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dc.contributor.author | Moreno-Càceres, J | |
dc.contributor.author | Caja, L | |
dc.contributor.author | Mainez, J | |
dc.contributor.author | Mayoral, R | |
dc.contributor.author | Martín-Sanz, P | |
dc.contributor.author | Moreno-Vicente, Roberto | |
dc.contributor.author | del Pozo, Miguel Angel | |
dc.contributor.author | Dooley, S | |
dc.contributor.author | Egea, G | |
dc.contributor.author | Fabregat, I | |
dc.date.accessioned | 2019-04-29T07:16:36Z | |
dc.date.available | 2019-04-29T07:16:36Z | |
dc.date.issued | 2014-07-17 | |
dc.identifier.citation | Cell Death Dis. 2014; 5:e1326 | es_ES |
dc.identifier.issn | 2041-4889 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7521 | |
dc.description.abstract | Transforming 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.sponsorship | This 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.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | ADAM Proteins | es_ES |
dc.subject.mesh | ADAM17 Protein | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Apoptosis | es_ES |
dc.subject.mesh | Caveolin 1 | es_ES |
dc.subject.mesh | Cells, Cultured | es_ES |
dc.subject.mesh | Enzyme Activation | es_ES |
dc.subject.mesh | ErbB Receptors | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | Hepatocytes | es_ES |
dc.subject.mesh | Male | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Mice, Knockout | es_ES |
dc.subject.mesh | Phosphorylation | es_ES |
dc.subject.mesh | Reactive Oxygen Species | es_ES |
dc.subject.mesh | Signal Transduction | es_ES |
dc.subject.mesh | Transforming Growth Factor beta | es_ES |
dc.subject.mesh | Transcriptional Activation | es_ES |
dc.title | Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17 | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 25032849 | es_ES |
dc.format.volume | 5 | es_ES |
dc.format.number | 7 | es_ES |
dc.format.page | e1326 | es_ES |
dc.identifier.doi | 10.1038/cddis.2014.294 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Instituto de Salud Carlos III | |
dc.contributor.funder | Government of Catalonia (España) | |
dc.contributor.funder | Unión Europea. Comisión Europea | |
dc.contributor.funder | Ministerio de Educación, Cultura y Deporte (España) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2041-4889 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/cddis.2014.294 | es_ES |
dc.identifier.journal | Cell death & disease | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Señalización por Integrinas | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BFU2012-35538 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/RD12-0036-0029 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2013-43713 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BFU2012-33932 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2011-25047 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/316549/EU | es_ES |
dc.rights.accessRights | open access | es_ES |