Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-Induced oxidative stress and apoptosis.

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...

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Autores: Martínez Palacián, Adoración, Castillo, Gaelle del, Suárez Causado, Amileth, García Álvaro, María, Morena Frutos, Diego de la, Fernández, Margarita, Roncero, Cesáreo, Fabregat Romero, Isabel, Herrera, Blanca, Sánchez, Aránzazu
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/36385
Acceso en línea:https://hdl.handle.net/2445/36385
Access Level:acceso abierto
Palabra clave:Apoptosi
Estrès oxidatiu
Cèl·lules hepàtiques
Apoptosis
Oxidative stress
Liver cells
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spelling Mouse hepatic oval cells require Met-dependent PI3K to impair TGF-β-Induced oxidative stress and apoptosis.Martínez Palacián, AdoraciónCastillo, Gaelle delSuárez Causado, AmilethGarcía Álvaro, MaríaMorena Frutos, Diego de laFernández, MargaritaRoncero, CesáreoFabregat Romero, IsabelHerrera, BlancaSánchez, AránzazuApoptosiEstrès oxidatiuCèl·lules hepàtiquesApoptosisOxidative stressLiver cellsWe 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.Public Library of Science (PLoS)2013201320132013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/36385Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0053108PLoS One, 2013, vol. 8, num. 1, p. 1-14http://dx.doi.org/10.1371/journal.pone.0053108cc-by (c) Martínez Palacián, Adoración et al., 2013http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/363852026-05-29T05:05:01Z
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.
Martínez Palacián, Adoración
Apoptosi
Estrès oxidatiu
Cèl·lules hepàtiques
Apoptosis
Oxidative stress
Liver cells
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 Martínez Palacián, Adoración
Castillo, Gaelle del
Suárez Causado, Amileth
García Álvaro, María
Morena Frutos, Diego de la
Fernández, Margarita
Roncero, Cesáreo
Fabregat Romero, Isabel
Herrera, Blanca
Sánchez, Aránzazu
author Martínez Palacián, Adoración
author_facet Martínez Palacián, Adoración
Castillo, Gaelle del
Suárez Causado, Amileth
García Álvaro, María
Morena Frutos, Diego de la
Fernández, Margarita
Roncero, Cesáreo
Fabregat Romero, Isabel
Herrera, Blanca
Sánchez, Aránzazu
author_role author
author2 Castillo, Gaelle del
Suárez Causado, Amileth
García Álvaro, María
Morena Frutos, Diego de la
Fernández, Margarita
Roncero, Cesáreo
Fabregat Romero, Isabel
Herrera, Blanca
Sánchez, Aránzazu
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Apoptosi
Estrès oxidatiu
Cèl·lules hepàtiques
Apoptosis
Oxidative stress
Liver cells
topic Apoptosi
Estrès oxidatiu
Cèl·lules hepàtiques
Apoptosis
Oxidative stress
Liver cells
description 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.
publishDate 2013
dc.date.none.fl_str_mv 2013
2013
2013
2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/36385
url https://hdl.handle.net/2445/36385
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0053108
PLoS One, 2013, vol. 8, num. 1, p. 1-14
http://dx.doi.org/10.1371/journal.pone.0053108
dc.rights.none.fl_str_mv cc-by (c) Martínez Palacián, Adoración et al., 2013
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Martínez Palacián, Adoración et al., 2013
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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