A Double-Negative Feedback Loop between ZEB1-SIP1 and the microRNA-200 Family Regulates Epithelial-Mesenchymal Transition
Cameron P. Bracken,Philip A. Gregory,Natasha Kolesnikoff,Andrew G. Bert,Jun Wang,M. Frances Shannon,Gregory J. Goodall +6 more
TLDR
A double-negative feedback loop controlling ZEB1-SIP1 and miR-200 family expression that regulates cellular phenotype is established and has direct relevance to the role of these factors in tumor progression.Abstract:
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/deltaEF1 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.read more
Citations
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Molecular mechanisms of epithelial–mesenchymal transition
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The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs
Ulrich F. Wellner,Jörg Schubert,Ulrike Burk,Otto Schmalhofer,Feng Zhu,Annika G Sonntag,Bettina Waldvogel,Corinne Vannier,Douglas S. Darling,Axel zur Hausen,Valerie G. Brunton,Jennifer P. Morton,Owen J. Sansom,Julia Schüler,Marc P. Stemmler,Christoph Herzberger,Ulrich T. Hopt,Tobias Keck,Simone Brabletz,Thomas Brabletz +19 more
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