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dc.contributor.authorCastillo, Gaelle del-
dc.contributor.authorHerrera, Blanca-
dc.contributor.authorSánchez, Aránzazu-
dc.identifierdoi: 10.1371/journal.pone.0053108-
dc.identifierissn: 1932-6203-
dc.identifier.citationPLoS ONE 8(1): e53108 (2013)-
dc.descriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.-
dc.description.abstractWe have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met-/- oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Metflx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Metflx/flx and Met-/- oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met-/- oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met-/- oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Metflx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met-/- oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Metflx/flx oval cells, whereas no effect was observed in Met-/- oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis. © 2013 Martínez-Palacián et al.-
dc.description.sponsorshipAMP was recipient of a research-training contract (grant SAF2006-12025) from the Ministry of Education and Science. GC was recipient of a researchtraining contract from the Ministry of Education and Science. ASC was recipient of an Alban scholarship program and then a research assistant contract (grant SAF2009-12477). MGA is recipient of a research assistant contract (grant S2010/BMD-2402). This work has been supported by grants SAF2006-12025 from Ministry of Education and Science (Spain), SAF2009-12477 from Ministry of Science and Innovation (Spain), and 920359 (CAM-UCM, BSCH-UCM).-
dc.publisherPublic Library of Science-
dc.relation.isversionofPublisher’s version-
dc.relation.isversionofPublisher's version-
dc.titleMouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis-
dc.description.versionPeer Reviewed-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderUniversidad Complutense de Madrid-
dc.contributor.funderBanco Santander-
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