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首页> 外文期刊>Cellular Signalling >SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells
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SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells

机译：SMAD3的表达受上皮和平滑肌细胞中有丝分裂原激活的蛋白激酶激酶-1的调节

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摘要

SMAD3 is a transcription factor that mediates TGF-beta 1 signaling and is known to be important in many of the cellular processes that regulate fibrosis and inflammation. Although several studies have examined SMAD3 activation, little is known about the control of SMAD3 expression. It is well established that the mitogen-activated protein kinase (MAPK) pathway is responsive to TGF-beta 1 stimulation and coordinates with SMAD signaling in many cases; therefore, the hypothesis of this study is that the MAPK pathway will be involved in the regulation of SMAD3 expression. Using a SMAD3 promoter construct, we demonstrate that inhibition of either c-Jun-N-terminal kinase (JNK) or p38 activity has little effect on SMAD3 promoter function. Inhibition of mitogen-activated protein kinase kinase-1 (MEK1) with either PD98059 or UO126, however, results in a substantial dose-dependent inhibition of SMAD3 promoter activity. Further studies confirm that promoter activity correlates with protein expression by demonstrating reduced SMAD3 protein expression in A549 cells and airway smooth muscle cells after treatment with MEK1 inhibitors. Positive regulation of SMAD3 expression is also demonstrated by expression of a constitutively active (ca)-MEK1 construct, where the presence of ca-MEK1 resulted in increased SMAD3 protein expression. These data lead to the conclusion that MEK1 is an important regulator of SMAD3 expression. (c) 2006 Elsevier Inc. All rights reserved.
机译：SMAD3是一种介导TGF-β1信号传导的转录因子，已知在调节纤维化和炎症的许多细胞过程中都非常重要。尽管有几项研究检查了SMAD3激活，但对控制SMAD3表达的了解甚少。公认的是，在许多情况下，有丝分裂原激活的蛋白激酶（MAPK）途径对TGF-β1刺激有反应并与SMAD信号协调。因此，这项研究的假设是MAPK途径将参与SMAD3表达的调节。使用SMAD3启动子构建体，我们证明抑制c-Jun-N-末端激酶（JNK）或p38活性对SMAD3启动子功能几乎没有影响。但是，用PD98059或UO126抑制丝裂原活化的蛋白激酶激酶1（MEK1）会导致SMAD3启动子活性受到剂量依赖性的抑制。进一步的研究证实，通过证明在用MEK1抑制剂治疗后，A549细胞和气道平滑肌细胞中SMAD3蛋白表达降低，启动子活性与蛋白表达相关。组成型活性（ca）-MEK1构建体的表达也证明了SMAD3表达的正调控，其中ca-MEK1的存在导致SMAD3蛋白表达增加。这些数据得出结论，认为MEK1是SMAD3表达的重要调节剂。 （c）2006 Elsevier Inc.保留所有权利。

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