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: The pro-senescence role of miR-20a  appears to be in contrast with its oncogenic role ; however a more subtle interpretation of the data highlights a particular aspect of miRNA properties discussed above: i.e. the cellular context may be decisive for the final effect of miRNAs. In tumour cells the miR-17–92 cluster increases the oncogenic power of cMYC in a self-regulating circuit whereby cMYC binds the promoter of the miR-17–92 cluster and increases its transcription . In turn two miRNAs of the cluster, miR-17–5p and miR-20a (belonging to the same seed family), target E2F1, which is able to activate both the cluster and cMYC . In other words, cMYC, while directly increasing the transcription of E2F1, indirectly decreases its translation by inducing miR-17–5p and miR-20a. In this way, cMYC uses the miR-17 seed family to maintain E2F1 protein levels below the pro-apoptotic threshold allowing the proliferative signal to prevail (Fig. 2A, left side) . Conversely in MEF, where E2F1 levels is limiting, its down-regulation by miR-20a contributes to senescence (Fig. 2A, right side) in agreement with the idea that miRNAs might have opposite effects in different cells. In this regard it would be interesting to test miR-20a in tumours where inhibition of E2F1 transcriptional activity has been found to block tumour growth [27, 54].
Affiliation: Laboratory of Gene and Molecular Therapy, Institute of Clinical Physiology, CNR, Pisa, Italy.