miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence.
Bottom Line: The INK4a/ARF locus which codifies for two proteins, p19ARF and p16INK4a, plays a central role in senescence by controlling both p53 and RB.Intriguingly, both miR-20a, member of the oncogenic miR-17-92 cluster, and miR-290, belonging to the miR-290-295 cluster, are highly expressed in embryonic stem (ES) cells.We propose that miRNAs may exert opposing functions depending on the miRNAs repertoire as well as target/s level/s present in different cellular contexts, suggesting the importance of evaluating miRNAs activity in diverse genetic settings before their therapeutic use as tumour suppressors.
Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.Show MeSH
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Mentions: A recurrent result found in culture-induced senescent MEF is the consistent association between miR-290 up-regulation and the increased expression of the INK4a/ARF locus (p19ARF and mainly p16INK4a) . It has been shown that the increase of p16INK4a and to a lesser extent that of p19ARF observed during senescence in primary fibroblast (including MEF) is due to down-regulation of EZH2, part of the PRC2 complex which inhibits the INK4a/ARF locus . In silico analysis and preliminary experiments utilizing a gene reporter assay indicate that the 3′UTR of murine EZH2 is a target of miR-290 (Rainaldi G., unpublished data). Future studies will establish whether EZH2 down-regulation during MEF senescence is causatively connected to miR-290 up-regulation; if this were the case p16INK4a increase observed after miR-20a overexpression  could be miR-290 dependent (Fig. 3).
Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.