miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements.
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.
Lal
Ashish
A
Immune Disease Institute, Children's Hospital Boston, Department of Pediatrics, Harvard Medical School, MA 02115, USA. alal@idi.harvard.edu
Navarro
Francisco
F
Maher
Christopher A
CA
Maliszewski
Laura E
LE
Yan
Nan
N
O'Day
Elizabeth
E
Chowdhury
Dipanjan
D
Dykxhoorn
Derek M
DM
Tsai
Perry
P
Hofmann
Oliver
O
Becker
Kevin G
KG
Gorospe
Myriam
M
Hide
Winston
W
Lieberman
Judy
J
D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004260:DNA Repair; D030541:Databases, Genetic; D015536:Down-Regulation; D050703:E2F2 Transcription Factor / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D053263:Gene Regulatory Networks; D018816:Genes, cdc; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008264:Macrophages / Q000378:metabolism; D008533:Megakaryocytes / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation
D020413:3' Untranslated Regions; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C543845:MIRN24 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger