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

• Published in: Molecular cell 2009-09, Vol.35 (5), p.610-625
• Main Authors: Lal, Ashish, Navarro, Francisco, Maher, Christopher, Maliszewski, Laura E., Yan, Nan, O'Day, Elizabeth, Chowdhury, Dipanjan, Dykxhoorn, Derek M., Tsai, Perry, Hofman, Oliver, Becker, Kevin G., Gorospe, Myriam, Hide, Winston, Lieberman, Judy
• Format: Article
• Language: English
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2009.08.020

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.