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dc.contributor.authorSalmón, Marina
dc.contributor.authorPaniagua, Guillem
dc.contributor.authorFernández-García, Fernando
dc.contributor.authorZarzuela, Eduardo
dc.contributor.authorÁlvarez-Díaz, Ruth
dc.contributor.authorMusteanu, Mónica 
dc.contributor.authorMuñoz, Javier
dc.contributor.authorDrosten, Matthias 
dc.contributor.authorLechuga, Carmen G 
dc.contributor.authorGuerra, Carmen 
dc.contributor.authorCaleiras, E 
dc.contributor.authorOrtega Jimenez, Sagrario 
dc.contributor.authorBarbacid, Mariano 
dc.date.accessioned2022-07-13T10:01:10Z
dc.date.available2022-07-13T10:01:10Z
dc.date.issued2021-07-27
dc.identifier.citationProc Natl Acad Sci U S A . 2021;118(30):e2023112118.es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/14703
dc.description.abstractIn mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.es_ES
dc.description.sponsorshipWe thank Marta San Roman, Raquel Villar, and Nuria Cabrera for excellent technical assistance; Mayte Lamparero and Isabel Blanco (Animal Facility) for mouse work; the Histopathology Unit for processing of mouse tissues; Lola Martinez (Flow Cytometry Unit) for her help with flow cytometry analyses; Diego Megias and Manuel Perez (Confocal Microscopy Unit) for assistance with confocal microscopy; and the Mouse Genome Editing Unit for support with the generation of the mouse strains described here. We also thank Ignacio Perez de Castro (Instituto de Salud Carlos III, Madrid, Spain) for sharing the EGFP-KRAS4B plasmid and Orlando Dominguez (Genomics Unit) and Pedro P. Lopez-Casas (Clinical Research Program) for their advice on exome sequencing. This work was supported by grants from the European Research Council (ERC-2015-AdG/695566, THERACAN), the Spanish Ministry of Science, Innovation and Universities (RTC-2017-6576-1), and the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM); a grant from the CRIS Cancer Foundation (to M.B.); and a grant from the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00, to M.B. and M.M.). M.B. is a recipient of an Endowed Chair from the AXA Research Fund. M.S. was supported by predoctoral contract "Severo Ochoa" (BES-2016-079096) from the SpanishMinistry of Science, Innovation and Universities. G.P. was a recipient of a "Young Ph.D." grant from the Government of the Community of Madrid. F.F.-G. was supported by a formacion de profesorado universitario (FPU) fellowship from the Spanish Ministry of Science, Innovation and Universities.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectK-RAS 4Aes_ES
dc.subjectSPLICE VARIANTes_ES
dc.subjectH-RASes_ES
dc.subjectMOUSEes_ES
dc.subjectSPECIFICITYes_ES
dc.subjectONCOGENESes_ES
dc.subjectCANCERes_ES
dc.subject4Bes_ES
dc.subject.meshAdenocarcinoma of Lung es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshApoptosis es_ES
dc.subject.meshCell Proliferation es_ES
dc.subject.meshFemale es_ES
dc.subject.meshHumans es_ES
dc.subject.meshLung Neoplasms es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Inbred C57BL es_ES
dc.subject.meshMice, Knockout es_ES
dc.subject.meshMutation es_ES
dc.subject.meshProtein Isoforms es_ES
dc.subject.meshProto-Oncogene Proteins p21(ras) es_ES
dc.subject.meshTumor Cells, Culturedes_ES
dc.subject.meshXenograft Model Antitumor Assays es_ES
dc.titleKRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID34301865es_ES
dc.format.volume118es_ES
dc.format.number30es_ES
dc.identifier.doi10.1073/pnas.2023112118es_ES
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) es_ES
dc.contributor.funderUnión Europea. Comisión Europea es_ES
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España) es_ES
dc.contributor.funderComunidad de Madrid (España) es_ES
dc.contributor.funderCRIS contra el Cáncer es_ES
dc.contributor.funderFundación AXA es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1091-6490es_ES
dc.relation.publisherversionhttps://doi.org/10.1073/pnas.2023112118es_ES
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaes_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/695566/EUes_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/B2017/BMD-3884 iLUNG-CMes_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTC2017-6576-1es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTI2018-094664-B-I00es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/BES-2016-079096es_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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