TY - JOUR
T1 - miR-24 Inhibits Cell Proliferation by Targeting E2F2, MYC, and Other Cell-Cycle Genes via Binding to "Seedless" 3′UTR MicroRNA Recognition Elements
AU - Lal, Ashish
AU - Navarro, Francisco
AU - Maher, Christopher A.
AU - Maliszewski, Laura E.
AU - Yan, Nan
AU - O'Day, Elizabeth
AU - Chowdhury, Dipanjan
AU - Dykxhoorn, Derek M.
AU - Tsai, Perry
AU - Hofmann, Oliver
AU - Becker, Kevin G.
AU - Gorospe, Myriam
AU - Hide, Winston
AU - Lieberman, Judy
N1 - Funding Information:
This work was supported, in part, by National Institutes of Health (NIH) AI070302 and a GSK-IDI Alliance grant (J.L.); the NIA-IRP, NIH (K.G.B., M.G.); the Harry Oppenheimer Memorial Trust (W.H.); a GSK-IDI Alliance fellowship (F.N.); and the Harvard Center for AIDS Research (N.Y.). We thank N. Dyson (Harvard Medical School) for the HA-E2F2 expression plasmid, Ray McGovern for programming support, and Lieberman laboratory members for useful discussions.
PY - 2009/9/11
Y1 - 2009/9/11
N2 - miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression 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, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, 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.
AB - miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression 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, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, 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.
KW - CELLCYCLE
KW - DNA
KW - RNA
UR - http://www.scopus.com/inward/record.url?scp=69949098536&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69949098536&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2009.08.020
DO - 10.1016/j.molcel.2009.08.020
M3 - Article
C2 - 19748357
AN - SCOPUS:69949098536
SN - 1097-2765
VL - 35
SP - 610
EP - 625
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -