The microRNA miR-92 increases proliferation of myeloid cells and by targeting p63 modulates the abundance of its isoforms.
MicroRNAs (miRs) are 21- to 23-nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs of proteins involved in cell growth and apoptosis. miR-92 is part of the mir-17-92 cluster, which comprises members with an effect on cell proliferation. However, the role of miR-92 is unknown, and its targets have not been identified. Here, we describe a mechanism through which miR-92 contributes to regulate cell proliferation. Using a miR-92 synthetic double-strand oligonucleotide, we demonstrate that miR-92 increases 32D myeloid cell proliferation and 5-bromo-2-deoxyuridine (BrdU) incorporation and inhibits cell death. The effect is miR-92 specific since the miR-92 antagomir inhibits cell proliferation. Moreover, we show that miR-92 acts by modulating p63-isoform abundance through down-regulatation of endogenous DeltaNp63beta. Using luciferase reporters containing p63 3'UTR fragments with wild-type or mutant miR-92 complementary sites, we demonstrate that the wild-type 3'UTR is a direct target of miR-92. Finally, we observed that a miR-92-resistant DeltaNp63beta isoform (without 3'UTR) inhibits cell proliferation and parallels the effect of the antagomir. We conclude that one of the molecular mechanisms through which miR-92 increases cell proliferation is by negative regulation of an isoform of the cell-cycle regulator p63.
Manni
Isabella
I
Experimental Oncology Department, Istituto Regina Elena, Via delle Messi D'Oro 156, 00158 Rome, Italy.
Artuso
Simona
S
Careccia
Silvia
S
Rizzo
Maria Giulia
MG
Baserga
Renato
R
Piaggio
Giulia
G
Sacchi
Ada
A
D020413:3' Untranslated Regions; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D022423:Myeloid Cells / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D060149:Tetraspanin 30
D020413:3' Untranslated Regions; D015703:Antigens, CD; C554586:CD63 protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D010980:Platelet Membrane Glycoproteins; D020033:Protein Isoforms; D060149:Tetraspanin 30