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Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells
BACKGROUND: Recent studies have shown that in the developing embryo, arterial and venous identity is established by genetic mechanisms before circulation begins. Vascular endothelial growth factor (VEGF) signaling and its downstream Notch pathway play critical roles in arterial cell fate determinati...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398774/ https://www.ncbi.nlm.nih.gov/pubmed/18545664 http://dx.doi.org/10.1371/journal.pone.0002401 |
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author | Hayashi, Hisaki Kume, Tsutomu |
author_facet | Hayashi, Hisaki Kume, Tsutomu |
author_sort | Hayashi, Hisaki |
collection | PubMed |
description | BACKGROUND: Recent studies have shown that in the developing embryo, arterial and venous identity is established by genetic mechanisms before circulation begins. Vascular endothelial growth factor (VEGF) signaling and its downstream Notch pathway play critical roles in arterial cell fate determination. We have recently shown that Foxc1 and Foxc2, two closely related Fox transcription factors, are essential for arterial cell specification during development by directly inducing the transcription of Delta-like 4 (Dll4), a ligand for Notch receptors. However, the basic mechanisms whereby the VEGF and Notch signaling pathways control transcriptional regulation of arterial-specific genes have yet to be elucidated. METHODOLOGIES/PRINCIPAL FINDINGS: In the current study, we examined whether and how Foxc transcription factors are involved in VEGF and Notch signaling in induction of Dll4 as well as the Notch target gene Hey2 in endothelial cells. We found that Foxc1 and Foxc2 directly activate the Hey2 promoter via Foxc binding elements. Significantly, Foxc2 physically and functionally interacts with a Notch transcriptional activation complex containing Su(H) and Notch intracellular domain to induce Hey2 promoter activity. Moreover, activation of the Dll4 and Hey2 promoters is induced by VEGF in conjunction with either Foxc1 or Foxc2 more than by either component alone. VEGF-activated PI3K and ERK intracellular pathways modulate the transcriptional activity of Foxc proteins in Dll4 and Hey2 induction. CONCLUSIONS/SIGNIFICANCE: Our new findings demonstrate that Foxc transcriptional factors interact with VEGF and Notch signaling to regulate arterial gene expression in multiple steps of the VEGF-Dll4-Notch-Hey2 signaling pathway. |
format | Text |
id | pubmed-2398774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-23987742008-06-11 Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells Hayashi, Hisaki Kume, Tsutomu PLoS One Research Article BACKGROUND: Recent studies have shown that in the developing embryo, arterial and venous identity is established by genetic mechanisms before circulation begins. Vascular endothelial growth factor (VEGF) signaling and its downstream Notch pathway play critical roles in arterial cell fate determination. We have recently shown that Foxc1 and Foxc2, two closely related Fox transcription factors, are essential for arterial cell specification during development by directly inducing the transcription of Delta-like 4 (Dll4), a ligand for Notch receptors. However, the basic mechanisms whereby the VEGF and Notch signaling pathways control transcriptional regulation of arterial-specific genes have yet to be elucidated. METHODOLOGIES/PRINCIPAL FINDINGS: In the current study, we examined whether and how Foxc transcription factors are involved in VEGF and Notch signaling in induction of Dll4 as well as the Notch target gene Hey2 in endothelial cells. We found that Foxc1 and Foxc2 directly activate the Hey2 promoter via Foxc binding elements. Significantly, Foxc2 physically and functionally interacts with a Notch transcriptional activation complex containing Su(H) and Notch intracellular domain to induce Hey2 promoter activity. Moreover, activation of the Dll4 and Hey2 promoters is induced by VEGF in conjunction with either Foxc1 or Foxc2 more than by either component alone. VEGF-activated PI3K and ERK intracellular pathways modulate the transcriptional activity of Foxc proteins in Dll4 and Hey2 induction. CONCLUSIONS/SIGNIFICANCE: Our new findings demonstrate that Foxc transcriptional factors interact with VEGF and Notch signaling to regulate arterial gene expression in multiple steps of the VEGF-Dll4-Notch-Hey2 signaling pathway. Public Library of Science 2008-06-11 /pmc/articles/PMC2398774/ /pubmed/18545664 http://dx.doi.org/10.1371/journal.pone.0002401 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Hayashi, Hisaki Kume, Tsutomu Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title | Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title_full | Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title_fullStr | Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title_full_unstemmed | Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title_short | Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells |
title_sort | foxc transcription factors directly regulate dll4 and hey2 expression by interacting with the vegf-notch signaling pathways in endothelial cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398774/ https://www.ncbi.nlm.nih.gov/pubmed/18545664 http://dx.doi.org/10.1371/journal.pone.0002401 |
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