RhoA/ROCK Signaling Regulates TGFβ-Induced Epithelial-Mesenchymal Transition of Lens Epithelial Cells through MRTF-A
RhoA/ROCK Signaling Regulates TGFβ-Induced Epithelial-Mesenchymal Transition of Lens Epithelial Cells through MRTF-A
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DOI：
10.2119/molmed.2016.00041
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
West-Mays, Judith A.
中科院分区：
文献类型：
--
作者：
Korol, Anna;Taiyab, Aftab;West-Mays, Judith A.
转化生长因子（TGF）-β诱导的上皮-间质转化（EMT）导致眼部纤维化病理的形成，例如前囊下白内障和后囊膜混浊。由Rho家族的GTP酶介导的肌动蛋白细胞骨架的重塑在EMT中起关键作用。然而，肌动蛋白动力学如何影响EMT的下游标记尚未完全确定。我们的前期工作提示肌动蛋白结合蛋白-肌红蛋白相关转录因子A（MRTF-A）可能是TGF β诱导透镜上皮细胞EMT的重要介质。本研究的目的是确定RhoA/ROCK信号传导在介导TGF β诱导的MRTF-A核积累和α-平滑肌肌动蛋白（α SMA）（收缩性肌成纤维细胞表型的标志物）的最终表达中的需求。使用大鼠透镜上皮外植体，我们证明使用Y-27632抑制ROCK可防止TGF β诱导的MRTF-A、E-钙粘蛋白/β-连环蛋白复合物分解和α SMA表达的核积累。使用特异性靶向MRTF-A信号传导的新型抑制剂CCG-203971，我们进一步证明了在诱导α SMA表达中MRTF-A核定位和活性的要求。总之，我们的研究结果表明，TGF β诱导的细胞骨架重组通过RhoA/ROCK/MRTF-A信号是至关重要的EMT的透镜上皮细胞。
Transforming growth factor (TGF)-beta-induced epithelial-mesenchymal transition (EMT) leads to the formation of ocular fibrotic pathologies, such as anterior subcapsular cataract and posterior capsule opacification. Remodeling of the actin cytoskeleton, mediated by the Rho family of GTPases, plays a key role in EMT. However, how actin dynamics affect downstream markers of EMT has not been fully determined. Our previous work suggests that myocardin-related transcription factor A (MRTF-A), an actin-binding protein, might be an important mediator of TGF beta-induced EMT in lens epithelial cells. The aim of the current study was to determine the requirement of RhoA/ROCK signaling in mediating TGF beta-induced nuclear accumulation of MRTF-A and ultimate expression of alpha-smooth muscle actin (alpha SMA), a marker of a contractile myofibroblast phenotype. Using rat lens epithelial explants, we demonstrate that ROCK inhibition using Y-27632 prevents TGF beta-induced nuclear accumulation of MRTF-A, E-cadherin/beta-catenin complex disassembly, and alpha SMA expression. Using a novel inhibitor specifically targeting MRTF-A signaling, CCG-203971, we further demonstrate the requirement of MRTF-A nuclear localization and activity in the induction of alpha SMA expression. Overall, our findings suggest that TGF beta-induced cytoskeletal reorganization through RhoA/ROCK/MRTF-A signaling is critical to EMT of lens epithelial cells.