Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element
| Autor: | M A, Olman, J S, Hagood, W L, Simmons, G M, Fuller, C, Vinson, K E, White |
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| Rok vydání: | 1999 |
| Předmět: |
Transcription
Genetic Recombinant Fusion Proteins Fibrinogen Genes fos Fibroblasts Transfection TATA Box Rats Inbred F344 Rats Fibrin Fibrinogen Degradation Products Transcription Factor AP-1 Gene Expression Regulation Plasminogen Activator Inhibitor 1 Animals RNA Messenger Lung Proto-Oncogene Proteins c-fos Cells Cultured Sequence Deletion |
| Zdroj: | Blood. 94(6) |
| ISSN: | 0006-4971 |
| Popis: | Plasminogen activator inhibitor type-1 (PAI-1), a serine protease inhibitor, affects the processes of fibrinolysis, wound healing, and vascular remodeling. We have demonstrated that PAI-1 transcription is induced by D dimer, a plasmin proteolytic fragment of fibrin, supporting its role in negative feedback on peri-cellular proteolysis. The focus of this study was to define the mechanism of D dimer's effects on PAI-1 transcription. D dimer increased the binding activity of the transcription factor activator protein-1 components c-fos/junD and c-fos mRNA levels in a time- and concentration-dependent manner to a greater extent than fibrinogen. Both basal and D dimer-induced PAI-1 transcriptional activity were entirely dependent on elements within the -161 to -48 bp region of the PAI-1 gene in fibroblasts. Mutations within the AP-1-like element (-59 to -52 bp) in the PAI-1 gene affected D dimer-induced transcriptional activity, c-fos/junD DNA binding, and basal and c-fos inducible PAI-1 transcriptional activity. Furthermore, expression of either wild-type or mutant c-fos proteins augmented or diminished the response of the PAI-1 promoter (-161 to +26 bp) to D dimer, respectively. D dimer-induced binding of c-fos/junD to the highly conserved and unique AP-1 like element in the PAI-1 gene provides a mechanism whereby specific fibrin fragments control fibrin persistence at sites of inflammation, fibrosis, and neoplasia. |
| Databáze: | OpenAIRE |
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