The ubiquitin-proteasome pathway and serine kinase activity modulate adenomatous polyposis coli protein-mediated regulation of β-catenin- lymphocyte enhancer-binding factor signaling

Abstract

The tumor suppressor function of the adenomatous polyposis coli protein (APC) depends, in part, on its ability to bind and regulate the multifunctional protein, β-catenin, β-Catenin binds the high mobility group box transcription factors, lymphocyte enhancer-binding factor (LEF) and T- cell factor, to directly regulate gene transcription. Using LEF reporter assays we find that APC-mediated down-regulation of β-catenin-LEF signaling is reversed by proteasomal inhibitors in a dose-dependent manner. APC down- regulates signaling induced by wild type β-catenin but not by the non- ubiquitinatable S37A mutant, β-catenin. Bisindoylmaleimide-type protein kinase C inhibitors, which prevent β-catenin ubiquitination, decrease the ability of APC to down-regulate β-catenin-LEF signaling. All these effects on LEF signaling are paralleled by changes in β-catenin protein levels. Lithium, an inhibitor of glycogen synthase kinase-3β, does not alter the ability of APC to down-regulate β-catenin protein and β-catenin-LEF signaling in the colon cancer cells that were tested. These results point to a role for β-catenin ubiquitination, proteasomal degradation, and potentially a serine kinase other than glycogen synthase kinase-3β in the tumor-suppressive actions of APC.