Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNF alpha -induced PAI-1 expression.
Blood
; 101(8): 3042-8, 2003 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-12506026
ABSTRACT
Plasminogen activator inhibitor 1 (PAI-1) is the main fibrinolysis inhibitor, and high plasma levels are associated with an increased risk for vascular diseases. Inflammatory cytokines regulate PAI-1 through a hitherto unclear mechanism. Using reporter gene analysis, we could identify a region in the PAI-1 promoter that contributes to basal expression as well as to tumor necrosis factor alpha (TNFalpha) induction of PAI-1 in endothelial cells. Using this region as bait in a genetic screen, we could identify Nur77 (NAK-1, TR3, NR4A1) as an inducible DNA-binding protein that binds specifically to the PAI-1 promoter. Nur77 drives transcription of PAI-1 through direct binding to an NGFI-B responsive element (NBRE), indicating monomeric binding and a ligand-independent mechanism. Nur77, itself, is transcriptionally up-regulated by TNFalpha. High expression levels of Nur77 and its colocalization with PAI-1 in atherosclerotic tissues indicate that the described mechanism for PAI-1 regulation may also be operative in vivo.
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Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Regulación de la Expresión Génica
/
Regiones Promotoras Genéticas
/
Factor de Necrosis Tumoral alfa
/
Inhibidor 1 de Activador Plasminogénico
/
Proteínas de Unión al ADN
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Blood
Año:
2003
Tipo del documento:
Article
País de afiliación:
Austria