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The airway branch regulator, Sprouty2, represses vasculogenesis in fetal lung by direct interaction with the VEGF promoter
Author(s) -
Land Stephen C,
Walker David J,
Scott Claire L
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.861.8
Subject(s) - chromatin immunoprecipitation , biology , microbiology and biotechnology , vascular endothelial growth factor , fibroblast growth factor , vasculogenesis , respiratory epithelium , gene knockdown , vascular endothelial growth factor a , progenitor cell , cancer research , promoter , epithelium , cell culture , gene expression , stem cell , gene , genetics , receptor , vegf receptors
Lung development requires co‐ordinated growth of airway and vascular structures to form the branched network of tubes which supply the blood/gas barrier. We have shown that the inducer of airway outgrowth, Fibroblast Growth Factor‐10 (FGF‐10), promotes vascular signalling from fetal airway epithelium through Sprouty2 cleavage and consequent mTORC1‐dependent activation of HIF‐1α. However, fetal airway epithelium displays a nuclear sub‐population of Sprouty2 which associates with chromatin. We therefore hypothesised that uncleaved Sprouty2 represses HIFα interaction with the VEGF‐A promoter by competitive interaction with the hypoxia response element (HRE). Chromatin immunoprecipitation (ChIP) revealed that Sprouty2 interacts with the VEGF promoter in fetal airway epithelium by: 1) weak, FGF‐10‐dependent, binding to the HRE promoter region, and, 2) constitutive, FGF‐10‐independent binding to GC‐rich regions near the transcriptional start site. This interaction was inhibitory as modulation of Sprouty2 activity by siRNA knockdown or null (Y55F) mutation augmented HIF‐dependent VEGF‐A production. Moreover, immunoprecipitation revealed an FGF‐10‐dependent interaction between Sprouty2 and the HIF‐competitive inhibitor, HIF‐3α. We conclude that Sprouty2 represses HIF‐mediated VEGF‐A production in fetal lung by direct association with critical sequences within the VEGF‐A promoter.