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Authordc.contributor.authorRivas, Solange 
Authordc.contributor.authorSilva, Patricio 
Authordc.contributor.authorReyes Rojas, Montserrat 
Authordc.contributor.authorSepúlveda, Hugo 
Authordc.contributor.authorSolano, Luis 
Authordc.contributor.authorAcuña, Juan 
Authordc.contributor.authorGuerrero, Marisol 
Authordc.contributor.authorVaras Godoy, Manuel 
Authordc.contributor.authorQuest, Andrew F. G. 
Authordc.contributor.authorMontecino, Martín 
Authordc.contributor.authorTorres Gómez, Vicente 
Admission datedc.date.accessioned2021-07-05T21:03:39Z
Available datedc.date.available2021-07-05T21:03:39Z
Publication datedc.date.issued2020
Cita de ítemdc.identifier.citationScientific Reports (2020) 10:22302es_ES
Identifierdc.identifier.other10.1038/s41598-020-79270-6
Identifierdc.identifier.urihttp://repositorio.uchile.cl/handle/2250/180416
Abstractdc.description.abstractTumor hypoxia and the hypoxia inducible factor-1, HIF-1, play critical roles in cancer progression and metastasis. We previously showed that hypoxia activates the endosomal GTPase Rab5, leading to tumor cell migration and invasion, and that these events do not involve changes in Rab protein expression, suggesting the participation of intermediate activators. Here, we identified ALS2, a guanine nucleotide exchange factor that is upregulated in cancer, as responsible for increased Rab5-GTP loading, cell migration and metastasis in hypoxia. Specifically, hypoxia augmented ALS2 mRNA and protein levels, and these events involved HIF-1 alpha -dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1 alpha -binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1 alpha stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1 alpha. Strikingly, ALS2 upregulation in hypoxia was required for Rab5 activation, tumor cell migration and invasion, as well as experimental metastasis in C57BL/6 mice. Finally, immunohistochemical analyses in patient biopsies with renal cell carcinoma showed that elevated HIF-1 alpha correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis.es_ES
Patrocinadordc.description.sponsorshipComision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1180495 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDAP 15130011 15090007 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 3170660 1170925 1170878 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)es_ES
Lenguagedc.language.isoenes_ES
Publisherdc.publisherNaturees_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
Sourcedc.sourceScientific Reportses_ES
Keywordsdc.subjectPredicts Poor-Prognosises_ES
Keywordsdc.subjectRAB11 Traffickinges_ES
Keywordsdc.subjectActivationes_ES
Keywordsdc.subjectExpressiones_ES
Keywordsdc.subjectALS2/ALSINes_ES
Keywordsdc.subjectOxygenes_ES
Keywordsdc.subjectMigrationes_ES
Keywordsdc.subjectEndocytosises_ES
Keywordsdc.subjectAdhesiones_ES
Keywordsdc.subjectInvasiones_ES
Títulodc.titleThe RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cellses_ES
Document typedc.typeArtículo de revistaes_ES
dcterms.accessRightsdcterms.accessRightsAcceso Abierto
Catalogueruchile.catalogadorcfres_ES
Indexationuchile.indexArtículo de publicación ISIes_ES


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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile