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dc.contributor.authorPantazopoulou, Areties_ES
dc.contributor.authorGalmarini, C.M.es_ES
dc.contributor.authorPeñalva, Miguel Ángeles_ES
dc.date.accessioned2018-07-06T09:51:48Z-
dc.date.available2018-07-06T09:51:48Z-
dc.date.issued2018-06-05-
dc.identifier.citationScientific Reports 8: 8616 (2018)es_ES
dc.identifier.issn2045-2322-
dc.identifier.urihttp://hdl.handle.net/10261/167419-
dc.description19 p.-8 fig.es_ES
dc.description.abstractPlocabulin (PM060184) is a microtubule depolymerizing agent with potent antiproliferative activity undergoing phase II clinical trials for the treatment of solid tumors. Plocabulin shows antifungal activity virtually abolishing growth of the filamentous fungus Aspergillus nidulans. A. nidulans hyphae depend both on mitotic and interphase microtubules, as human cells. Here, we exploited the A. nidulans genetic amenability to gain insight into the mechanism of action of plocabulin. By combining mutations in the two A. nidulans β-tubulin isotypes we obtained a plocabulin-insensitive strain, showing that β-tubulin is the only molecular target of plocabulin in fungal cells. From a genetic screen, we recovered five mutants that show plocabulin resistance but do not carry mutations in β-tubulin. Resistance mutations resulted in amino acid substitutions in (1) two subunits of the eukaryotic translation initiation factor eIF2B activating the General Amino Acid Control, (2) TIM44, an essential component of the inner mitochondrial membrane translocase, (3) two transcription factors of the binuclear zinc cluster family potentially interfering with the uptake or efflux of plocabulin. Given the conservation of some of the identified proteins and their respective cellular functions in the tumor environment, our results pinpoint candidates to be tested as potential biomarkers for determination of drug efficiency.es_ES
dc.description.sponsorshipThis work was supported by the Spanish Ministry of Economy and Competitiveness [INNPACTO, project number IPT-2011-0752-900000 and BIO2015-65090R] and by a CSIC-Pharmamar contract.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.relationMINECO/ICTI2013-2016/BIO2015-65090Res_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rightsopenAccesses_ES
dc.subjectGuanine-nucleotide exchangees_ES
dc.subjectInitiation-factor 2bes_ES
dc.subjectIntegrative genomics vieweres_ES
dc.subjectFungus Aspergillus-Nidulanses_ES
dc.subjectAmino-acid controles_ES
dc.subjectTranslation initiationes_ES
dc.subjectBeta-Tubulines_ES
dc.subjectAlpha-subunites_ES
dc.subjectTranscriptional regulatorses_ES
dc.subjectSaccharomyces-Cerevisiaees_ES
dc.titleMolecular basis of resistance to the microtubule-depolymerizing antitumor compound plocabulines_ES
dc.typeartículoes_ES
dc.identifier.doihttp://dx.doi.org/10.1038/s41598-018-26736-3-
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41598-018-26736-3es_ES
dc.identifier.e-issn2045-2322-
dc.rights.licensehttps://creativecommons.org/licenses/by/4.0/es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)es_ES
dc.relation.csices_ES
oprm.item.hasRevisionno ko 0 false*
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003339es_ES
dc.contributor.orcidPantazopoulou, Areti [0000-0002-1985-6525]es_ES
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