miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the @entity14905 and XXXX transcriptional repressor complexes.

@entity71285 @entity0 @entity12841 @entity19 @entity641 @entity21602 @entity14905 @entity2989 @entity9682 @entity35824 @entity71287 @entity14570 @entity8385 @entity71286 @entity22575 @entity71284 @entity31002 @entity46066 @entity14904
UNASSIGNED: The miR-200 family promotes the epithelial state by suppressing the @entity14904 / @entity14905 epithelial gene transcriptional repressors. To identify other miR-200-regulated genes, we isolated mRNAs bound to transfected biotinylated @entity46066 in @entity19 @entity0 cells. In all, 520 mRNAs were significantly enriched in @entity46066 binding at least twofold. Putative miR-200-regulated genes included @entity14905 , enriched 3.5-fold in the pull down. However, @entity14905 knockdown does not fully recapitulate @entity46066 overexpression, suggesting that regulating other miR-200 targets contributes to miR-200's enhancement of epithelial gene expression. Candidate genes were highly enriched for @entity46066 seed pairing in their 3'UTR and coding sequence and for genes that were downregulated by @entity46066 overexpression. @entity12841 and downstream MAPK signaling pathways were the most enriched pathways. Genes whose products mediate transforming growth factor (TGF)-b signaling were also significantly overrepresented, and miR-200 counteracted the suppressive effects of @entity641 and @entity8385 ( @entity8385 ) on epithelial gene expression. @entity46066 regulated the 3'UTRs of 12 of 14 putative @entity46066 -binding mRNAs tested. The extent of mRNA binding to @entity46066 strongly correlated with gene suppression. Twelve targets of @entity46066 ( @entity71284 , @entity71285 , @entity14570 , @entity9682 , @entity71286 , @entity71287 /14-3-3y, Ywhab/14-3-3b, @entity21602 , @entity31002 , @entity2989 , @entity35824 , @entity22575 ) were experimentally validated by identifying their 3'UTR miR-200 recognition elements. @entity14570 and @entity21602 form a complex with @entity14905 and Ywhab/14-3-3b and @entity71287 /14-3-3y form a complex with @entity22575 . These complexes that repress transcription assemble on epithelial gene promoters. miR-200 overexpression induced RNA polymerase II localization and reduced @entity14905 and @entity22575 binding to epithelial gene promoters. Expression of miR-200-resistant @entity21602 modestly, but significantly, reduced epithelial gene induction by miR-200. miR-200 expression and @entity14905 knockdown are known to inhibit cell invasion in in vitro assays. Knockdown of each of three novel miR-200 target genes identified here, @entity21602 , @entity71287 and @entity71284 , also profoundly suppressed cell invasion. Thus, miR-200 suppresses @entity641 /BMP signaling, promotes epithelial gene expression and suppresses cell invasion by regulating a network of genes.Oncogene advance online publication, 23 March 2015; doi:10.1038/onc.2015.69.
