title: Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNF alpha -induced PAI-1 expression.
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.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.forename: Peter
authors.initials: P
authors.lastname: Hufnagl
authors.forename: Renate
authors.initials: R
authors.lastname: Hofer-Warbinek
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Schmid
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Breuss
authors.forename: Renate
authors.initials: R
authors.lastname: Huber-Beckmann
authors.forename: Markus
authors.initials: M
authors.lastname: Lucerna
authors.forename: Nikolina
authors.initials: N
authors.lastname: Papac
authors.forename: Hanna
authors.initials: H
authors.lastname: Harant
authors.forename: Ivan
authors.initials: I
authors.lastname: Lindley
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
mesh_terms: D001161:Arteriosclerosis / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017395:Plasminogen Activator Inhibitor 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha