faretta, F. Fuks, F. Lo Coco, T. Kouzarides, C. Nervi, S. Minucci, P. G. Pelicci, Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082 (2002). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"1 1","pages":"tw67 - tw67"},"PeriodicalIF":0.0,"publicationDate":"2002-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88109400","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 : 2002-01-29DOI: 10.1126/scisignal.1172002tw42
{"title":"Celebrating T Cell Diversity","authors":"","doi":"10.1126/scisignal.1172002tw42","DOIUrl":"https://doi.org/10.1126/scisignal.1172002tw42","url":null,"abstract":"The duration of signals emanating from the T cell receptor (TCR) is finely regulated through several processes that control protein half-life, posttranslational modification of proteins, and the recruitment of inhibitory proteins. Egen and Allison have found that the inhibitory protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is recruited to the immunological synapse, in direct proportion to the strength of the TCR signal, where it acts to extinguish TCR-dependent signals. CTLA-4 in T cells that were cultured with antigen-presenting cells (APCs) bearing agonistic or weakly agonistic peptides translocated to microtubule-organizing centers (MTOCs) close to the site of T cell-APC apposition. However, only T cells stimulated with the stronger agonist peptides led to the movement of CTLA-4 to the immune synapse at the plasma membrane. These data suggest that the location of CTLA-4 is dependent on the strength of the signal sent by the TCR. More important, the data suggest a reason why T cells would need a mechanism to inhibit TCR-dependent signaling after a strong signal is elicited. It is in an organism's best interest to have a widely varied immune response to a pathogen. Strong signals by a few T cells (that have high affinity for an antigen) could quickly lead to the proliferation of a very small subset of T cells at the expense of a diverse group of proliferating T cells with varying degrees of affinity for the antigen. Thus, a large number of T cells would recognize a very narrow repertoire of antigen--clearly a situation to the pathogen's advantage. However, by recruiting CTLA-4 to the immune synapse, the prolonged signaling that would be mediated by strongly agonistic antigens is attenuated, such that weakly stimulated T cells have an opportunity to proliferate and increase the diversity of T cell-mediated responses. J. G. Egen, J. P. Allison, Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16, 23-35 (2002). [Online Journal]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"24 1","pages":"tw42 - tw42"},"PeriodicalIF":0.0,"publicationDate":"2002-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87333892","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 : 2002-01-29DOI: 10.1126/scisignal.1172002tw47
{"title":"Cells Stabbed in the Gut","authors":"","doi":"10.1126/scisignal.1172002tw47","DOIUrl":"https://doi.org/10.1126/scisignal.1172002tw47","url":null,"abstract":"Helicobacter pylori is a prevalent human parasite (infecting half the world's population) and is linked to a variety of gut disorders, including severe gastritis and gastric carcinoma. Higashi et al. have elucidated the steps taken by the bacterial CagA protein that transform host cells. After CagA protein is injected by H. pylori into host cells, it is phosphorylated on tyrosine residues by host kinases. Phosphorylated CagA then binds to the Src homology 2 (SH2) domain-containing tyrosine phosphatase (SHP-2), which stimulates SHP-2 translocation to the cell surface where it displays its phosphatase activity. Active membrane-associated SHP-2 then stimulates morphological changes in the host cell that are the prelude to cellular transformation. H. Higashi, R. Tsutsumi, S. Muto, T. Sugiyama, T. Azuma, M. Asaka, M. Hatakeyama, SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295, 683-686 (2002). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"541 1","pages":"tw47 - tw47"},"PeriodicalIF":0.0,"publicationDate":"2002-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79649290","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 : 2002-01-22DOI: 10.1126/scisignal.1162002tw32
{"title":"Coordinating Synaptic Development","authors":"","doi":"10.1126/scisignal.1162002tw32","DOIUrl":"https://doi.org/10.1126/scisignal.1162002tw32","url":null,"abstract":"Two different mechanisms guide the development of the central nervous system. Molecular signals initially guide developing neurons to the correct position and, once neuronal activity begins, repeated stimulation helps synapses form and mature. Takasu et al. (see the Perspective by Ghosh) describe a signaling mechanism that may integrate these two processes. Ephrins and their receptors are cell-surface proteins that participate in interactions of developing axons and dendrites that are largely independent of neuronal activity. However, the activation of the EphB subtype of ephrin receptors in rat neurons potentiated signaling by N-methyl-D-aspartate (NMDA)-type glutamate