A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition
A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition
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DOI：
10.1158/0008-5472.can-08-1942
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Goodall, Gregory J.
中科院分区：
文献类型：
--
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
上皮 - 间质转化发生在胚胎发育过程中，以实现组织重塑，并且被认为是上皮源性肿瘤转移的关键步骤。微小RNA的miR - 200家族通过阻止转录抑制因子ZEB1/δEF1和SIP1/ZEB2的表达，在确定上皮表型方面发挥重要作用。我们在此表明，miR - 200a、miR - 200b以及相关的miR - 429均编码在一个7.5 kb的多顺反子初级微小RNA（pri - miR）转录本上。我们发现pri - miR的启动子位于miR - 200b上游4 kb处的一个300 bp片段内。该启动子区域足以在上皮细胞中赋予表达，并且在间质细胞中被ZEB1和SIP1抑制，其抑制方式是通过它们与位于转录起始位点附近的一对保守的ZEB型E - 盒元件结合。这些发现建立了一个控制ZEB1 - SIP1和miR - 200家族表达的双负反馈回路，该回路调节细胞表型，并且与这些因子在肿瘤进展中的作用直接相关。
Epithelial to mesenchymal transition occurs during embryologic development to allow tissue remodeling and is proposed to be a key step in the metastasis of epithelial-derived tumors. The miR-200 family of microRNAs plays a major role in specifying the epithelial phenotype by preventing expression of the transcription repressors, ZEB1/delta EF1 and SIP1/ZEB2. We show here that miR-200a, miR-200b, and the related miR-429 are all encoded on a 7.5-kb polycistronic primary miRNA (pri-miR) transcript. We show that the promoter for the pri-miR is located within a 300-bp segment located 4 kb upstream of miR-200b. This promoter region is sufficient to confer expression in epithelial cells and is repressed in mesenchymal cells by ZEB1 and SIP1 through their binding to a conserved pair of ZEB-type E-box elements located proximal to the transcription start site. These findings establish a double-negative feedback loop controlling ZEB1-SIP1 and miR-200 family expression that regulates cellular phenotype and has direct relevance to the role of these factors in tumor progression.