Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro
Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro
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DOI：
10.1593/neo.04241
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Moses, HL
中科院分区：
文献类型：
--
作者：
Lu, X;Law, BK;Moses, HL
转化生长因子-β1(TGF-β1)可通过激活Smad介导的信号通路抑制肿瘤生长。转化生长因子-β1还可以通过其他途径刺激上皮向间充质转化(EMT)，从而促进肿瘤的进展。EMT的特征是获得成纤维细胞样的细胞形态，紧密连接溶解，粘连连接断裂，并形成肌动蛋白应激纤维。有证据表明，丝裂原活化蛋白激酶通路的激活与转化生长因子-β1介导的EMT的诱导有关。然而，ERK在诱导转化生长因子-β1介导的EMT中的作用尚不清楚。芯片分析和实时定量聚合酶链式反应显示，转化生长因子-β1处理正常小鼠乳腺(NMuMG)上皮细胞后，RAS、Raf、MEK1/2和ERK1/2基因表达增加。在用转化生长因子-β1处理24和48h后，NMuMG和小鼠皮质小管(MCT)上皮细胞进行EMT，表现为细胞形态的变化，闭锁带-1和E-钙粘蛋白从细胞-细胞连接处脱位，以及肌动蛋白应激纤维的形成。转化生长因子-β1处理还导致磷酸化的ERK和ERK活性增加。MEK抑制剂U0126可抑制这两种细胞中ERK的磷酸化和激酶活性的增加，并阻断转化生长因子-β1诱导的EMT。这些数据表明，转化生长因子-β1诱导ERK信号通路的激活，这是转化生长因子-β1介导的体外EMT所必需的。
Transforming growth factor-beta1 (TGF-beta1) can be tumor-suppressive through the activation of the Smad-mediated signaling pathway. TGF-beta1 can also enhance tumor progression by stimulating epithelial-to-mesenchymal transition (EMT) through additional pathways. EMT is characterized by the acquisition of a fibroblast-like cell morphology, dissolution of tight junctions, disruption of adherence junctions, and formation of actin stress fibers. There is evidence linking the activation of mitogen-activated protein kinase pathways to the induction of TGF-beta1-mediated EMT. However, the role of Erk in the induction of TGF-beta1-mediated EMT remains unclear. TGF-beta1 treatment of normal murine mammary gland (NMuMG) epithelial cells resulted in increased gene expression of Ras, Raf, MEK1/2, and Erk1/2, as shown by microarray analysis and real-time polymerase chain reaction. Upon 24 and 48 hours of treatment with TGF-beta1, NMuMG and mouse cortical tubule (MCT) epithelial cells underwent EMT as shown by changes in cell morphology, delocalization of zonula occludens-1 and E-cadherin from cell-cell junctions, and formation of actin stress fibers. TGF-beta1 treatment also resulted in increased levels of phosphorylated Erk and Erk kinase activity. Treatment with an MEK inhibitor, U0126, inhibited increased Erk phosphorylation and kinase activity, and blocked TGF-beta1-induced EMT in both cell lines. These data show that TGF-beta1 induces the activation of the Erk signaling pathway, which is required for TGF-beta1 -mediated EMT in vitro.