The ZFHX1A gene is differentially autoregulated by its isoforms
The ZFHX1A gene is differentially autoregulated by its isoforms
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DOI：
10.1016/j.bbrc.2007.06.088
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发表时间：
2007-08-31
影响因子：
3.1
通讯作者：
Cabanillas, Ana M.
中科院分区：
文献类型：
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作者：
Manavella, Pablo A.;Roqueiro, Gonzalo;Cabanillas, Ana M.
Zfhx 1a基因表达两种不同的亚型;全长Zfhx 1a-1和截短的亚型称为Zfhx 1a-2缺乏第一个外显子。Zfhx 1a-1启动子的缺失分析定位于细胞特异性阻遏物，以及反式激活所必需的近端G-弦。转染Zfhx 1a-1 cDNA，而不是Zfhx 1a-2，下调Zfhx 1a-1启动子活性。E2盒突变破坏了两种Zfhx 1a亚型的结合。与此一致，转染的Zfhx 1a-1不调节E-box突变的Zfhx 1a-1启动子的转录活性。竞争性EMSA和转染试验表明，Zfhx 1a-2可以作为一个显性负亚型，因为它能够竞争和取代Zfhx 1a-1从其结合位点，并克服Zfhx 1a-1诱导的阻遏Zfhx 1a-1启动子在细胞中。因此，Zfhx 1a-1基因部分地通过其自身启动子的负反馈进行自我调节，而该启动子又被负显性同种型Zfhx 1a-2的可用性修饰。(c)2007年爱思唯尔公司All rights reserved.
The Zfhx1a gene expresses two different isoforms; the full length Zfhx1a-1 and a truncated isoform termed Zfhx1a-2 lacking the first exon. Deletion analysis of the Zfhx1a-1 promoter localized cell-specific repressors, and a proximal G-string that is critically required for transactivation. Transfection of Zfhx1a-1 cDNA, but not Zfhx1a-2, downregulates Zfhx1a-1 promoter activity. Mutation of an E2-box disrupted the binding of both Zfhx1a isoforms. Consistent with this, transfected Zfhx1a-1 does not regulate the transcriptional activity of the E-box mutated Zfhx1a-1 promoter. Competitive EMSAs and transfection assays show that Zfhx1a-2 can function as a dominant negative isoform since it is able to compete and displace Zfhx1a-1 from its binding site and overcome Zfhx1a-1 induced repression of the Zfhx1a-1 promoter in cells. Hence, the Zfhx1a-1 gene is autoregulated in part by negative feedback oil its own promoter which is, in turn, modified by the avilability of the negative dominant isoform Zfhx1a-2. (c) 2007 Elsevier Inc. All rights reserved.