E-钙黏蛋白和上皮-间质转化控制失巢凋亡敏感性的途径。
A pathway for the control of anoikis sensitivity by E-cadherin and epithelial-to-mesenchymal transition.
机构信息
Department of Biochemistry and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, USA.
出版信息
Mol Cell Biol. 2011 Oct;31(19):4036-51. doi: 10.1128/MCB.01342-10. Epub 2011 Jul 11.
Abstract
Detachment of epithelial cells from matrix or attachment to an inappropriate matrix engages an apoptotic response known as anoikis, which prevents metastasis. Cellular sensitivity to anoikis is compromised during the oncogenic epithelial-to-mesenchymal transition (EMT), through unknown mechanisms. We report here a pathway through which EMT confers anoikis resistance. NRAGE (neurotrophin receptor-interacting melanoma antigen) interacted with a component of the E-cadherin complex, ankyrin-G, maintaining NRAGE in the cytoplasm. Oncogenic EMT downregulated ankyrin-G, enhancing the nuclear localization of NRAGE. The oncogenic transcriptional repressor protein TBX2 interacted with NRAGE, repressing the tumor suppressor gene p14ARF. P14ARF sensitized cells to anoikis; conversely, the TBX2/NRAGE complex protected cells against anoikis by downregulating this gene. This represents a novel pathway for the regulation of anoikis by EMT and E-cadherin.
摘要
上皮细胞从基质上脱离或附着在不合适的基质上，会引发一种称为凋亡的反应，称为 anoikis，它可以防止转移。在致癌的上皮细胞-间充质转化 (EMT) 过程中，细胞对 anoikis 的敏感性通过未知机制受到损害。我们在这里报告了一条 EMT 赋予 anoikis 抗性的途径。NRAGE（神经营养因子受体相互作用的黑色素瘤抗原）与 E-钙粘蛋白复合物的一个成分锚蛋白-G 相互作用，使 NRAGE 保持在细胞质中。致癌 EMT 下调锚蛋白-G，增强 NRAGE 的核定位。致癌转录抑制蛋白 TBX2 与 NRAGE 相互作用，抑制肿瘤抑制基因 p14ARF。p14ARF 使细胞对 anoikis 敏感；相反，TBX2/NRAGE 复合物通过下调该基因来保护细胞免受 anoikis。这代表了 EMT 和 E-钙粘蛋白调节 anoikis 的新途径。
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