REGULATION OF HUMAN INTERSTITIAL COLLAGENASE (MATRIX METALLOPROTEINASE-1) PROMOTER ACTIVITY BY FIBROBLAST GROWTH-FACTOR

Basic fibroblast growth factor (bFGF) is a pleiotropic factor that is implicated in tissue remodeling. The growth factor is capable of up-re gulating the expression of the interstitial collagenase (matrix metall oproteinase-1 or MMP-1) gene. In this study, the full-length human MMP -1 promoter, spanning 4.3 kb, was sequenced and the regulatory control of its activity by bFGF was examined in NIH3T3 fibroblasts. Several r egulatory sequences, including five activator protein-1 (AP-1), five a ctivator protein-2 (AP-2), five glucocorticoid-response elements and m ultiple ets/polyoma enhancer-binding 3 elements, were identified. Dele tion constructs were prepared and transiently transfected into fibrobl ast cultures incubated with and without bFGF. The results showed that bFGF enhanced the activity of the deletion promoter fragments and the full-length MMP-1 promoter by sixfold or more in the cell cultures. St imulation of the MMP-1 promoter activity by bFGF was reflected in subs tantial increase of the collagenase mRNA levels. A bFGF-responsive ele ment appeared to be the AP-1 consensus sequence. Mutation of the first AP-1 site resulted in major reduction of the basal level of the MMP-1 promoter activity, supporting the notion that the AP-1 consensus sequ ence is essential for the constitutive expression of the MMP-1 gene. F urthermore, bFGF induction of the activity of the promoter constructs containing a mutant AP-1 site was essentially absent, suggesting that the regulatory element is necessary for the induction of the promoter activity by the growth factor Thus, bFGF up-regulates MMP-1 gene expre ssion in NIH3T3 fibroblasts via induction of its promoter activity tha t is dependent on an AP-1 consensus sequence.