Glucocorticoid Receptor-mediated Expression of Caldesmon Regulates Cell Migration via the Reorganization of the Actin Cytoskeleton
Glucocorticoid Receptor-mediated Expression of Caldesmon Regulates Cell Migration via the Reorganization of the Actin Cytoskeleton
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DOI：
10.1074/jbc.m801606200
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发表时间：
2008-11-07
影响因子：
4.8
通讯作者：
Sobue, Kenji
中科院分区：
文献类型：
--
作者：
Mayanagi, Taira;Morita, Tsuyoshi;Sobue, Kenji
糖皮质激素（GC）在许多细胞过程中发挥重要作用，包括生长，发育，稳态，抑制炎症和免疫抑制。在这里，我们发现，GC处理的人肺癌A549细胞表现出增强的厚应力纤维和局灶性粘连的形成，导致细胞迁移的抑制。在筛选GC响应基因编码肌动蛋白相互作用的蛋白质，我们确定了钙调蛋白（CaD），这是专门上调响应GC。CaD是一种调节蛋白，参与基于肌动蛋白的收缩和肌动蛋白丝的稳定性。我们进一步证明了CaD表达的上调是由糖皮质激素受体（GR）控制的。GR的活化形式直接与人CALD1启动子中的两个糖皮质激素反应元件样序列结合，并反式激活CALD1基因，从而上调CaD蛋白。强迫表达的钙调素，没有GC处理，也增强了厚应力纤维和局灶性粘连的形成和抑制细胞迁移。相反，CaD的耗竭废除了GC诱导的表型。本研究的结果表明，GR依赖的上调CaD通过肌动蛋白细胞骨架的重组在调节细胞迁移中起着关键作用。
Glucocorticoids (GCs) play important roles in numerous cellular processes, including growth, development, homeostasis, inhibition of inflammation, and immunosuppression. Here we found that GC-treated human lung carcinoma A549 cells exhibited the enhanced formation of the thick stress fibers and focal adhesions, resulting in suppression of cell migration. In a screen for GC-responsive genes encoding actin-interacting proteins, we identified caldesmon (CaD), which is specifically up-regulated in response to GCs. CaD is a regulatory protein involved in actomyosin-based contraction and the stability of actin filaments. We further demonstrated that the up-regulation of CaD expression was controlled by glucocorticoid receptor (GR). An activated form of GR directly bound to the two glucocorticoid-response element-like sequences in the human CALD1 promoter and transactivated the CALD1 gene, thereby up-regulating the CaD protein. Forced expression of CaD, without GC treatment, also enhanced the formation of thick stress fibers and focal adhesions and suppressed cell migration. Conversely, depletion of CaD abrogated the GC-induced phenotypes. The results of this study suggest that the GR-dependent up-regulation of CaD plays a pivotal role in regulating cell migration via the reorganization of the actin cytoskeleton.