The transcription factor Net regulates the angiogenic switch.
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.
Zheng
Hong
H
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
Wasylyk
Christine
C
Ayadi
Abdelkader
A
Abecassis
Joseph
J
Schalken
Jack A
JA
Rogatsch
Hermann
H
Wernert
Nicolas
N
Maira
Sauveur-Michel
SM
Multon
Marie-Christine
MC
Wasylyk
Bohdan
B
D000818:Animals; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D015513:Oncogene Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism
C086924:Elk3 protein, mouse; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins