miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells.
p27(kip1) (p27) is a cell cycle inhibitor and tumor suppressor whose expression is tightly regulated in the cell. Translational control of p27 mRNA has emerged as a prominent mechanism to regulate p27 expression during differentiation, quiescence, and cancer progression. The microRNAs miR-221 and miR-222 repress p27 expression in various cancer cells, and this repression promotes tumor cell proliferation. In addition, the presence of an internal ribosome entry site in the 5' untranslated region (UTR) of p27 mRNA has been reported. Here, we show that p27 mRNA is translated via a cap-dependent mechanism in HeLa and HL60 cells and that the previously reported IRES activity can be attributed to cryptic promoters in the sequence corresponding to the p27 5' UTR. Furthermore, cap-dependent translation of p27 mRNA is repressed by miR-181a in undifferentiated HL60 cells. Repression by miR-181a is relieved during differentiation of HL60 into monocyte-like cells, allowing the accumulation of p27, which is necessary to fully block cell cycle progression and reach terminal differentiation. These results identify miR-181a as a regulator of p27 mRNA translation during myeloid cell differentiation.
Cuesta
Rafael
R
Centre de Regulació Genòmica (CRG-UPF), Gene Regulation Programme, Dr. Aiguader 88, 08003 Barcelona, Spain. cuestr01@nyumc.org
Martínez-Sánchez
Aida
A
Gebauer
Fátima
F
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012315:RNA Caps; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012315:RNA Caps; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27