Titre
Phosphorylation regulates FOXC2-mediated transcription in lymphatic endothelial cells.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Ivanov, K.I.
Auteure/Auteur
Agalarov, Y.
Auteure/Auteur
Valmu, L.
Auteure/Auteur
Samuilova, O.
Auteure/Auteur
Liebl, J.
Auteure/Auteur
Houhou, N.
Auteure/Auteur
Maby-El Hajjami, H.
Auteure/Auteur
Norrmén, C.
Auteure/Auteur
Jaquet, M.
Auteure/Auteur
Miura, N.
Auteure/Auteur
Zangger, N.
Auteure/Auteur
Ylä-Herttuala, S.
Auteure/Auteur
Delorenzi, M.
Auteure/Auteur
Petrova, T.V.
Auteure/Auteur
Liens vers les personnes
ISSN
1098-5549
Statut éditorial
Publié
Date de publication
2013
Volume
33
Numéro
19
Première page
3749
Dernière page/numéro d’article
3761
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
One of the key mechanisms linking cell signaling and control of gene expression is reversible phosphorylation of transcription factors. FOXC2 is a forkhead transcription factor that is mutated in the human vascular disease lymphedema-distichiasis and plays an essential role in lymphatic vascular development. However, the mechanisms regulating FOXC2 transcriptional activity are not well understood. We report here that FOXC2 is phosphorylated on eight evolutionarily conserved proline-directed serine/threonine residues. Loss of phosphorylation at these sites triggers substantial changes in the FOXC2 transcriptional program. Through genome-wide location analysis in lymphatic endothelial cells, we demonstrate that the changes are due to selective inhibition of FOXC2 recruitment to chromatin. The extent of the inhibition varied between individual binding sites, suggesting a novel rheostat-like mechanism by which expression of specific genes can be differentially regulated by FOXC2 phosphorylation. Furthermore, unlike the wild-type protein, the phosphorylation-deficient mutant of FOXC2 failed to induce vascular remodeling in vivo. Collectively, our results point to the pivotal role of phosphorylation in the regulation of FOXC2-mediated transcription in lymphatic endothelial cells and underscore the importance of FOXC2 phosphorylation in vascular development.
Sujets
PID Serval
serval:BIB_6A93F96A93DA
PMID
Open Access
Oui
Date de création
2013-10-10T07:06:33.921Z
Date de création dans IRIS
2025-05-20T22:24:29Z