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dc.contributor.authorManieri, Elisa-
dc.contributor.authorVerdugo, Ángeles-
dc.contributor.authorGonzález-Rodríguez, Águeda-
dc.contributor.authorValverde, Ángela M.-
dc.contributor.authorSabio, Guadalupe-
dc.identifierdoi: 10.1172/JCI65124-
dc.identifierissn: 0021-9738-
dc.identifiere-issn: 1558-8238-
dc.identifier.citationJournal of Clinical Investigation 123(1): 164-178 (2013)-
dc.description15 páginas, 7 figuras.-- et al.-
dc.description.abstractBacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δMAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δpathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.-
dc.description.sponsorshipG. Sabio is an investigator of the Ramón y Cajal Program and a recipient of a Principe de Girona Impulsa award. R.J. Davis is an investigator of the Howard Hughes Medical Institute. Á. Verdugo is a recipient of a Madrid Regional Government fellowship. E. Manieri is a fellow of the La Caixa Foundation Á. González-Rodríguez was supported by CIBERDEM (ISCIII, Spain). This work was funded by the following grants: ERC 260464, EFSD 2030, MICINN SAF2010-19347, and Comunidad de Madrid S2010/BMD-2326 (to G. Sabio:); MICINN SAF2011-27330 (to P. Martin); and MICINN SAF2012-3328 (to Á. Valverde). The CNIC is supported by the Ministry of Economy and Competitiveness and the Pro-CNIC Foundation.-
dc.publisherAmerican Society for Clinical Investigation-
dc.relation.isversionofPublisher's version-
dc.titleEukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis-
dc.description.versionPeer Reviewed-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderEuropean Research Council-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderEuropean Commission-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderObra Social la Caixa-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
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