Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein
Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein
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DOI：
10.1038/onc.2009.120
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发表时间：
2009-07-16
期刊：
影响因子：
8
通讯作者：
Lallemand, F.
中科院分区：
文献类型：
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作者：
Bouteille, N.;Driouch, K.;Lallemand, F.
WWOX基因编码与多种人类疾病如癌症有关的候选肿瘤抑制蛋白（WWOX）。为了更好地理解WWOX作用的分子机制，我们研究了这种蛋白质的新伙伴。使用双杂交系统和免疫共沉淀试验，我们观察到WWOX和Dishevelled蛋白（Dvl）家族信号元件参与Wnt/β-连环蛋白途径之间的物理关联。我们发现，强制WWOX表达抑制，内源性WWOX表达的抑制刺激Wnt/β-连环蛋白途径的转录活性。内源性WWOX表达的抑制也增强了Wnt-3a对β-连环蛋白稳定性的影响。此外，我们通过WWOX观察到Dvl-2野生型和Dvl-2NESm（主要位于细胞核中的Dvl-2的突变形式）在细胞质区室中的隔离。我们的研究结果表明，WWOX是一种新的Wnt/β-catenin通路的抑制剂。WWOX将至少部分地通过阻止Dvl蛋白质的核输入来起作用。Oncogene（2009）28，2569-2580; doi：10.1038/onc.2009.120; 2009年5月25日在线发表
The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/beta-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/beta-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on beta-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/beta-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins. Oncogene (2009) 28, 2569-2580; doi: 10.1038/onc.2009.120; published online 25 May 2009