Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.

Detalles Bibliográficos
Autores: Castillo, Gaelle del, Herrera, Blanca, Sánchez, Aránzazu
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/77434
Acceso en línea:http://hdl.handle.net/10261/77434
Access Level:acceso abierto
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spelling Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosisCastillo, Gaelle delHerrera, BlancaSánchez, AránzazuThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.We 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.AMP 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).Peer ReviewedPublic Library of ScienceComunidad de MadridMinisterio de Educación y Ciencia (España)Ministerio de Ciencia e Innovación (España)Universidad Complutense de MadridBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2013201320132013info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versionPublisher's versioninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/77434reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#S2010/BMD-2402/MITOLABhttp://dx.doi.org/10.1371/journal.pone.0053108Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/774342026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
title Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
spellingShingle Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
Castillo, Gaelle del
title_short Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
title_full Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
title_fullStr Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
title_full_unstemmed Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
title_sort Mouse hepatic oval cells require met-dependent PI3K to impair TGF-β-induced oxidative stress and apoptosis
dc.creator.none.fl_str_mv Castillo, Gaelle del
Herrera, Blanca
Sánchez, Aránzazu
author Castillo, Gaelle del
author_facet Castillo, Gaelle del
Herrera, Blanca
Sánchez, Aránzazu
author_role author
author2 Herrera, Blanca
Sánchez, Aránzazu
author2_role author
author
dc.contributor.none.fl_str_mv Comunidad de Madrid
Ministerio de Educación y Ciencia (España)
Ministerio de Ciencia e Innovación (España)
Universidad Complutense de Madrid
Banco Santander
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
publishDate 2013
dc.date.none.fl_str_mv 2013
2013
2013
2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
Publisher's version
info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/77434
url http://hdl.handle.net/10261/77434
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
S2010/BMD-2402/MITOLAB
http://dx.doi.org/10.1371/journal.pone.0053108
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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