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dc.contributor.authorMoreno-Càceres, J
dc.contributor.authorCaja, L
dc.contributor.authorMainez, J
dc.contributor.authorMayoral, R
dc.contributor.authorMartín-Sanz, P
dc.contributor.authorMoreno-Vicente, Roberto 
dc.contributor.authordel Pozo, Miguel Angel 
dc.contributor.authorDooley, S
dc.contributor.authorEgea, G
dc.contributor.authorFabregat, I
dc.date.accessioned2019-04-29T07:16:36Z
dc.date.available2019-04-29T07:16:36Z
dc.date.issued2014-07-17
dc.identifier.citationCell Death Dis. 2014; 5:e1326es_ES
dc.identifier.issn2041-4889es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7521
dc.description.abstractTransforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1(-/-) hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1(-/-) hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1(-/-) hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1(+/+) cells, which was not the case in Cav1(-/-) cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells.es_ES
dc.description.sponsorshipThis work was supported by grants from: (1) the Ministry of Economy and Competitiveness (MINECO), Spain (BFU2012-35538 and ISCIII-RTICC: RD12-0036-0029 to IF; SAF2013-43713 to PM-S; BFU2012-33932 to GE; SAF2011-25047 and CSD2009-00016 to MAdP); (2) AGAUR-Generalitat de Catalunya (2009SGR-312 to IF); and (3) People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PITN-GA-2012-316549 (IT LIVER) to IF JM-C and RM-V were recipients of pre-doctoral fellowships from the FPU program (Ministry of Education, Culture and Sport, Spain) and the FPI program (associated to SAF201125047, MINECO, Spain), respectively. We acknowledge the review and suggestions of Dr. Christoph Meyer (University of Heidelberg, Mannheim, Germany).es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Group es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshADAM Proteins es_ES
dc.subject.meshADAM17 Protein es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshApoptosis es_ES
dc.subject.meshCaveolin 1 es_ES
dc.subject.meshCells, Cultured es_ES
dc.subject.meshEnzyme Activation es_ES
dc.subject.meshErbB Receptors es_ES
dc.subject.meshFemale es_ES
dc.subject.meshHepatocytes es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Knockout es_ES
dc.subject.meshPhosphorylation es_ES
dc.subject.meshReactive Oxygen Species es_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshTransforming Growth Factor beta es_ES
dc.subject.meshTranscriptional Activation es_ES
dc.titleCaveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID25032849es_ES
dc.format.volume5es_ES
dc.format.number7es_ES
dc.format.pagee1326es_ES
dc.identifier.doi10.1038/cddis.2014.294es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderGovernment of Catalonia (España) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España) 
dc.description.peerreviewedes_ES
dc.identifier.e-issn2041-4889es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/cddis.2014.294es_ES
dc.identifier.journalCell death & diseasees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización por Integrinases_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2012-35538es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12-0036-0029es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2013-43713es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2012-33932es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2011-25047es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/316549/EUes_ES
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución 4.0 Internacional