Differential expression of prostaglandin endoperoxide H synthase-2 and formation of activated beta-catenin-LEF-1 transcription complex in mouse colonic epithelial cells contrasting in Apc

Mutations in Ape underlie the intestinal lesions in familial adenomatous po lyposis and are found in >85% of sporadic colon cancers. They are frequentl y associated with overexpression of prostaglandin endoperoxide H synthase-2 (PGHS-2) in colonic adenomas. It has been suggested that Ape mutations are linked mechanistically to increased PGHS-2 expression by elevated nuclear accumulation of beta-catenin-Tcf-LEF transcription complex. In the present study, we show that PGHS-2 is differentially expressed in mouse colonic epi thelial cells with distinct Ape status. Cells with a mutated Ape expressed markedly higher levels of PGHS-2 mRNA and protein and produced significantl y more prostaglandin E-2 than cells with normal Ape. Using electrophoretic mobility shift assays, we demonstrate that DNA-beta-catenin-LEF-1 complex f ormation is differentially induced in these two cell lines in an Ape-depend ent manner. Our data indicate that the differential induction of beta-caten in-LEF-1 complex correlates closely with differential expression of PGHS-2. These findings support the hypothesis that the differential expression of PGHS-2 is mediated through the proposed beta-catenin/Tcf-LEF signaling path way.