The canonical Wnt pathway is necessary for gut epithelial cell proliferation, and aberrant activation of this pathway causes intestinal neoplasia. We report a novel mechanism by which the Sox family of transcription factors regulate the canonical Wnt signaling pathway. We found that some Sox proteins antagonize while others enhance ␤-catenin/T-cell factor (TCF) activity. Sox17, which is expressed in the normal gut epithelium but exhibits reduced expression in intestinal neoplasia, is antagonistic to Wnt signaling. When overexpressed in SW480 colon carcinoma cells, Sox17 represses ␤-catenin/TCF activity in a dose-dependent manner and inhibits proliferation. Sox17 and Sox4 are expressed in mutually exclusive domains in normal and neoplastic gut tissues, and gain-and loss-of-function studies demonstrate that Sox4 enhances ␤-catenin/TCF activity and the proliferation of SW480 cells. In addition to binding ␤-catenin, both Sox17 and Sox4 physically interact with TCF/lymphoid enhancer factor (LEF) family members via their respective high-mobility-group box domains. Results from gain-and loss-of-function experiments suggest that the interaction of Sox proteins with ␤-catenin and TCF/LEF proteins regulates the stability of ␤-catenin and TCF/LEF. In particular, Sox17 promotes the degradation of both ␤-catenin and TCF proteins via a noncanonical, glycogen synthase kinase 3␤-independent mechanism that can be blocked by proteasome inhibitors. In contrast, Sox4 may function to stabilize ␤-catenin protein. These findings indicate that Sox proteins can act as both antagonists and agonists of ␤-catenin/TCF activity, and this mechanism may regulate Wnt signaling responses in many developmental and disease contexts.

SummarySox17 and β-catenin cooperate to regulate the transcription of endodermal genes

The SOX family of transcription factors have emerged as modulators of canonical Wnt/β-catenin signaling in diverse development and disease contexts. There are over twenty SOX proteins encoded in the vertebrate genome and recent evidence suggests that many of these can physically interact with β-catenin and modulate the transcription of Wnt-target genes. The precise mechanisms by which SOX proteins regulate β-catenin/TCF activity are still being resolved and there is evidence to support a number of models including; protein-protein interactions, the binding of SOX factors to Wnt-target gene promoters, the recruitment of co-repressors or co-activators, modulation of protein stability and nuclear translocation. In some contexts Wnt signaling also regulates SOX expression resulting in feedback regulatory loops that fine tune cellular responses to β-catenin/TCF activity. In this review we summarize the examples of Sox-Wnt interactions and examine the underlying mechanisms of this potentially wide spread and underappreciated mode of Wnt-regulation.