Phosphorylation modulates FOXC2 transcriptional program by controlling the high-order interaction with DNA.

Détails

ID Serval
serval:BIB_8E30AF9856AD
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Institution
Titre
Phosphorylation modulates FOXC2 transcriptional program by controlling the high-order interaction with DNA.
Titre de la conférence
Joint Meeting of the Society for Microcirculation and Vascular Biology/Swiss Society for Microcirculation
Auteur⸱e⸱s
Ivanov K., Valmu L., Norrmen C., Hajjami H. M.-E., Delorenzi M., Agalarov Y.a.n., Samuilova O., Jaquet M., Miura N., Alitalo K., Yla-Herttuala S., Petrova T. V.
Adresse
Bern, Switzerland, Oct 08, 2009
ISBN
1018-1172
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
46
Série
Journal of Vascular Research
Pages
44-44
Langue
anglais
Notes
Meeting Abstract
Résumé
Phosphorylation of transcription factors is a rapid and reversible process linking cell signaling and control of gene expression, therefore understanding how it controls the transcription factor functions is one of the challenges of functional genomics. We performed such analysis for the forkhead transcription factor FOXC2 mutated in human hereditary disease lymphedemadistichiasis and important for the development of venous and lymphatic valves and lymphatic collecting vessels. We found that FOXC2 is phosphorylated in a cell-cycle dependent manner on eight evolutionary conserved serine/threonine residues, seven of which are clustered within a 70 amino acid domain. Surprisingly, the mutation of phosphorylation sites or a complete deletion of the domain did not affect the transcriptional activity of FOXC2 in a synthetic reporter assay. However, overexpression of the wild type or phosphorylation-deficient mutant resulted in overlapping but distinct gene expression profiles suggesting that binding of FOXC2 to individual sites under physiological conditions is affected by phosphorylation. To gain a direct insight into the role of FOXC2 phosphorylation, we performed comparative genome-wide location analysis (ChIP-chip) of wild type and phosphorylation-deficient FOXC2 in primary lymphatic endothelial cells. The effect of loss of phosphorylation on FOXC2 binding to genomic sites ranged from no effect to nearly complete inhibition of binding, suggesting a mechanism for how FOXC2 transcriptional program can be differentially regulated depending on FOXC2 phosphorylation status. Based on these results, we propose an extension to the enhanceosome model, where a network of genomic context-dependent DNA-protein and protein-protein interactions not only distinguishes a functional site from a nonphysiological site, but also determines whether binding to the functional site can be regulated by phosphorylation. Moreover, our results indicate that FOXC2 may have different roles in quiescent versus proliferating lymphatic endothelial cells in vivo.
Web of science
Création de la notice
27/10/2009 16:22
Dernière modification de la notice
20/08/2019 14:52
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