Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element.
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.
Olman
M A
MA
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama, Birmingham, AL 35294, USA. Olman@pulm.dom.uab.edu
Hagood
J S
JS
Simmons
W L
WL
Fuller
G M
GM
Vinson
C
C
White
K E
KE
D000818:Animals; D002478:Cells, Cultured; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology / Q000502:physiology*; D005340:Fibrinogen / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos; D008168:Lung / Q000166:cytology / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D016385:TATA Box; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D005340:Fibrinogen