Regulation of matrilysin expression in endothelium by fibroblast growth factor-2.
Matrilysin (MMP7) is a secreted matrix metalloproteinase, which contributes to angiogenesis by breaking down basement membranes. We show that the angiogenic factor FGF-2 induces MMP7 expression in human endothelial cells. The promoter contains a Lef/Tcf consensus sequence, but using wildtype or Lef/Tcf-mutated promoter constructs, FGF-2-induced MMP7 reporter activity is independent from Lef/Tcf sites. Instead, we show that overexpression of a dominant negative Stat3 mutant reduces FGF-2-mediated MMP7 promoter activity. However, Stat3 does not bind to the MMP7 promoter, but activates MMP7 gene expression indirectly via AP-1. This is confirmed by MMP7 promoter constructs with mutated AP-1 sites which did not respond to FGF-2 and by siRNAs against Stat1 and Stat3, which repressed FGF-2-induced MMP7 protein expression. In conclusion, we show that FGF-2-induced MMP7 expression in endothelium depends on AP-1 and FGF-2 signaling to AP-1 involves a Stat1/3-dependent pathway.
Holnthoner
Wolfgang
W
Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Vienna, Austria.
Kerenyi
Marc
M
Gröger
Marion
M
Kratochvill
Franz
F
Petzelbauer
Peter
P
D001665:Binding Sites / Q000235:genetics; D016895:Culture Media, Serum-Free; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016895:Culture Media, Serum-Free; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D018808:Transcription Factor AP-1; D016222:Fibroblast Growth Factor 2; D020783:Matrix Metalloproteinase 7