Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity
Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity
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DOI：
10.1038/onc.2009.224
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发表时间：
2009-10-15
期刊：
影响因子：
8
通讯作者：
Coumoul, X.
中科院分区：
文献类型：
--
作者：
Bui, L-C;Tomkiewicz, C.;Coumoul, X.
芳基碳氢化合物受体 (AhR) 或二恶英受体是一种转录因子，可诱导适应性代谢途径以响应环境污染物。最近，发现 AhR 及其配体可以改变其他途径。事实上，AhR 配体引起的发育缺陷表明该受体可能靶向其他细胞功能，包括细胞迁移和可塑性。在这里，我们发现二恶英介导的 Ahr 激活会诱导 Nedd9/Hef1/Cas-L，这是最近被鉴定为转移标志物的 Cas 蛋白家族的成员。 Hef1 基因诱导是由该基因启动子中存在的两个异生素反应元件介导的。此外，利用RNA干扰，我们发现Nedd9/Hef1/Cas-L介导二恶英引起的与细胞可塑性相关的变化，包括细胞粘附和形状的改变、细胞骨架重组和细胞迁移增加。此外，我们发现二恶英和 AhR 对 E-钙粘蛋白的抑制和 Jun N 末端激酶的激活也依赖于 Nedd9/Hef1/Cas-L 的表达。我们的研究首次揭示了污染物暴露与转移标记物诱导表达之间的联系，并表明细胞迁移和可塑性标记物受到 AhR 及其毒性配体的调节。癌基因 (2009) 28, 3642-3651; doi：10.1038/onc.2009.224； 2009 年 8 月 3 日在线发布
Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands. Oncogene (2009) 28, 3642-3651; doi:10.1038/onc.2009.224; published online 3 August 2009