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
Jm. Mei et al., 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, CARCINOGENE, 20(4), 1999, pp. 737-740
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.