dc.contributor.author | Bechmann, Nicole | |
dc.contributor.author | Poser, Isabel | |
dc.contributor.author | Seifert, Verena | |
dc.contributor.author | Greunke, Christian | |
dc.contributor.author | Ullrich, Martin | |
dc.contributor.author | Qin, Nan | |
dc.contributor.author | Walch, Axel | |
dc.contributor.author | Peitzsch, Mirko | |
dc.contributor.author | Robledo Mercedes, Mercedes | |
dc.contributor.author | Pacak, Karel | |
dc.contributor.author | Pietzsch, Jens | |
dc.contributor.author | Richter, Susan | |
dc.contributor.author | Eisenhofer, Graeme | |
dc.date.accessioned | 2019-07-02T08:10:07Z | |
dc.date.available | 2019-07-02T08:10:07Z | |
dc.date.issued | 2019-04-28 | |
dc.identifier.citation | Cancers (Basel). 2019;11(5) | es_ES |
dc.identifier.issn | 2072-6694 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/7834 | |
dc.description.abstract | Pheochromocytomas 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.sponsorship | Funding: 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.iso | eng | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | EPAS1 | es_ES |
dc.subject | HIF | es_ES |
dc.subject | Catecholamine | es_ES |
dc.subject | Hypoxia | es_ES |
dc.subject | Pheochromocytoma and paraganglioma | es_ES |
dc.subject | Phosphorylation tyrosine hydroxylase | es_ES |
dc.subject | Pseudohypoxia | es_ES |
dc.subject | Spheroids | es_ES |
dc.title | Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 31035382 | es_ES |
dc.format.volume | 11 | es_ES |
dc.format.number | 5 | es_ES |
dc.format.page | 594 | es_ES |
dc.identifier.doi | 10.3390/cancers11050594 | es_ES |
dc.contributor.funder | Deutsche Forschungsgemeinschaft (Alemania) | |
dc.contributor.funder | Paradifference Foundation | |
dc.description.peerreviewed | Sí | es_ES |
dc.relation.publisherversion | https://doi.org/10.3390/cancers11050594. | es_ES |
dc.identifier.journal | Cancers | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Cáncer Endocrino Hereditario | es_ES |
dc.rights.accessRights | open access | es_ES |