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Characterization of endothelial to mesenchymal transition induced by Notch

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dc.contributor.author Frías Hernández, Àlex
dc.contributor.other Díaz Cortés, Víctor Manuel
dc.contributor.other García de Herreros, Antonio
dc.contributor.other Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.date.accessioned 2024-03-16T02:34:50Z
dc.date.available 2024-03-16T02:34:50Z
dc.date.issued 2017-04-10T10:27:42Z
dc.date.issued 2017-04-10T10:27:42Z
dc.date.issued 2015-12-10
dc.identifier http://hdl.handle.net/10803/402193
dc.identifier.uri http://hdl.handle.net/10230/32442
dc.description.abstract Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces an endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT resulting in down-regulation of VE-cadherin and up-regulation of mesenchymal genes such as Fibronectin and Snail1/2. In these cells, TGF-β1 exacerbates Notch effects increasing Snail1 and Fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in GSK-3β phosphorylation and inactivation what facilitates Snail1 nuclear retention and protein stabilization. However, the total activity of Akt was down-regulated. The discrepancy between Akt activity and GSK-3β phosphorylation is explained because Notch induces a switch in the Akt isoforms since it decreases Akt1, the predominant isoform expressed in ECs, and up-regulates Akt2 transcription. Mechanistically, Akt2 induction requires the stimulation of TCF-4/β-catenin transcriptional complex that activates the Akt2 promoter. Active phosphorylated Akt2 translocates to the nucleus in Notch-expressing cells resulting in GSK-3β inactivation in this compartment. In the nucleus Akt2, but not Akt1 co-localizes with Lamin B in the nuclear envelope. Besides promoting GSK-3β inactivation, Notch down-regulates FoxO1, another Akt2 nuclear substrate. As a consequence, Notch protects ECs against oxidative stress-induced apoptosis through an Akt2 and Snail1-dependent mechanism.
dc.description.abstract Programa de doctorat en Biomedicina
dc.format 139 p.
dc.format application/pdf
dc.format application/pdf
dc.language.iso eng
dc.publisher Universitat Pompeu Fabra
dc.rights ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
dc.rights info:eu-repo/semantics/openAccess
dc.source TDX (Tesis Doctorals en Xarxa)
dc.title Characterization of endothelial to mesenchymal transition induced by Notch
dc.type info:eu-repo/semantics/doctoralThesis
dc.type info:eu-repo/semantics/publishedVersion
dc.date.modified 2024-03-15T10:57:27Z
dc.subject.keyword Snail1
dc.subject.keyword EndMT
dc.subject.keyword Akt2
dc.subject.keyword Apoptosis
dc.subject.keyword Notch
dc.subject.keyword 576


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