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dc.contributor.author
Menacho Márquez, Mauricio Ariel
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dc.contributor.author
Rodríguez Hernández, Carlos J.
dc.contributor.author
Villarong, M. Ángeles
dc.contributor.author
Pérez Valle, Jorge
dc.contributor.author
Gadea, José
dc.contributor.author
Belandia, Borja
dc.contributor.author
Murguía, José R.
dc.date.available
2018-03-05T21:37:02Z
dc.date.issued
2015-02
dc.identifier.citation
Menacho Márquez, Mauricio Ariel; Rodríguez Hernández, Carlos J.; Villarong, M. Ángeles; Pérez Valle, Jorge; Gadea, José; et al.; EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells; Landes Bioscience; Cell Cycle; 14; 4; 2-2015; 630-640
dc.identifier.issn
1538-4101
dc.identifier.uri
http://hdl.handle.net/11336/37916
dc.description.abstract
β-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Landes Bioscience
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ANTITUMORAL DRUG
dc.subject
DNA DAMAGE
dc.subject
INTEGRATED STRESS RESPONSE
dc.subject
REACTIVE OXYGEN SPECIES
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-03-02T14:18:06Z
dc.journal.volume
14
dc.journal.number
4
dc.journal.pagination
630-640
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Austin
dc.description.fil
Fil: Menacho Márquez, Mauricio Ariel. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
dc.description.fil
Fil: Rodríguez Hernández, Carlos J.. Hospital Sant Joan de Déu; España
dc.description.fil
Fil: Villarong, M. Ángeles. Instituto Universitario de Oncología del Principado de Asturias; España
dc.description.fil
Fil: Pérez Valle, Jorge. Instituto de Biología Molecular de Barcelona; España
dc.description.fil
Fil: Gadea, José. Instituto de Biología Molecular y Celular de Plantas; España
dc.description.fil
Fil: Belandia, Borja. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; España
dc.description.fil
Fil: Murguía, José R.. Universidad Politécnica de Valencia; España
dc.journal.title
Cell Cycle
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.4161/15384101.2014.994904
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.4161/15384101.2014.994904
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