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The microRNA miR-92 increases proliferation of myeloid cells and by targeting p63 modulates the abundance of its isoforms

Isabella Manni^*,1, Simona Artuso^*,1, Silvia Careccia^*, Maria Giulia Rizzo^*, Renato Baserga, Giulia Piaggio^*,,2 and Ada Sacchi^*

^* Experimental Oncology Department and

Rome Oncogenomic Center (ROC), Istituto Regina Elena, Rome, Italy; and

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

² Correspondence: Istituto Regina Elena, Via delle Messi D’Oro 156, 00158 Rome, Italy. E-mail: piaggio{at}ifo.it

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 Np63β. 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 Np63β 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, I., Artuso, S., Careccia, S., Rizzo, M. G., Baserga, R., Piaggio, G., Sacchi, A. The microRNA miR-92 increases proliferation of myeloid cells and by targeting p63 modulates the abundance of its isoforms.

Key Words: 3'UTR • hematopoiesis • p53 family • small noncoding RNAs

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