title: Synergistic and multidimensional regulation of plasminogen activator inhibitor type 1 expression by transforming growth factor type β and epidermal growth factor.
abstract: The major physiological inhibitor of plasminogen activator, type I plasminogen activator inhibitor (PAI-1), controls blood clotting and tissue remodeling events that involve cell migration. Transforming growth factor type β (TGFβ) and epidermal growth factor (EGF) interact synergistically to increase PAI-1 mRNA and protein levels in human HepG2 and mink Mv1Lu cells. Other growth factors that activate tyrosine kinase receptors can substitute for EGF. EGF and TGFβ regulate PAI-1 by synergistically activating transcription, which is further amplified by a decrease in the rate of mRNA degradation, the latter being regulated only by EGF. The combined effect of transcriptional activation and mRNA stabilization results in a rapid 2-order of magnitude increase in the level of PAI-1. TGFβ also increases the sensitivity of the cells to EGF, thereby recruiting the cooperation of EGF at lower than normally effective concentrations. The contribution of EGF to the regulation of PAI-1 involves the MAPK pathway, and the synergistic interface with the TGFβ pathway is downstream of MEK1/2 and involves phosphorylation of neither ERK1/2 nor Smad2/3. Synergism requires the presence of both Smad and AP-1 recognition sites in the promoter. This work demonstrates the existence of a multidimensional cellular mechanism by which EGF and TGFβ are able to promote large and rapid changes in PAI-1 expression.
authors.affiliation: Department of Biochemistry, Biophysics and Molecular Biology, Iowa State and Ames National Laboratories, lowa 50011, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.forename: Frederic W
authors.initials: FW
authors.lastname: Thalacker
authors.forename: Marit
authors.initials: M
authors.lastname: Nilsen-Hamilton
mesh_terms: D000818:Animals; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D008907:Mink; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D049410:Luciferases, Renilla