title: NAB2, a corepressor of EGR-1, inhibits vascular endothelial growth factor-mediated gene induction and angiogenic responses of endothelial cells.
abstract: In this study we have investigated the role of a specific corepressor of EGR-1, NAB2, to down-regulate vascular endothelial growth factor (VEGF)-induced gene expression in endothelial cells and to inhibit angiogenesis. Firstly, we show a reciprocal regulation of EGR-1 and NAB2 following VEGF treatment. During the initial phase EGR-1 is rapidly induced and NAB2 levels are down-regulated. This is followed by a reduction of EGR-1 and a concomitant increase of NAB2. Secondly, using the tissue factor gene as a readout for VEGF-induced and EGR-1-regulated gene expression we demonstrate that NAB2 can completely block VEGF-induced tissue factor reporter gene activity. Thirdly, by adenovirus-mediated expression we show that NAB2 inhibits up-regulation of tissue factor, VEGF receptor-1, and urokinase plasminogen activator mRNAs even when a combination of VEGF and bFGF is used for induction. In addition, NAB2 overexpression significantly reduced tubule and sprout formation in two different in vitro angiogenesis assays and largely prevented the invasion of cells and formation of vessel-like structures in the murine Matrigel model. These data suggest that NAB2 regulation represents a mechanism to guarantee transient EGR-1 activity following exposure of endothelial cells to VEGF and that NAB2 overexpression could be used to inhibit signals involved in the early phase of angiogenesis.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Vienna International Research Cooperation Center, University of Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Lucerna
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Romana
authors.initials: R
authors.lastname: Schäfer
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.forename: Yuri
authors.initials: Y
authors.lastname: Koshelnick
authors.forename: Horst-Dietmar
authors.initials: HD
authors.lastname: Müller
authors.forename: Katja
authors.initials: K
authors.lastname: Issbrücker
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
authors.forename: Erhard
authors.initials: E
authors.lastname: Hofer
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D051766:Early Growth Response Protein 1; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007797:Laminin; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D009363:Neoplasm Proteins; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011509:Proteoglycans; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D004338:Drug Combinations; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016228:Endothelial Growth Factors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008222:Lymphokines; C491000:NAB2 protein, human; D009363:Neoplasm Proteins; D011509:Proteoglycans; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen