Pumilio facilitates miRNA regulation of the E2F3 oncogene
- 15 February 2012
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 26 (4), 356-368
- https://doi.org/10.1101/gad.182568.111
Abstract
E2F transcription factors are important regulators of cell proliferation and are frequently dysregulated in human malignancies. To identify novel regulators of E2F function, we used Drosophila as a model system to screen for mutations that modify phenotypes caused by reduced levels of dE2F1. This screen identified components of the Pumilio translational repressor complex (Pumilio, Nanos, and Brain tumor) as suppressors of dE2F1-RNAi phenotypes. Subsequent experiments provided evidence that Pumilio complexes repress dE2F1 levels and that this mechanism of post-transcriptional regulation is conserved in human cells. The human Pumilio homologs Pum 1 and Pum 2 repress the translation of E2F3 by binding to the E2F3 3′ untranslated region (UTR) and also enhance the activity of multiple E2F3 targeting microRNAs (miRNAs). E2F3 is an oncogene with strong proliferative potential and is regularly dysregulated or overexpressed in cancer. Interestingly, Pumilio/miRNA-mediated regulation of E2F3 is circumvented in cancer cells in several different ways. Bladder carcinomas selectively down-regulate miRNAs that cooperate with Pumilio to target E2F3, and multiple tumor cell lines shorten the 3′ end of the E2F3 mRNA, removing the Pumilio regulatory elements. These studies suggest that Pumilio–miRNA repression of E2F3 translation provides an important level of E2F regulation that is frequently abrogated in cancer cells.Keywords
This publication has 56 references indexed in Scilit:
- PUF proteins: repression, activation and mRNA localizationTrends in Cell Biology, 2011
- Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer CellsCell, 2009
- Atypical E2Fs: new players in the E2F transcription factor familyTrends in Cell Biology, 2009
- The TRIM-NHL Protein TRIM32 Activates MicroRNAs and Prevents Self-Renewal in Mouse Neural ProgenitorsCell, 2009
- Intrinsic Negative Cell Cycle Regulation Provided by PIP Box- and Cul4Cdt2-Mediated Destruction of E2f1 during S PhaseDevelopmental Cell, 2008
- Life and death decisions by the E2F transcription factorsCurrent Opinion in Cell Biology, 2007
- MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed PairingMolecular Cell, 2007
- The Caenorhabditis elegans pumilio homolog, puf-9, is required for the 3′UTR-mediated repression of the let-7 microRNA target gene, hbl-1Developmental Biology, 2007
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005
- The Hallmarks of CancerCell, 2000