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首页> 外文期刊>Molecular and Cellular Biology >Sox17 and Sox4 Differentially Regulate β-Catenin/T-Cell Factor Activity and Proliferation of Colon Carcinoma Cells
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Sox17 and Sox4 Differentially Regulate β-Catenin/T-Cell Factor Activity and Proliferation of Colon Carcinoma Cells

机译：Sox17和Sox4差异性调节结肠癌细胞的β-Catenin/ T细胞因子活性和增殖

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摘要

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 β-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 β-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 β-catenin/TCF activity and the proliferation of SW480 cells. In addition to binding β-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 β-catenin and TCF/LEF proteins regulates the stability of β-catenin and TCF/LEF. In particular, Sox17 promotes the degradation of both β-catenin and TCF proteins via a noncanonical, glycogen synthase kinase 3β-independent mechanism that can be blocked by proteasome inhibitors. In contrast, Sox4 may function to stabilize β-catenin protein. These findings indicate that Sox proteins can act as both antagonists and agonists of β-catenin/TCF activity, and this mechanism may regulate Wnt signaling responses in many developmental and disease contexts.
机译：规范的Wnt途径对于肠道上皮细胞增殖是必需的，并且该途径的异常激活会引起肠道肿瘤。我们报告了一种新的机制，通过该机制，Sox转录因子家族调节经典的Wnt信号通路。我们发现某些Sox蛋白具有拮抗作用，而另一些则增强β-catenin/ T细胞因子（TCF）活性。在正常肠上皮中表达的 Sox17 在肠道肿瘤中表达减少，它与Wnt信号拮抗。当在SW480结肠癌细胞中过表达时， Sox17 会以剂量依赖性方式抑制β-catenin/ TCF活性并抑制增殖。 Sox17 和 Sox4 在正常和赘生性肠道组织的互斥域中表达，功能获得和丧失研究表明 Sox4 增强β-catenin/ TCF活性和SW480细胞的增殖。除了结合β-连环蛋白外，Sox17和Sox4都通过其各自的高迁移率族框域与TCF /淋巴增强因子（LEF）家族成员进行物理相互作用。功能获得和丧失的实验结果表明，Sox蛋白与β-catenin和TCF / LEF蛋白的相互作用调节了β-catenin和TCF / LEF的稳定性。尤其是，Sox17通过非经典的糖原合酶激酶3β独立机制（可被蛋白酶体抑制剂阻断）促进β-catenin和TCF蛋白的降解。相反，Sox4可能起到稳定β-catenin蛋白的作用。这些发现表明，Sox蛋白可以同时充当β-catenin/ TCF活性的拮抗剂和激动剂，并且该机制可能在许多发育和疾病背景下调节Wnt信号应答。

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