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, Cotransfection 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.