V-SRC ACTIVATES THE EXPRESSION OF 92-KDA TYPE-IV COLLAGENASE GENE THROUGH THE AP-1 SITE AND THE GT BOX HOMOLOGOUS TO RETINOBLASTOMA CONTROLELEMENTS - A MECHANISM REGULATING GENE-EXPRESSION INDEPENDENT OF THATBY INFLAMMATORY CYTOKINES

The 92-kDa type IV collagenase (matrix metalloproteinase-9; MMP-9) is frequently expressed in cells showing an invasive nature during physio logical and pathological processes, and the expression is strictly con trolled by a variety of trans-membrane signals. Binding sites for NF-k appaB, Sp-1, and AP-1 are reportedly required for induction of MMP-9 g ene expression by tumor necrosis factor-alpha or 12-O-tetradecanoylpho rbol-13-acetate. Comparison of the sequence of the newly cloned mouse MMP-9 promoter region with our previous human isolate revealed that, i n addition to the above mentioned elements, four units of GGGG(T/A)GGG G sequence (GT box) were conserved between the two species. In this st udy, we have demonstrated that one of the GT boxes located downstream of the AP-1 site is essential along with the AP-1 site for the activat ion of the promoter by v-Src but not by tumor necrosis factor-alpha or 12-O-tetradecanoylphorbol-13-acetate. Gel mobility-shift assays revea led that binding proteins for retinoblastoma control element, includin g Sp-1 family protein, can bind specifically to GT boxes. Thus, the v- Src signals to the AP-1 site and to the GT box homologous to retinobla stoma control element acted synergistically in transcriptional activat ion. These results suggest that certain v-Src-mediated signals are pro pagated along pathways that are independent of inflammatory cytokines.