The Purα/Purβ Single-Strand DNA-Binding Proteins Attenuate Smooth-Muscle Actin Gene Transactivation in Myofibroblasts
The Purα/Purβ Single-Strand DNA-Binding Proteins Attenuate Smooth-Muscle Actin Gene Transactivation in Myofibroblasts
复制标题
DOI：
10.1002/jcp.24564
复制
发表时间：
2014-09-01
影响因子：
5.6
通讯作者：
Strauch, Arthur Roger
中科院分区：
文献类型：
--
作者：
Hariharan, Seethalakshmi;Kelm, Robert J., Jr.;Strauch, Arthur Roger
平滑肌α-肌动蛋白（SMA）的表达对于组织损伤后肌成纤维细胞介导的伤口收缩是必不可少的。Pur /和YB-1转录抑制因子在诱导人肺肌成纤维细胞SMA基因表达过程中控制血清反应因子（SRF）和磷酸化Smad 3（pSmad 3）转录激活因子的DNA结合活性。在静止的成纤维细胞中，Pur在增强预先存在的SRF复合物与SMA核心启动子DNA的稳定性方面表现出新的功能，而Pur在破坏SRF-DNA相互作用方面更有效。Pur蛋白是TGF 1激活的肌成纤维细胞核提取物中既含有SRF又含有pSmad 3的预先存在的核心启动子复合物的效率较低的竞争者。TGF-1信号转导使SRF/Pur蛋白复合物解离，同时在早期肌成纤维细胞分化过程中形成瞬时pSmad 3/MRTF-A/Pur复合物。在成熟肌成纤维细胞中，pSmad 3/MRTF-A复合物中的Pur被Pur取代。结合所有三种阻遏物，有效地抑制SRF和pSmad 3结合到启动子DNA在静止的成纤维细胞和TGF-1激活的肌成纤维细胞，分别。结果表明，在肌成纤维细胞分化过程中，转录激活因子和抑制因子在调节SMA基因输出方面存在动态相互作用。靶向调节SMA启动子的核蛋白复合物的治疗可以防止与慢性心肺纤维化和功能障碍性组织重塑相关的过度肌成纤维细胞积聚。J.细胞。229：1256-1271，2014。(c)2014 Wiley Periodicals，Inc.
Expression of smooth muscle alpha-actin (SMA) is essential for myofibroblast-mediated wound contraction following tissue injury. The Pur / and YB-1 transcriptional repressors govern the DNA-binding activity of serum response factor (SRF) and phosphorylated Smad3 (pSmad3) transcriptional activators during induction of SMA gene expression in human pulmonary myofibroblasts. In quiescent fibroblasts, Pur exhibited a novel function in enhancing stability of pre-existing SRF complexes with SMA core promoter DNA, whereas Pur was more effective in disrupting SRF-DNA interaction. Pur proteins were less efficient competitors of pre-existing, core-promoter complexes containing both SRF and pSmad3 in nuclear extracts from TGF1-activated myofibroblasts. TGF1 signaling dissociated a SRF/Pur protein complex with concurrent formation of a transient pSmad3/MRTF-A/Pur complex during early phase myofibroblast differentiation. Pur was replaced by Pur in the pSmad3/MRTF-A complex in mature myofibroblasts. Combining all three repressors potently inhibited SRF and pSmad3 binding to promoter DNA in quiescent fibroblasts and TGF1-activated myofibroblasts, respectively. The results point to dynamic interplay between transcriptional activators and repressors in regulating SMA gene output during myofibroblast differentiation. Therapeutic targeting of nucleoprotein complexes regulating the SMA promoter may prevent excessive myofibroblast accumulation associated with chronic cardiopulmonary fibrosis and dysfunctional tissue remodeling. J. Cell. Physiol. 229: 1256-1271, 2014. (c) 2014 Wiley Periodicals, Inc.