II. Medizinische Klinik, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.
J Cell Sci. 2010 Dec 15;123(Pt 24):4231-9. doi: 10.1242/jcs.071100. Epub 2010 Nov 16.
The epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ-SMAD signaling pathway is an inductor of EMT in many tumor types. One hallmark of EMT is downregulation of the adherens junction protein E-cadherin, a process mediated by transcription factors such as the zinc fingers SNAIL and SLUG. Here, we report that the catalytic IκB kinase (IKK) subunit IKKα is necessary for the silencing of E-cadherin in a Panc1 cell model of TGFβ-SMAD-mediated EMT, independently of NFκB. IKKα regulates canonical TGFβ-SMAD signaling by interacting with SMAD3 and controlling SMAD complex formation on DNA. Furthermore, we demonstrate that the TGFβ-IKKα-SMAD signaling pathway induces transcription of the genes encoding SNAIL and SLUG. In addition, we demonstrate that IKKα also modulates canonical TGFβ-SMAD signaling in human MDA-MB231 breast cancer cells, arguing for a more general impact of IKKα on the control of TGFβ-SMAD signaling. Taken together, these findings indicate that IKKα contributes to the tumor-promoting function of the TGFβ-SMAD signaling pathway in particular cancers.
上皮间质转化（EMT）是肿瘤进展的关键步骤，而 TGFβ-SMAD 信号通路是许多肿瘤类型 EMT 的诱导因素。EMT 的一个标志是细胞间黏附连接蛋白 E-钙黏蛋白的下调，这一过程由锌指转录因子 SNAIL 和 SLUG 等介导。在这里，我们报告说，催化 IκB 激酶（IKK）亚基 IKKα 在 TGFβ-SMAD 介导的 EMT 的 Panc1 细胞模型中，是沉默 E-钙黏蛋白所必需的，而不依赖于 NFκB。IKKα 通过与 SMAD3 相互作用并控制 SMAD 复合物在 DNA 上的形成来调节经典的 TGFβ-SMAD 信号。此外，我们证明 TGFβ-IKKα-SMAD 信号通路诱导编码 SNAIL 和 SLUG 的基因的转录。此外，我们还证明 IKKα 还调节人 MDA-MB231 乳腺癌细胞中的经典 TGFβ-SMAD 信号，这表明 IKKα 对 TGFβ-SMAD 信号的控制具有更普遍的影响。总之，这些发现表明 IKKα 有助于 TGFβ-SMAD 信号通路在特定癌症中的促肿瘤功能。