receptors, which mediate activity-dependent effects on developing neurons. Activated EphB proteins were associated physically with NMDA receptors and caused the activation of the Src tyrosine kinase, which apparently phosphorylates the NMDA receptor and thus modulates activity-dependent control of neuronal gene expression. M. A. Takasu, M. B. Dalva, R. E. Zigmond, M. E. Greenberg, Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491-495 (2002). [Abstract] [Full Text] A. Ghosh, Learning more about NMDA receptor regulation. Science 295, 449-450 (2002). [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"52 1","pages":"tw32 - tw32"},"PeriodicalIF":0.0,"publicationDate":"2002-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87023607","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 : 2002-01-15DOI: 10.1126/scisignal.1152002tw20
{"title":"SH3 Search Committee","authors":"","doi":"10.1126/scisignal.1152002tw20","DOIUrl":"https://doi.org/10.1126/scisignal.1152002tw20","url":null,"abstract":"Src-homology 3 domains (SH3 domains) are so named for their similarity to a region in the proto-oncogene protein kinase Src. SH3 domain family members bind to protein domains characterized by paired proline residues, and so mediate protein-protein interactions in cell signaling and cytoskeleton reorganization. Tong et al. (see the Perspective by Gerstein et al.) used phage display to search peptide libraries of random sequences to identify preferred binding motifs for the various SH3 domains. They then searched the predicted proteome of Saccharomyces cerevisiae for potential binding partners, and also used a two-hybrid assay to identify proteins that interacted with the various SH3 domains when expressed in yeast. The common interactions from the networks predicted by each of these procedures were then assessed for likely biological significance. A. H. Y. Tong, B. Drees, G. Nardelli, G. D. Bader, B. Brannetti, L. Castagnoli, M. Evangelista, S. Ferracuti, B. Nelson, S. Paoluzi, M. Quondam, A. Zucconi, C. W. V. Hogue, S. Fields, C. Boone, G. Cesareni, A combined experimental and computational strategy to define protein interaction networks for peptide recognition modules. Science 295, 321-324 (2002). [Abstract] [Full Text] M. Gerstein, N. Lan, R. Jansen, Integrating interactomes. Science 295, 284-287 (2002). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"7 1","pages":"tw20 - tw20"},"PeriodicalIF":0.0,"publicationDate":"2002-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88749429","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 : 2002-01-15DOI: 10.1126/scisignal.1152002tw21
{"title":"Have Lipid, Will Travel","authors":"","doi":"10.1126/scisignal.1152002tw21","DOIUrl":"https://doi.org/10.1126/scisignal.1152002tw21","url":null,"abstract":"The serine-threonine kinase protein kinase D (PKD) binds to the trans-Golgi network (TGN) in mammalian cells and is involved in the release of transport vesicles destined for the plasma membrane. Baron and Malhotra (see the Perspective by Bankaitis) now show that in order for PKD to bind to the TGN, it must specifically bind to the lipid diacylglycerol. When concentrations of this lipid were reduced in cells, both PKD recruitment to the TGN and transport out of the TGN were inhibited. C. L. Baron, V. Malhotra, Role of diacylglycerol in PKD recruitment to the TGN and protein transport to the plasma membrane. Science 295, 325-328 (2002). [Abstract] [Full Text] V. A. Bankaitis, Slick recruitment to the Golgi. Science 295, 290-291 (2002). [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"1 1","pages":"tw21 - tw21"},"PeriodicalIF":0.0,"publicationDate":"2002-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75616167","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 : 2001-12-18DOI: 10.1126/scisignal.1132001tw464
{"title":"X Function","authors":"","doi":"10.1126/scisignal.1132001tw464","DOIUrl":"https://doi.org/10.1126/scisignal.1132001tw464","url":null,"abstract":"Hepatitis B virus (HBV) infects 300 million people worldwide and causes liver disease and cancer. The X-protein of HBV is essential for viral infection and has been implicated in carcinogenesis, but its exact role has been enigmatic. It is known to infiltrate cell signaling pathways and to activate modest transcription from various promoters, as well as strongly activate viral replication in certain cell lines. The X-protein activates Src without interacting directly with Src. Bouchard et al. (see the Perspective by Ganem) have now discovered that this activation is mediated the activation of another kinase called Pyk. The activation of Pyk is caused by a release of calcium from intracellular stores (most likely the mitochondrion) triggered by X-protein. M. J. Bouchard, L.-H. Wang, R. J. Schneider, Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science 294, 2376-2378 (2001). [Abstract] [Full Text] D. Ganem, The X files--one step closer to closure. Science 294, 2299-2300 (2001). [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"11 1","pages":"tw464 - tw464"},"PeriodicalIF":0.0,"publicationDate":"2001-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74270459","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 : 2001-12-18DOI: 10.1126/scisignal.1132001tw461
