Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts
Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts
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DOI：
10.1016/s1357-2725(01)00041-3
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发表时间：
2001-07-01
影响因子：
4
通讯作者：
Phan, SH
中科院分区：
文献类型：
--
作者：
Roy, SG;Nozaki, Y;Phan, SH
肌成纤维细胞表达α-平滑肌肌动蛋白并具有介于成纤维细胞和平滑肌细胞之间的中间表型。它们的出现可以由转化生长因子β等细胞因子诱导；但在肌成纤维细胞分化过程中诱导α-平滑肌肌动蛋白基因表达的调控机制尚未确定。为了在α-平滑肌肌动蛋白启动子水平上检查这一机制，用与氯霉素乙酰转移酶报告基因连接的不同长度的α-平滑肌肌动蛋白启动子转染大鼠肺成纤维细胞，并用转化生长因子β1处理。结果表明，最短的诱导型启动子长150个碱基对，表明该区域存在对转化生长因子β1诱导的肌成纤维细胞分化具有潜在重要性的顺式元件。对应于序列Fur的“诱饵”寡核苷酸的转染四种可疑调节因子证明，只有转化生长因子β控制元件参与肌成纤维细胞分化中转化生长因子β1诱导的α-平滑肌肌动蛋白表达的调节。与这一结论一致的是，转化生长因子β控制元件的突变导致启动子活性显着降低。这些观察结果表明，肌成纤维细胞分化期间的α-平滑肌肌动蛋白启动子调节与平滑肌细胞和其他细胞系中的调节独特不同。由于肌成纤维细胞在伤口收缩和细胞外基质合成中发挥关键作用，阐明这种分化机制应该为纤维发生提供新的见解，并提出未来调节伤口愈合和控制纤维化的新策略。 (C) 2001 Elsevier Science Ltd. 保留所有权利。
Myofibroblasts express alpha -smooth muscle actin and have a phenotype intermediate between fibroblasts and smooth muscle cells. Their emergence can be induced by cytokines such as transforming growth factor beta; but the regulatory mechanism for induction of alpha -smooth muscle actin gene expression in myofibroblast differentiation has not been determined. To examine this mechanism at the level of the alpha -smooth muscle actin promoter, rat lung fibroblasts were transfected with varying lengths of the alpha -smooth muscle actin promoter linked to the chloramphenicol acetyl transferase reporter gene and treated with transforming growth factor beta1. The results show that the shortest inducible promoter was 150 base pairs long, suggesting the presence in this region of cis-elements of potential importance in transforming growth factor beta1 induced myofibroblast differentiation. transfection of "decoy" oligonucleotides corresponding to sequences Fur Four suspected regulatory factors demonstrated that only the transforming growth Factor beta control element is involved in the regulation of transforming growth factor beta1-induced alpha -smooth muscle actin expression in myofibroblast differentiation. Consistent with this conclusion is the finding that a mutation in the transforming growth factor beta control element caused a significant reduction in promoter activity. These observations taken together show that alpha -smooth muscle actin promoter regulation during myofibroblast differentiation is uniquely different from that in smooth muscle cells and other cell lines. Since myofibroblasts play a key role in wound contraction and synthesis of extracellular matrix, clarification of this differentiation mechanism should provide new insight into fibrogenesis and suggest Future novel strategies for modulation of wound healing and controlling fibrosis. (C) 2001 Elsevier Science Ltd. All rights reserved.