Ets transcription factors cooperate with Sp1 to activate the human Tenascin-C promoter
Ets transcription factors cooperate with Sp1 to activate the human Tenascin-C promoter
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DOI：
10.1038/sj.onc.1203360
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发表时间：
1999-12-16
期刊：
影响因子：
8
通讯作者：
Trojanowska, M
中科院分区：
文献类型：
--
作者：
Shirasaki, F;Makhluf, HA;Trojanowska, M
腱生蛋白-C（TN-C）是一种细胞外基质糖蛋白，在胚胎发育过程中表达，但在正常成人组织中仅以低水平存在。TN-C在伤口愈合、纤维化疾病和癌症中重新表达。为了更好地理解控制TN-C基因表达的机制，我们研究了人成纤维细胞中人TN-C启动子的调控。我们证明TN-C启动子的一个短片段bp -133和-27之间含有三个进化上保守的Ets结合位点（EBS）。这三种EBSs结合体外表达的Fli 1蛋白，并介导Fli 1对TN-C基因的反式激活。此外，两个近端EBSs显著促进TN-C启动子的基础活性。存在于人成纤维细胞核提取物中的GABP与两个近端EBSs相互作用。此外，几个Sp1和Sp3结合位点已经位于该启动子区域内的EBSs附近。在果蝇细胞中进行的研究表明，Fli 1或GABP α + β 1与Spl功能性相互作用，导致TN-C启动子活性的协同刺激。总之，本研究首次表明TN-C基因受Ets蛋白调节，Ets蛋白与Spl一起作为TN-C表达的有效激活剂。
Tenascin-C (TN-C), an extracellular matrix glycoprotein is expressed during embryonic development, but is present only at low levels in normal adult tissues. TN-C is re-expressed during wound healing, fibrotic diseases and in cancer. To better understand the mechanisms that control TN-C gene expression, we examined the regulation of the human TN-C promoter in human fibroblasts. We demonstrate that a short segment of the TN-C promoter between bp -133 and -27 contains three evolutionarily conserved Ets binding sites (EBS). These three EBSs bind in vitro expressed Fli1 protein and mediate transactivation of the TN-C gene by Fli1. Furthermore, two proximal EBSs contribute significantly to basal activity of the TN-C promoter. GABP, which is present in human fibroblast nuclear extracts, interacts with the two proximal EBSs, In addition, several Spl and Sp3 binding sites have been located in close proximity to the EBSs within this promoter region. The studies performed in Drosophila cells demonstrate that either Fli1 or GABP alpha + beta 1 functionally interact with Spl resulting in a synergistic stimulation of the TN-C promoter activity. In conclusion, this study shows for the first time that the TN-C gene is regulated by Ets proteins, which together with Spl act as potent activators of TN-C expression.