{"title":"Screening Reluctant Genes on the Double","authors":"","doi":"10.1126/scisignal.1132001tw461","DOIUrl":"https://doi.org/10.1126/scisignal.1132001tw461","url":null,"abstract":"Genome sequencing projects have revealed thousands of genes of unknown functions. For the budding yeast Saccharomyces cerevisiae, large-scale gene deletion analysis has shown that >80% of the ~6200 predicted or known yeast genes are not required for viability. Thus, many genes and pathways of eukaryotic cells may be functionally redundant, or may not show easily recognizable phenotypes if perturbed. To address this problem, Tong et al. developed an automated method for systematic construction of double mutants called synthetic genetic array (SGA) analysis. A yeast strain that carries a mutation in the \"query\" gene is linked to a selectable marker and crossed to members of a collection of haploid deletion strains in which almost every nonessential gene in the yeast genome is represented. If a double mutant cannot be produced or grows much more slowly than normal, it is an indication that there may be a functional interaction between the two genes. Putative interactions that are identified through this technology can then be readily confirmed by tetrad analysis. Eight query genes involved in cytoskeletal organization, DNA repair, or unknown functions were analyzed, resulting in the construction of a network identifying 291 putative genetic interactions involving 204 genes. A. H. Y. Tong, M. Evangelista, A. B. Parsons, H. Xu, G. D. Bader, N. Pagé, M. Robinson, S. Raghibizadeh, C. W. V. Hogue, H. Bussey, B. Andrews, M. Tyers, C. Boone, Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364-2368 (2001). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"4 1","pages":"tw461 - tw461"},"PeriodicalIF":0.0,"publicationDate":"2001-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75623231","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 : 2001-12-11DOI: 10.1126/scisignal.1122001tw460
{"title":"Getting Used to a Smell","authors":"","doi":"10.1126/scisignal.1122001tw460","DOIUrl":"https://doi.org/10.1126/scisignal.1122001tw460","url":null,"abstract":"In vertebrate olfactory neurons, odor molecules stimulate the opening of cyclic nucleotide-gated channels (CNGs). The resulting influx of Ca2+ ions also triggers a negative-feedback mechanism in which channel activity is inhibited when bound to a Ca2+-calmodulin (CaM) complex. This mechanism promotes olfactory adaptation and allows animals to evaluate the odor environment continually. Two groups have determined that two of the channel's three subunits are required for odor adaptation. Munger et al. show that channels from mice lacking the CNGA4 subunit exhibited slower Ca2+-CaM-mediated inhibition. Bradley et al. have used a heterologous expression system to show that both the CNGA4 and CNGB1b subunits facilitate Ca2+-CaM binding to the open state of channel. S. D. Munger, A. P. Lane, H. Zhong, T. Leinders-Zufall, K.-W. Yau, F. Zufall, R. R. Reed, Central role of the CNGA4 channel subunit in Ca2+-calmodulin-dependent odor adaptation. Science 294, 2172-2175 (2001). [Online Journal] J. Bradley, D. Reuter, S. Frings, Facilitation of calmodulin-mediated odor adaptation by cAMP-gated channel subunits. Science 294, 2176-2178 (2001). [Online Journal]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"7 1","pages":"tw460 - tw460"},"PeriodicalIF":0.0,"publicationDate":"2001-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82873733","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 : 2001-12-04DOI: 10.1126/scisignal.1112001tw447
{"title":"G Proteins and Vesicle Trafficking","authors":"","doi":"10.1126/scisignal.1112001tw447","DOIUrl":"https://doi.org/10.1126/scisignal.1112001tw447","url":null,"abstract":"Attenuating a cellular signal is just as critical as inducing it. For example, regulator of G protein signaling (RGS) proteins modulate the signaling output from receptor-coupled heterotrimeric G proteins. Zheng et al. (see the Perspective by von Zastrow and Mostov) have identified what has been an elusive RGS for the Gαs class of G proteins. Named RGS-PX1, it also contains a membrane-interacting PhoX domain whose presence suggests a link between G protein signaling and vesicle trafficking in cells. B. Zheng, Y.-C. Ma, R. S. Ostrom, C. Lavoie, G. N. Gill, P. A. Insel, X.-Y. Huang, M. G. Farquhar, RGS-PX1, a GAP for Gαs and sorting nexin in vesicular trafficking. Science 294, 1939-1942 (2001). [Abstract] [Full Text] M. von Zastrow, K. Mostov, A new thread in an intricate web. Science 294, 1845-1847 (2001). [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"970 1","pages":"tw447 - tw447"},"PeriodicalIF":0.0,"publicationDate":"2001-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91457405","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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