Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells.
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 beta-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 beta-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 beta-catenin/TCF activity and the proliferation of SW480 cells. In addition to binding beta-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 beta-catenin and TCF/LEF proteins regulates the stability of beta-catenin and TCF/LEF. In particular, Sox17 promotes the degradation of both beta-catenin and TCF proteins via a noncanonical, glycogen synthase kinase 3beta-independent mechanism that can be blocked by proteasome inhibitors. In contrast, Sox4 may function to stabilize beta-catenin protein. These findings indicate that Sox proteins can act as both antagonists and agonists of beta-catenin/TCF activity, and this mechanism may regulate Wnt signaling responses in many developmental and disease contexts.
PubMed ID: 17875931
PMC ID: PMC2169141
Article link: Mol Cell Biol.
Grant support: GM072915 NIGMS NIH HHS , HD42572 NICHD NIH HHS , T32 HD07463 NICHD NIH HHS , R01 HD042572-04 NICHD NIH HHS , R01 HD042572-05 NICHD NIH HHS , R01 HD042572 NICHD NIH HHS
Genes referenced: ctnnb1 gys1 sox17a sox17b.1 sox17b.2 sox4
Morpholinos referenced: ctnnb1 MO1 sox17a MO1 sox17a MO2 sox17a MO3 sox17a MO4 sox17b.1 MO1