The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors

Matrilysin is a matrix metalloproteinase expressed in the tumor cells of gr eater than 80% of intestinal adenomas, The majority of these intestinal tum ors are associated with the accumulation of beta-catenin, a component of th e cadherin adhesion complex and, through its association with the T Cell Fa ctor (Tcf) DNA binding proteins, a regulator in the Wnt signal transduction pathway. In murine intestinal tumors, matrilysin transcripts show striking overlap with the accumulation of beta-catenin protein, The matrilysin prom oter is upregulated as much as 12-fold by beta-catenin in colon tumor cell lines in a manner inversely proportional to the endogenous levels of beta-c atenin/Tcf complex and is dependent upon a single optimal Tcf-4 recognition site. Coexpression of the E-cadherin cytoplasmic domain blocked this induc tion and reduced basal promoter activity in every colon cancer cell line te sted. Inactivation of the Tcf binding site increased promoter activity and overexpression of the Tcf factor, LEF-1, significantly downregulated matril ysin promoter activity, suggesting that beta-catenin transactivates the mat rilysin promoter by virtue of its ability to abrogate Tcf-mediated repressi on. Because genetic ablation of matrilysin decreases tumor formation in mul tiple intestinal neoplasia (Min) mice, we propose that regulation of matril ysin production by beta-catenin accumulation is a contributing factor to in testinal tumorigenesis.