Transcriptional induction of stromelysin-3 in mesodermal cells is mediatedby an upstream CCAAT/enhancer-binding protein element associated with a DNase I-hypersensitive site

Stromelysin-3 (ST3) is a matrix metalloproteinase whose synthesis is marked ly increased in stromal fibroblasts of most invasive human carcinomas. In t he present study, we have investigated the molecular mechanisms by which hi gh levels of ST3 expression can be induced. In contrast to the early and tr ansient induction of interstitial collagenase by 12-O-tetradecanoylphorbol- 13-acetate (TPA), the fibroblastic induction of ST3 was found to be delayed and to require protein neosynthesis. We demonstrated that this induction i s transcriptional and does not result from changes in RNA stability. By loo king next to promoter regions accessible to DNase I upon gene induction, we have identified two distal elements and have characterized their role in t he transcriptional regulation of ST3. The first one is a TPA-responsive ele ment that controls the base-line ST3 promoter activity but is not required for its activation. We demonstrate that ST3 gene induction is actually medi ated by the second element, a C/EBP-binding site, by showing: (i) that this element becomes accessible in cells induced to express ST3, (ii) that endo genous C/EBP beta binds to the ST3 promoter, and (iii) that this binding le ads to ST3 transcriptional activation. Our study provides new insights into the regulation of ST3 and suggests an additional role for C/EBP transcript ion factors in tissue remodeling processes associated with this MMP.