Document Detail


A p21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster.
MedLine Citation:
PMID:  24277930     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The tumor suppressor p21 acts as a cell cycle inhibitor and has also been shown to regulate gene expression by functioning as a transcription corepressor. Here, we identified p21-regulated microRNAs (miRNAs) by sequencing small RNAs from isogenic p21(+/+) and p21(-/-) cells. Three abundant miRNA clusters, miR-200b-200a-429, miR-200c-141, and miR-183-96-182, were downregulated in p21-deficient cells. Consistent with the known function of the miR-200 family and p21 in inhibition of the epithelial-mesenchymal transition (EMT), we observed EMT upon loss of p21 in multiple model systems. To explore a role of the miR-183-96-182 cluster in EMT, we identified its genome-wide targets and found that miR-183 and miR-96 repressed common targets, including SLUG, ZEB1, ITGB1, and KLF4. Reintroduction of miR-200, miR-183, or miR-96 in p21(-/-) cells inhibited EMT, cell migration, and invasion. Conversely, antagonizing miR-200 and miR-183-96-182 cluster miRNAs in p21(+/+) cells increased invasion and elevated the levels of VIM, ZEB1, and SLUG mRNAs. Furthermore, we found that p21 forms a complex with ZEB1 at the miR-183-96-182 cluster promoter to inhibit transcriptional repression of this cluster by ZEB1, suggesting a reciprocal feedback loop.
Authors:
Xiao Ling Li; Toshifumi Hara; Youngeun Choi; Murugan Subramanian; Princy Francis; Sven Bilke; Robert L Walker; Marbin Pineda; Yuelin Zhu; Yuan Yang; Ji Luo; Lalage M Wakefield; Thomas Brabletz; Ben Ho Park; Sudha Sharma; Dipanjan Chowdhury; Paul S Meltzer; Ashish Lal
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2013-11-25
Journal Detail:
Title:  Molecular and cellular biology     Volume:  34     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-01-08     Completed Date:  2014-03-18     Revised Date:  2014-08-03    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  533-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD29 / genetics,  metabolism
Cell Line
Cell Movement / genetics
Cyclin-Dependent Kinase Inhibitor p21 / genetics*,  metabolism
Epithelial-Mesenchymal Transition*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HCT116 Cells
HEK293 Cells
Homeodomain Proteins / genetics*,  metabolism
Humans
Immunoblotting
Kruppel-Like Transcription Factors / genetics,  metabolism
MicroRNAs / genetics*
Multigene Family
Mutation
Oligonucleotides, Antisense / genetics
Protein Binding
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
R01 CA142698/CA/NCI NIH HHS; SC1 GM093999/GM/NIGMS NIH HHS; SC1GM093999/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD29; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/GKLF protein; 0/Homeodomain Proteins; 0/Kruppel-Like Transcription Factors; 0/MIRN183 microRNA, human; 0/MIRN200 microRNA, human; 0/MIRN96 microRNA, human; 0/MicroRNAs; 0/Mirn182 microRNA, human; 0/Oligonucleotides, Antisense; 0/Transcription Factors; 0/ZEB1 protein, human; 0/snail family transcription factors
Comments/Corrections

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