The transcriptional corepressor NAB2 blocks Egr-1-mediated growth factor activation and angiogenesis.
Effective tissue repair results from a rapid, temporally orchestrated series of events. At the site of local tissue injury, the production of many growth factors and cytokines is, in part, stimulated by the early growth response transcription factors such as Egr-1. Egr-1 protein binds to a family of corepressor proteins called NAB which function to block or limit Egr-1 trans-activation of cognate target genes. NAB2 blocks Egr-1 activation of the tissue factor (TF) promoter, Egr-1 stimulated production of PDGF-AB, HGF, TGFbeta(1), and VEGF and the endogenous expression of PDGF-AB and TGFbeta(1). Expression of a wild-type NAB2 but not a dominant negative NAB2 mutant abrogates Egr-1 driven TF promoter activity and tubule formation in an in vitro model of angiogenesis. These findings may have importance in any tissue that is subject to scarring after acute or chronic injury.
Houston
P
P
Cardiovascular Systems Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England. pb6174@glaxowellcome.co.uk
Campbell
C J
CJ
Svaren
J
J
Milbrandt
J
J
Braddock
M
M
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D017874:Immediate-Early Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006133:Growth Substances; D017874:Immediate-Early Proteins; C491000:NAB2 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D013925:Thromboplastin