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dc.contributor.authorCiria, Maria
dc.contributor.authorGarcia, Nahuel A.
dc.contributor.authorOntoria-Oviedo, Imelda
dc.contributor.authorGonzalez-King, Hernan
dc.contributor.authorCarrero, Ruben
dc.contributor.authorde la Pompa, Jose Luis 
dc.contributor.authorAnastasio Montero, Jose
dc.contributor.authorSepulveda, Pilar
dc.date.accessioned2017-10-20T10:23:10Z
dc.date.available2017-10-20T10:23:10Z
dc.date.issued2017
dc.identifierISI:000404053100004
dc.identifier.citationStem Cells Dev. 2017; 26(13):973-985
dc.identifier.issn1547-3287
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5108
dc.description.abstractMesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1 alpha) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1 alpha in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1 alpha in MSCs increased protein levels of the Notch ligands Jagged 1-2 and Delta-like (Dll) 1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by gamma-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1 alpha expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization.
dc.description.sponsorshipThis work was supported, in part, by grants from the Instituto de Salud Carlos III PI13/00414, PI16/0107, RE-TICS RD12/0019/0025 to P.S. and RETICS RD12/0019/0003 (TERCEL) to J.L.D.L.P cofunded by FEDER ``una manera de hacer Europa. It was also supported by the Regenerative Medicine Program of Instituto de Salud Carlos III and Valencian Community to Centro de Investigacion Principe Felipe. The authors are grateful to Dr. A. Dorronsoro for critical review of the work and Dr. K McCreath for manuscript editing.
dc.language.isoeng
dc.publisherMary Ann Liebert 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/*
dc.subjectMesenchymal stem cells
dc.subjectHypoxia-inducible factor
dc.subjectNotch
dc.subjectSUMOylation
dc.subjectMigration
dc.subjectProliferation
dc.subjectTRANSCRIPTIONAL ACTIVITY
dc.subjectMYOCARDIAL-INFARCTION
dc.subjectGAMMA-SECRETASE
dc.subjectBREAST-CANCER
dc.subjectACTIVATION
dc.subjectSUMOYLATION
dc.subjectHIF-1-ALPHA
dc.subjectHIF-1
dc.subjectDIFFERENTIATION
dc.subjectOxygen
dc.titleMesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1 alpha Upstream of Notch and SUMO Pathways
dc.typejournal article
dc.rights.licenseAtribución-NoComercial 4.0 Internacional*
dc.identifier.pubmedID28520516
dc.format.volume26
dc.format.page973-985
dc.identifier.doi10.1089/scd.2016.0331
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderGeneralitat Valenciana (España) 
dc.description.peerreviewed
dc.identifier.e-issn1557-8534
dc.relation.publisherversionhttps://doi.org/10.1089/scd.2016.0331
dc.identifier.journalSTEM CELLS AND DEVELOPMENT
dc.repisalud.orgCNICCNIC::Grupos de investigación::Señalización Intercelular durante el Desarrollo y la Enfermedad Cardiovascular
dc.repisalud.institucionCNIC
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI13/00414es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI16/0107es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0019/0025es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0019/0003es_ES
dc.rights.accessRightsopen accesses_ES


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