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HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

Oncogene volume 26, pages 7480–7489 (2007)Cite this article

Abstract

The mechanisms that are responsible for the restricted pattern of expression of the VE-cadherin gene in endothelial cells are not clearly understood. Regulation of expression is under the control of an approximately 140 bp proximal promoter that provides basal, non-endothelial specific expression. A larger region contained within the 2.5 kb genomic DNA sequence located ahead of the transcription start is involved in the specific expression of the gene in endothelial cells. We show here that the VE-cadherin promoter contains several putative hypoxia response elements (HRE) which are able to bind endothelial nuclear factors under normoxia. The VE-cadherin gene is not responsive to hypoxia but hypoxia-inducible factor (HIF)-2α specifically activates the promoter while HIF-1α does not. The HRE, that are involved in this activity have been identified. Further, we show that HIF-2α cooperates with the Ets-1 transcription factor for activation of the VE-cadherin promoter and that this synergy is dependent on the binding of Ets-1 to DNA. This cooperative action of HIF-2α with Ets-1 most probably participates to the transcriptional regulation of expression of the gene in endothelial cells. This mechanism may also be involved in the expression of the VE-cadherin gene by tumor cells in the process of vascular mimicry.

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Acknowledgements

We thank Dr P Huber for providing us the H5 V and 3T3 cells, Drs M Gassman and D Russell for providing us with the HIF-1 and EPAS-1 expression plasmids. This work was funded by Ligue Nationale contre le Cancer (Equipe labellisée La Ligue 2005), Association for International Cancer Research, Association pour la Recherche sur le Cancer, and Fondation de France. AL, EL, BC and FL were recipients of Ligue Nationale contre le Cancer fellowships. FS is Directeur de Recherche INSERM.

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  1. A Le Bras and F Lionneton: These authors equally contributed to this work.

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  1. CNRS, UMR8161, Lille France; Univ Lille I, Lille, France; Univ Lille II, Lille, France; Inst Pasteur de Lille, Lille, France

    A Le Bras, F Lionneton, V Mattot, E Lelièvre, B Caetano, N Spruyt & F Soncin

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  1. A Le Bras
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Correspondence to F Soncin.

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Le Bras, A., Lionneton, F., Mattot, V. et al. HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites. Oncogene 26, 7480–7489 (2007). https://doi.org/10.1038/sj.onc.1210566

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