The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

中文翻译：

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VBP1通过介导转录因子TCF / LEF的稳定性来调节Wnt /β-catenin信号传导

Wnt /β-catenin途径是调节胚胎发育，成年体内稳态和干细胞自我更新的主要途径之一。在此途径中，转录因子T细胞因子/淋巴增强因子（TCF / LEF）分别是通过招募阻遏物分子或与β-catenin效应子相互作用来抑制或激活Wnt靶基因转录的关键开关。显而易见的是，TCF / LEF家族成员的蛋白质稳定性可能在控制Wnt /β-catenin信号传导途径的活性中起关键作用。但是，调节TCF / LEFs稳定性的因素仍然未知。在这里，我们报告pVHL结合蛋白1（VBP1）通过控制TCF / LEFs的稳定性来调节Wnt /β-catenin信号通路。出奇，我们发现在培养细胞和斑马鱼胚胎中，VBP1的过表达或敲低都会降低Wnt /β-catenin信号传导活性。从机制上讲，VBP1直接与所有四个TCF / LEF家族成员和von Hippel-Lindau肿瘤抑制蛋白（pVHL）结合。VBP1的过表达或敲低会增加TCF / LEF与pVHL之间的关联，然后通过蛋白酶体降解降低TCF / LEF的蛋白质水平。在一起，我们的结果提供了有关VBP1在控制TCF / LEFs蛋白质稳定性和调节Wnt /β-catenin信号通路活性中作用的机制的见解。VBP1的过表达或敲低会增加TCF / LEF与pVHL之间的关联，然后通过蛋白酶体降解降低TCF / LEF的蛋白质水平。在一起，我们的结果提供了有关VBP1在控制TCF / LEFs蛋白质稳定性和调节Wnt /β-catenin信号通路活性中作用的机制的见解。VBP1的过表达或敲低会增加TCF / LEF与pVHL之间的关联，然后通过蛋白酶体降解降低TCF / LEF的蛋白质水平。在一起，我们的结果提供了有关VBP1在控制TCF / LEFs蛋白质稳定性和调节Wnt /β-catenin信号通路活性中作用的机制的见解。