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dc.contributor.authorFernández, Almudena-
dc.contributor.authorValverde, Ángela M.-
dc.contributor.authorGonzález-Rodríguez, Águeda-
dc.contributor.authorHerrera, Blanca-
dc.contributor.authorMontoliu, Lluís-
dc.contributor.authorFernández, Margarita-
dc.contributor.authorSánchez, Aránzazu-
dc.contributor.authorFabregat, Isabel-
dc.identifierdoi: 10.1002/hep.28134-
dc.identifiere-issn: 1527-3350-
dc.identifierissn: 0270-9139-
dc.identifier.citationHepatology 63(2): 604-619 (2016)-
dc.description.abstractDifferent data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-β pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-β through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process. Conclusion: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (Hepatology 2016;63:604-619)-
dc.description.sponsorshipCofunded by the Ministry of Economy and Competitiveness-MINECO and the European Regional Development Fund-FEDER, Spain (Contract grant numbers: BFU2012-35538 and ISCIII-RTICC RD12-0036-0029 to I.F.-IDIBELL; SAF2009-12477 to A.S.-UCM/IdISSC; RETICS-RD12/0019/0023 and SAF2011-30526-C02-01 to J.-C.S.-CIEMAT/CIBERER/IIS-FJD; SAF2012-33283 to A.M.V.-CSIC/CIBERDEM). People Programme (Marie Curie Actions) of the FP7-2012, under REA grant agreement #PITN-GA-2012-316549 (IT-LIVER) to I.F.-IDIBELL and to A.S.-UCM/IdISSC. AGAUR-Generalitat de Catalunya to I.F-IDIBELL (Contract grant number: 2009SGR-312). Dirección General de Investigación de la Comunidad de Madrid, Spain (Contract grant number S2010/BMD-2402 to A.S.-UCM/IdISSC). Fundación Eugenio Rodríguez Pascual to M.G.-B.-CIEMAT/CIBERER/IIS-FJD. J.L.-L. was recipient of a predoctoral fellowship from IDIBELL; D.C.-D. and A.M.-P. were recipients of predoctoral fellowships from MINECO, Spain (Contract grant number: FPI - BES-2013-064609 and BES-2007-16187, respectively).-
dc.publisherJohn Wiley & Sons-
dc.titleDissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis-
dc.description.versionPeer Reviewed-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderUniversidad Complutense de Madrid-
dc.contributor.funderFundación Eugenio Rodríguez Pascual-
dc.contributor.funderEuropean Commission-
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)-
dc.contributor.funderCentro de Investigación Biomédica en Red Enfermedades Raras (España)-
dc.contributor.funderGeneralitat de Catalunya-
dc.contributor.funderComunidad de Madrid-
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