Oncogenic function of DACT1 in colon cancer through the regulation of β-catenin.
Oncogenic function of DACT1 in colon cancer through the regulation of β-catenin.
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DOI：
10.1371/journal.pone.0034004
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fu W
中科院分区：
文献类型：
--
作者：
Yuan G;Wang C;Ma C;Chen N;Tian Q;Zhang T;Fu W
Wnt/β-catenin信号通路在结肠癌的发生发展中起重要作用。DACT 1通过与经典和非经典Wnt通路的中心介体Dishevelled（Dvl）相互作用而被鉴定为Wnt信号传导的调节剂。然而，DACT 1在WNT/β-连环蛋白信号通路中的功能仍不清楚。在这里，我们提出的证据表明，DACT 1是一个重要的积极调节剂，通过调节β-连环蛋白的稳定性和亚定位在结肠癌。我们已经证明，DACT 1促进癌细胞在体外增殖和肿瘤在体内生长，并提高结肠癌细胞的迁移和侵袭潜力。此外，DACT 1的高表达不仅增加了β-catenin的核和胞浆分数，而且还增加了其膜相关分数。DACT 1的过表达导致非磷酸化β-连环蛋白在细胞质中，特别是在细胞核中的积累增加。我们已经证明DACT 1与GSK-3β和β-catenin相互作用。DACT 1通过DACT 1对GSK-3β的诱导作用稳定β-连环蛋白，并直接与β-连环蛋白相互作用。在DACT 1表达升高后，Ser 9处的磷酸化GSK-3β水平显著增加。DACT 1通过增加GSK-3β Ser 9位磷酸化水平，抑制GSK-3 β活性，介导β-catenin的亚细胞定位。总之，我们的研究确定DACT 1是结肠癌中重要的正调节因子，并提出了治疗控制β-连环蛋白依赖性通路的潜在策略。
The Wnt/β-catenin signaling pathway plays important roles in the progression of colon cancer. DACT1 has been identified as a modulator of Wnt signaling through its interaction with Dishevelled (Dvl), a central mediator of both the canonical and noncanonical Wnt pathways. However, the functions of DACT1 in the WNT/β-catenin signaling pathway remain unclear. Here, we present evidence that DACT1 is an important positive regulator in colon cancer through regulating the stability and sublocation of β-catenin. We have shown that DACT1 promotes cancer cell proliferation in vitro and tumor growth in vivo and enhances the migratory and invasive potential of colon cancer cells. Furthermore, the higher expression of DACT1 not only increases the nuclear and cytoplasmic fractions of β-catenin, but also increases its membrane-associated fraction. The overexpression of DACT1 leads to the increased accumulation of nonphosphorylated β-catenin in the cytoplasm and particularly in the nuclei. We have demonstrated that DACT1 interacts with GSK-3β and β-catenin. DACT1 stabilizes β-catenin via DACT1-induced effects on GSK-3β and directly interacts with β-catenin proteins. The level of phosphorylated GSK-3β at Ser9 is significantly increased following the elevated expression of DACT1. DACT1 mediates the subcellular localization of β-catenin via increasing the level of phosphorylated GSK-3β at Ser9 to inhibit the activity of GSK-3β. Taken together, our study identifies DACT1 as an important positive regulator in colon cancer and suggests a potential strategy for the therapeutic control of the β-catenin-dependent pathway.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.102657399
发表时间：
2002-05-14
影响因子：
11.1
作者：
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通讯作者：
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