title: Hepatocyte growth factor regulates E box-dependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells.
abstract: OBJECTIVE
  We sought to determine the etiologic mechanism of pleiotropic growth factor, hepatocyte growth factor (HGF), as a regulator of hepatic synthesis of plasminogen activator inhibitor (PAI)-1, the physiological inhibitor of fibrinolysis and a potential inducer of atherothrombosis.
  
  
  RESULTS
  HGF increased PAI-1 mRNA expression and PAI-1 protein accumulation in the conditioned media of human liver-derived HepG2 cells, and increased hepatic PAI-1 mRNA expression in vivo in mice. HGF-inducible PAI-1 mRNA was attenuated by U0126, a specific inhibitor of mitogen-activated protein kinase (MAPK) kinase, and genistein, an inhibitor of tyrosine kinase. HGF increased the human PAI-1 promoter (-829 to +36 bp) activity, and deletion and mutation analysis uncovered a functional E box (5'-CACATG-3') at positions -158 to -153 bp. Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways. Co-transfection of USF1 expression vector increased PAI-1 promoter activity. Sterol regulatory element-binding protein-1 attenuated HGF-inducible PAI-1 promoter activity.
  
  
  CONCLUSIONS
  Because USFs are involved in the regulation of carbohydrates and lipid metabolism, HGF-mediated PAI-1 production may provide a novel link between atherothrombosis and metabolic derangements. Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients.
authors.affiliation: The Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kitaku, Sapporo, Japan 060-8638.
authors.forename: Shogo
authors.initials: S
authors.lastname: Imagawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.forename: Tomoo
authors.initials: T
authors.lastname: Furumoto
authors.forename: Takeaki
authors.initials: T
authors.lastname: Kaneko
authors.forename: Tarikuz
authors.initials: T
authors.lastname: Zaman
authors.forename: Yuki
authors.initials: Y
authors.lastname: Satoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA; D024721:E-Box Elements; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology; D051720:Upstream Stimulatory Factors / Q000502:physiology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; D051720:Upstream Stimulatory Factors; D017228:Hepatocyte Growth Factor; D004247:DNA; D011505:Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases