Differential regulation of interstitial collagenase (MMP-1) gene expression by ETS transcription factors.
Expression of interstitial collagenase (MMP-1) has been detected in stromal fibroblasts of various malignant tumors. Here, we have studied the effect of three structurally different ETS transcription factors (ETS-1, ERGB/Fli-1, and PU.1) on MMP-1 promoter activity in NIH3T3 fibroblasts. ETS-1 increased the activity of 3.8 kb MMP-1 promoter construct up to tenfold, while ERGB/Fli-1 or PU.1 alone had no marked effect on basal promoter activity. ETS-1 also markedly potentiated enhancement of MMP-1 promoter by both c-Jun and JunB, whereas ERGB/Fli-1 augmented only the effect of c-Jun. Interestingly, PU.1 abolished induction of MMP-1 promoter by both c-Jun and JunB. Stimulation of MMP-1 promoter by 12-O-tetradecanoyl phorbol-13-acetate and okadaic acid was differentially augmented by ETS-1 and ERGB/Fli-1, and abrogated by PU.1. Co-transfection studies with MMP-1 promoter 5'-deletion constructs revealed that AP-1 site was necessary for PU.1-elicited suppression. As compared to control cell lines, PU.1-positive stable cells exhibited clearly weaker binding of c-Jun and JunD containing AP-1 complexes to MMP-1 promoter AP-1 element, as well as marked reduction in basal level and induction of c-jun mRNA by 12-O-tetradecanoyl phorbol-13-acetate and okadaic acid, suggesting a novel mechanism for PU.1-mediated inhibition of AP-1 dependent gene expression. These results show that three structurally distinct ETS transcription factors differently modulate AP-1 dependent upregulation of MMP-1 gene expression.
Westermarck
J
J
Department of Dermatology, Turku University Central Hospital, Finland.
Seth
A
A
Kähäri
V M
VM
D016475:3T3 Cells; D000818:Animals; D017364:Collagenases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D020781:Matrix Metalloproteinase 1; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors; D019319:Okadaic Acid; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate