miR-24 inhibits cell proliferation by suppressing expression of E2F2, MYC and other cell cycle regulatory genes by binding to “seedless” 3′UTR microRNA recognition elements

By A. Lal, Francisco Navarro, C. Maher, L. Maliszewski, Nan Yan, Elizabeth M. O'Day, Dipanjan Chowdhury, D. Dykxhoorn, Perry Tsai, Oliver Hofmann and 4 more. Molecules and Cells, 2009

604 citations recorded by the source corpus.

Summary miR-24, up-regulated during terminal differentiation of multiple lineages, inhibits cell cycle progression. Antagonizing miR-24 restores post-mitotic cell proliferation and enhances fibroblast proliferation, while over-expressing miR-24 increases the G1 compartment. The 248 mRNAs down-regulated upon miR-24 over-expression are highly enriched for DNA repair and cell cycle regulatory genes that form a direct interaction network with prominent nodes at genes that enhance (MYC, E2F2, CCNB1, CDC2) or inhibit (p27Kip1, VHL) cell cycle progression. miR-24 directly regulates MYC and E2F2 and some genes they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 over-expression, is rescued by miR-24-insensitive E2F2. Therefore, E2F2 is a critical miR-24 target. The E2F2 3′UTR lacks a predicted miR-24 recognition element. In fact, miR-24 regulates expression of E2F2, MYC, AURKB, CCNA2, CDC2, CDK4 and FEN1 by recognizing seedless, but highly complementary, sequences.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a8ca94581244ecb89b794cb419665f52672a253e

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Citations in the corpus

Expanding the MicroRNA Targeting Code: Functional Sites with Centered Pairing (2010, background): “On the other hand, detailed experimental follow-up on mRNAs that respond to the miRNA despite lacking any of these established site types seems to indicate that some of them should not be dismissed as secondary targets but might instead be direct targets (Lal et al., 2009).”
ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, background): “On the other hand, another study found that hsa-miR-24 can inhibit proliferation[61].”
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, positive): “Although computational algorithms relying on miRNA seed sequence analysis failed to identify mouse Stat1 as a miR-146a putative target, it was recently shown that some microRNAs, like miR24, control multiple genes in the absence of canonical target seed sequences (Lal et al., 2009).”
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MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “The same group had already provided evidence that miR-24 inhibits proliferation through direct targeting of c-Myc, E2F1 and a number of related molecules (Lal et al, 2009).”
Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding (2013, neutral): “Human cells express more than 1,000 miRNAs, each potentially binding to hundreds of messenger RNAs (mRNAs) (Lewis et al., 2005), but only a small fraction of these interactions has been validated experimentally.”
The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs (2013, result): “Importantly, our results are consistent with data from genetic testing (Didiano and Hobert, 2006), mammalian studies (Lal et al., 2009; Tay et al., 2008) and high throughput RIP-Chip and CLIP studies (Chi et al., 2009; Hafner et al., 2010; Landthaler et al., 2008; Loeb et al., 2012).”
microRNAs in action: biogenesis, function and regulation (2023, background): “Other examples of non-conventional miRNA targeting include extensively ‘centred’ base-pairing 58 , and certain variations of interrupted seeds 59,60 (Fig.”
Predicting effective microRNA target sites in mammalian mRNAs (2015, background): “…of functional non-canonical sites might exist but have not yet been characterized to the point that they can be used for miRNA target prediction ( Lal et al., 2009 ), our analysis of the CLIP results justified a focus on the abundant site types that are predictive of targeting and are at least…”