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dc.contributor.authorPattwell, Siobhan S
dc.contributor.authorArora, Sonali
dc.contributor.authorCimino, Patrick J
dc.contributor.authorOzawa, Tatsuya
dc.contributor.authorSzulzewsky, Frank
dc.contributor.authorHoellerbauer, Pia
dc.contributor.authorBonifert, Tobias
dc.contributor.authorHoffstrom, Benjamin G
dc.contributor.authorBoiani, Norman E
dc.contributor.authorBolouri, Hamid
dc.contributor.authorCorrenti, Colin E
dc.contributor.authorOldrini, Barbara 
dc.contributor.authorSilber, John R
dc.contributor.authorSquatrito, Massimo 
dc.contributor.authorPaddison, Patrick J
dc.contributor.authorHolland, Eric C
dc.contributor.authorSquatrito, Massimo 
dc.date.accessioned2021-03-09T15:47:29Z
dc.date.available2021-03-09T15:47:29Z
dc.date.issued2020-11-01
dc.identifier.citationNat Commun.2020;11(1):2977es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/12179
dc.description.abstractIndependent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.es_ES
dc.description.sponsorshipWe thank James Yan, Jenny Zhang, Deby Kumasaka, and Denis Adair for continued technical and administrative assistance and support throughout these experiments. Eero Castren at University of Helsinki provided pEF-BOS-TrkB plasmids used for RCAS-TrkB.T1 generation. We thank Francis S. Lee and Lino Tessarollo for providing breeding pairs of TrkB.T1-/- mice for antibody production. Luis Chiriboga at New York University School of Medicine provided helpful insight into histology protocols. We thank William A. Johnsen and Midori Clarke for assistance with antibody sequencing and protein purification. We thank the Tracy A. Goodpaster and Julie Randolph-Habecker at the Fred Hutchinson Experimental Histopathology Core for histology assistance during the antibody validation phase and Elizabeth Jensen at the Fred Hutchinson Genomics Core for help with all DNA sequencing. We thank Jeongwu Lee Do-Hyun Nam and Steven M. Pollard for providing cell isolates. Funding was provided by National Institutes of Health R01 CA195718 (E.C.H.), U54 CA193461 (E.C.H., F.S.), R01 CA100688 (E.C.H.), T32 CA965725 (S.S.P.), U54 DK106829 (S.S.P.), R21 CA223531 (S.S.P., E.C.H.), T32 CA080416 (P.H.), R01 CA190957 (P.J.P.; T.B.); Jacobs Foundation Research Fellowship (S.S.P.); American Cancer Society ACS-RSG-14-056-01 (P.J.P.); National Research Agency RTI2018-102035-B-I00 (M.S.); Seve Ballesteros Foundation (M.S.). Autopsy materials used in this study were obtained from the University of Washington Neuropathology Core, which is supported by the Alzheimer's Disease Research Center (AG05136), the Adult Changes in Thought Study (AG006781), and Morris K Udall Center of Excellence for Parkinson's Disease Research (NS062684)es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshRNA Splicing es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBrain es_ES
dc.subject.meshBrain Neoplasms es_ES
dc.subject.meshCarcinogenesis es_ES
dc.subject.meshCells, Cultured es_ES
dc.subject.meshGene Expression Profiling es_ES
dc.subject.meshGene Ontology es_ES
dc.subject.meshGlioma es_ES
dc.subject.meshHigh-Throughput Nucleotide Sequencing es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMembrane Glycoproteins es_ES
dc.subject.meshMice es_ES
dc.subject.meshNIH 3T3 Cells es_ES
dc.subject.meshNeural Stem Cells es_ES
dc.subject.meshOncogene Proteins, Fusion es_ES
dc.subject.meshOncogenes es_ES
dc.subject.meshPhosphatidylinositol 3-Kinases es_ES
dc.subject.meshRNA Isoforms es_ES
dc.subject.meshReceptor, trkBes_ES
dc.subject.meshSignal Transduction es_ES
dc.titleA kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.es_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID32532995es_ES
dc.format.volume11es_ES
dc.format.number1es_ES
dc.format.page2977es_ES
dc.identifier.doi10.1038/s41467-020-16786-5es_ES
dc.contributor.funderUnited States Department of Health & Human Services National Institutes of Health (NIH) - USAes_ES
dc.contributor.funderAmerican Cancer Societyes_ES
dc.contributor.funderFrench National Research Agency (ANR)es_ES
dc.contributor.funderAlzheimer's Disease Research Centeres_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-1723es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-020-16786-5.es_ES
dc.identifier.journalNature communicationses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Tumores Cerebrales Fundación Seve-Ballesteroses_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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