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dc.contributor.authorSimón-Carrasco, Lucía
dc.contributor.authorGraña Castro, Osvaldo 
dc.contributor.authorSalmón, Marina
dc.contributor.authorJacob, Harrys K C
dc.contributor.authorGutierrez, Alejandro
dc.contributor.authorJiménez, Gerardo
dc.contributor.authorDrosten, Matthias 
dc.contributor.authorBarbacid, Mariano 
dc.date.accessioned2019-10-01T10:52:20Z
dc.date.available2019-10-01T10:52:20Z
dc.date.issued2017-07-15
dc.identifier.citationGenes Dev. 2017 ;31(14):1456-1468.es_ES
dc.identifier.issn0890-9369es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8392
dc.description.abstractCIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4 Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy.es_ES
dc.description.sponsorshipWe are grateful to Carol MacKintosh (University of Dundee, UK) for the pcDNA5/FRT/TO-GFP-CIC plasmid, and Huda Zoghbi (Baylor College of Medicine, Houston, TX) and Yoontae Lee (University of Pohang, Korea) for Cic antisera. We thank Scott Brown and Robert Holt (University of Vancouver, Canada) for their help with TCR abundance calculations. We also thank Carmen G. Lechuga, Marta San Roman, Raquel Villar, Beatriz Jimenez, and Nuria Cabrera for excellent technical assistance. We value the support of Sagrario Ortega (Transgenic Mice Core Unit, CNIO) for help in generating the Cic mutant mice, Orlando Dominguez (Genomics Core Unit, CNIO) for the RNA-seq analysis, and the Histopathology Core Unit. This work was supported by grants from the Fundacio La Marato de TV3 (20131730/1) to G.J. and M.B., and the European Research Council (ERC-AG/250297-RAS AHEAD), the EU-Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM), the Spanish Ministry of Economy and Competitiveness (SAF2014-59864-R), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE), and the Asociacion Espanola contra el Cancer (AECC) (GC16173694BARB) to M.B. M.B. is the recipient of an Endowed Chair from the AXA Research Fund. L.S.-C. was supported by a fellowship from the Programa de Formacion de Personal Investigator (FPI) of the Spanish Ministry of Economy and Competitiveness. M.D. and M.B. conceived and designed the study. L.S.-C., O.G., G.J., M.D., and M.B. developed the methodology. L.S.-C., O.G., M.S., and M.D. acquired the data. L.S.-C., O.G., M.S., H.K.C.J., G.J., M.D., and M.B. analyzed and interpreted the data. L.S-C., O.G., G.J., M.D., and M.B. wrote, reviewed, and/or revised the manuscript. G.J. provided material support. A. G. analyzed the T-ALL sequencing. M.D. and M.B. supervised the study.es_ES
dc.language.isoenges_ES
dc.publisherCOLD SPRING HARBOR LAB PRESSes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectCICes_ES
dc.subjectEtv4es_ES
dc.subjectRas signalinges_ES
dc.subjectT-ALLes_ES
dc.subjectmouse modelses_ES
dc.subject.meshAdenovirus E1A Proteins es_ES
dc.subject.meshAlleles es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBrain Neoplasms es_ES
dc.subject.meshCell Line, Tumor es_ES
dc.subject.meshEmbryonic Development es_ES
dc.subject.meshFibroblasts es_ES
dc.subject.meshGenes, ras es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMAP Kinase Signaling System es_ES
dc.subject.meshMice es_ES
dc.subject.meshMutation es_ES
dc.subject.meshOligodendroglioma es_ES
dc.subject.meshPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma es_ES
dc.subject.meshProto-Oncogene Proteins es_ES
dc.subject.meshProto-Oncogene Proteins c-ets es_ES
dc.subject.meshRepressor Proteins es_ES
dc.subject.meshTranscription, Genetices_ES
dc.titleInactivation of Capicua in adult mice causes T-cell lymphoblastic lymphomaes_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID28827401es_ES
dc.format.volume31es_ES
dc.format.number14es_ES
dc.format.page1456-1468es_ES
dc.identifier.doi10.1101/gad.300244.117es_ES
dc.contributor.funderFundacio La Marato de TV3es_ES
dc.contributor.funderEuropean Research Counciles_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderComunidad de Madrides_ES
dc.contributor.funderAsociación Española Contra el Cánceres_ES
dc.contributor.funderAXA Research Fundes_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1549-5477es_ES
dc.relation.publisherversionhttps://doi.org/ 10.1101/gad.300244.117es_ES
dc.identifier.journalGenes & developmentes_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/EC/250297es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2014-59864-Res_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/S2011/BDM-2470/ONCOCYCLEes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/GC16173694BARBes_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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