Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts.
We have studied the mechanism of a transforming growth factor-beta (TGF-beta)-stimulated production of type-1 plasminogen activator inhibitor (PAI-1) in WI-38 human lung fibroblasts. TGF-beta causes an early increase in the PAI-1 mRNA level which reaches a maximal 50-fold enhancement after 8 h. Blocking of protein synthesis with cycloheximide causes an equally strong increase in the level of PAI-1 mRNA. Quantitative studies of the effect of TGF-beta on PAI-1 protein levels in cell extracts and culture media by using monoclonal antibodies are consistent with the effect on PAI-1 mRNA. The results suggest a primary effect of TGF-beta on PAI-1 gene transcription, and also suggest the possibility that the transcription of this gene in non-induced cells may be suppressed by a short-lived negatively regulating protein. Urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators are decreased in the culture media of TGF-beta-treated cells concomitantly with the increase in PAI-1 accumulation. These findings show that a primary and important biological effect of TGF-beta may be an overall decreased extracellular proteolytic activity, and give an insight into the molecular mechanisms underlying TGF-beta action at the genetic level.
D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007700:Kinetics; D010455:Peptides / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors; D015849:Plasminogen Inactivators; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D015291:Transforming Growth Factors
D006023:Glycoproteins; D006133:Growth Substances; D010455:Peptides; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D015291:Transforming Growth Factors; D004247:DNA; D010960:Plasminogen Activators