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RESEARCH PAPER

The transcription factor Net regulates the angiogenic switch

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch Cedex, France , ² UPRES EA 34-30, Centre Paul Strauss, 67085 Strasbourg Cedex, France , ³ University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands , ⁴ Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria , ⁵ Institute of Pathology, University of Bonn, 53011 Bonn, Germany , ⁶ Aventis, Recherche-Développement, 94403 Vitry-sur-seine, France

Angiogenesis is fundamental to physiological and pathological processes. Despite intensive efforts, little is known about the intracellular circuits that regulate angiogenesis. The transcription factor Net is activated by phosphorylation induced by Ras, an indirect regulator of angiogenesis. Net is expressed at sites of vasculogenesis and angiogenesis during early mouse development, suggesting that it could have a role in blood vessel formation. We show here that down-regulation of Net inhibits angiogenesis and vascular endothelial growth factor (VEGF) expression in vivo, ex vivo, and in vitro. Ras-activated phosphorylated Net (P-Net) stimulates the mouse VEGF promoter through the -80 to -53 region that principally binds Sp1. P-Net and VEGF are coexpressed in angiogenic processes in wild-type mouse tissues and in human tumors. We conclude that Net is a regulator of angiogenesis that can switch to an activator following induction by pro-angiogenic molecules.

[Keywords: Wound healing; tumors; VEGF; Sp1; KSHV-GPCR]

Received May 13, 2003; revised version accepted July 11, 2003.

⁷ Present address: Novartis Pharma AG, BU Oncology, In Vivo Pharmacology, Klybeckstrasse, CH4002 Basel, Switzerland.

⁸ Corresponding author.
E-MAIL boh{at}titus.u-strasbg.fr; FAX 33-3-8865-3201.

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