Sox4 단백질에 의한 β-catenin의 분해 유도 기전

Abstract

β-catenin is a cytoplasmic protein that participates in the assembly of cell-cell adherens junctions by binding cadherins to the cytoskeleton. In addition, it is a key component of the Wnt signaling pathway. Activation of this pathway triggers the accumulation of β-catenin in the nucleus, where it activates the transcription of target genes. Abnarmal accumulation of β-catenin is characteristic of polyposis coli (APC) or Axin tumor suppressor proteins, which regulates β-catenin degradation, or activating mutations in β-catenin molecule itself. Here we show that overexpression of Sox4 down-regulates wild type β-catenin in HEK 293 cells. The inhibitory effect of Sox4 on wild type β-catenin is apparently mediated by the ubiquitin-proteasoem system and requires an active glycogen synthase kinase 3β (GSK3β). Mutations in the N-terminus of β-catenin (S33Y) which compromise its degradation by the proteasomes or inhibition of GSK3β activity rendered β-catenin resistant to down-regulation by Sox4. In light of recent evidence that Sox4 expression is activated in colon and other tumors with β-catenin dysregulation, our findings suggest that Sox4 is part of a feedback inhibitory pathway for Wnt signaling in normal cells. Moreover, the mutations in APC, Axin or β-catenin in cancer cells appear to render β-catenin resistant to the effects of Sox4 inhibition.