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ETS1 lowers capillary endothelial cell density at confluence and induces the expression of VE-cadherin

Oncogene volume 19, pages 2438–2446 (2000)Cite this article

Abstract

Ets1 is a transcription factor expressed in endothelial cells during angiogenesis but its target genes and function in blood vessel formation are still unknown. We have over-expressed Ets1 as a tagged protein in brain capillary endothelial cells and in 3T3 fibroblasts using a retroviral vector. Over-expression of Ets1 reduced by nearly half cell density at confluence of endothelials but not of fibroblasts. As density at confluence is controlled in part by cadherins, this growth arrest could be due to the up-regulation of these cell contact molecules. Indeed, Ets1 increased the expression of the endothelial-specific VE-cadherin without affecting N-cadherin expression levels. In parallel, both a dominant negative mutant of Ets members and an Ets1 anti-sense oligonucleotide inhibited VE-cadherin expression in endothelial cells. Ets1 bound to two Ets-binding sites located in the proximal region of the VE-cadherin promoter. Mutation of these sites abolished Ets1-induced transactivation of the promoter. The present work is the first demonstration of a function of Ets1 in the regulation of a specific endothelial marker based on its endogenous gene and protein expression.

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Abbreviations

3T3:

mouse fibroblasts

EBS:

Ets-binding site

H5V:

mouse heart endothelioma cells

IBE:

new born mouse brain capillary endothelial cells

MBE:

mouse brain capillary endothelial cells

EMSA:

electromobility-shift assay

rEts1:

recombinant Ets1

Tag:

haemophilus influenzae hemaglutinin epitope

FGF-2:

fibroblast growth factor-2

VEGF:

vascular-endothelial growth factor/vascular permeability factor

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Acknowledgements

We thank Drs Robert Auerbach and Marco Presta for MBE cells, Laena Claesson-Welsh for IBE cells, Arthur Bank for GP+E86 cells, Richard Mulligan for the pMFG plasmid, Bernard Hoflack, Roland Leborgne, Eric Maire and Gérard Torpier for their help with fluorescence microscopy analysis. We thank Agnès Bègue and Dr Patrick Martin for technical help with vector cloning, and Drs Simon Saule, Yvan De Launoit and Thierry Calmels for helpful discussions. This work was funded by Association pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer, Fondation pour la Recherche Médicale, Association for International Cancer Research, Groupement des Entreprises Françaises dans la Lutte contre le Cancer. F Soncin is ‘Chargé de Recherche de l'Institut National de la Santé et de la Recherche Médicale'. E Lelièvre is supported by a fellowship from the ‘Ministère de l'Education Nationale, de la Recherche et de la Technologie’.

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  1. V Mattot

    Present address: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

Authors and Affiliations

  1. CNRS EP560 – Institut de Biologie de Lille, Institut Pasteur de Lille, 1 rue Calmette, Lille Cedex, 59021, France

    E Lelièvre, V Mattot, B Vandenbunder & F Soncin

  2. Laboratoire de Transgenèse et Differenciation Cellulaire, CEA-Grenoble, Grenoble, France

    P Huber

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Lelièvre, E., Mattot, V., Huber, P. et al. ETS1 lowers capillary endothelial cell density at confluence and induces the expression of VE-cadherin. Oncogene 19, 2438–2446 (2000). https://doi.org/10.1038/sj.onc.1203563

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