Endothelial-to-mesenchymal transition (EndMT) is a biological process that allows the transdifferentiation of endothelial cells into mesenchymal cells, thus originating cells capable of novel functions necessary for the surrounding environment. EndMT regulates endocardial cushion formation during embryo development, and it is stimulated by the TGFβ/BMP family of ligands. In adults, EndMT is activated upon an injury event or during pathological conditions like organ fibrosis, cerebral cavernous malformation, cancer-associated fibroblast generation, and others. Hence, it is necessary to better characterize the molecular regulators cooperating with TGFβ signaling in driving EndMT, to possibly provide novel therapeutic targets to treat these pathological conditions. Here we studied YAP, a co-transcriptional regulator involved in several cell biology processes, among which epithelial-to-mesenchymal transition (EMT). Since EndMT is considered a “specialized” form of EMT, and since YAP and TGFβ signaling were shown to cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling, and characterized the underlying molecular mechanism. Results here presented demonstrate that YAP is required for a complete TGFβ-mediated EndMT response in vitro, and that YAP contributes specifically to SMAD3-, but not SMAD1-, driven EndMT gene transcription. We provide novel evidence that YAP positively regulates EndMT playing the twofold role of acting as SMAD3 co-transcriptional factor on the promoter of EndMT target genes and, in parallel, preventing SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-driven EndMT.
|Titolo:||THE DUAL ROLE OF YAP IN DRIVING TGFß-MEDIATED ENDMT|
|Supervisori e coordinatori interni:||DEJANA, ELISABETTA|
|Data di pubblicazione:||26-mar-2018|
|Parole Chiave:||EndMT; YAP; TGFβ|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Citazione:||THE DUAL ROLE OF YAP IN DRIVING TGFß-MEDIATED ENDMT ; supervisor: E. Dejana; added supervisor: C. Giampietro. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, Università degli Studi di Milano, 2018 Mar 26. ((29. ciclo, Anno Accademico 2017.|
|Appare nelle tipologie:||Tesi di dottorato|