A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition.
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.
Bracken
Cameron P
CP
Hanson Institute, Institute of Medical and Veterinary Science, The University of Adelaide, Adelaide, SA, Australia.
Gregory
Philip A
PA
Kolesnikoff
Natasha
N
Bert
Andrew G
AG
Wang
Jun
J
Shannon
M Frances
MF
Goodall
Gregory J
GJ
D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D024721:E-Box Elements / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D005810:Multigene Family / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
C108381:GEMIN2 protein, human; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1