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dc.contributor.authorBechmann, Nicole
dc.contributor.authorPoser, Isabel
dc.contributor.authorSeifert, Verena
dc.contributor.authorGreunke, Christian
dc.contributor.authorUllrich, Martin
dc.contributor.authorQin, Nan
dc.contributor.authorWalch, Axel
dc.contributor.authorPeitzsch, Mirko
dc.contributor.authorRobledo Mercedes, Mercedes 
dc.contributor.authorPacak, Karel
dc.contributor.authorPietzsch, Jens
dc.contributor.authorRichter, Susan
dc.contributor.authorEisenhofer, Graeme
dc.date.accessioned2019-07-02T08:10:07Z
dc.date.available2019-07-02T08:10:07Z
dc.date.issued2019-04-28
dc.identifier.citationCancers (Basel). 2019;11(5)es_ES
dc.identifier.issn2072-6694es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7834
dc.description.abstractPheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis. For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catecholamine biosynthesis in pheochromocytoma cells naturally lacking Hif2α (MPC and MTT) or expressing both Hif1α and Hif2α (PC12). Cultivation under extrinsic hypoxia or in spheroid culture (intrinsic hypoxia) increased cellular dopamine and norepinephrine contents in all cell lines. To distinguish further between Hif1α- and Hif2α-driven effects we expressed Hif2α in MTT and MPC-mCherry cells (naturally lacking Hif2α). Presence of Hif2α resulted in similarly increased cellular dopamine and norepinephrine under hypoxia as in the control cells. Furthermore, hypoxia resulted in enhanced phosphorylation of tyrosine hydroxylase (TH). A specific knockdown of Hif1α in PC12 diminished these effects. Pseudohypoxic conditions, simulated by expression of Hif2α under normoxia resulted in increased TH phosphorylation, further stimulated by extrinsic hypoxia. Correlations with PPGL tissue data led us to conclude that catecholamine biosynthesis under hypoxia is mainly mediated through increased phosphorylation of TH, regulated as a short-term response (24-48 h) by HIF1α. Continuous activation of hypoxia-related genes under pseudohypoxia leads to a HIF2α-mediated phosphorylation of TH (permanent status).es_ES
dc.description.sponsorshipFunding: This research was funded by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio205/1 (project number: 314061271-TRR 205), Project No. B12 (N.B. and G.E.), Project No. B10 (S.R., J.P. and M.U.)and Project No. S01 (A.W., C.G. and M.P.) “The Adrenal: Central Relay in Health and Disease“, and by theParadi erence Foundation (N.B., I.P., S.R. and G.E.).es_ES
dc.language.isoenges_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectEPAS1es_ES
dc.subjectHIFes_ES
dc.subjectCatecholaminees_ES
dc.subjectHypoxiaes_ES
dc.subjectPheochromocytoma and paragangliomaes_ES
dc.subjectPhosphorylation tyrosine hydroxylasees_ES
dc.subjectPseudohypoxiaes_ES
dc.subjectSpheroidses_ES
dc.titleImpact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cellses_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID31035382es_ES
dc.format.volume11es_ES
dc.format.number5es_ES
dc.format.page594es_ES
dc.identifier.doi10.3390/cancers11050594es_ES
dc.contributor.funderDeutsche Forschungsgemeinschaft (Alemania) 
dc.contributor.funderParadifference Foundation 
dc.description.peerreviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.3390/cancers11050594.es_ES
dc.identifier.journalCancerses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Cáncer Endocrino Hereditarioes_ES
dc.rights.accessRightsopen accesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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