Central role of the p53 pathway in the noncoding-RNA response to oxidative stress

P Fuschi, M Carrara, C Voellenkle, JM Garcia-Manteiga, P Righini, B Maimone, E Sangalli, F Villa, C Specchia, M Picozza, G Nano, C Gaetano, G Spinetti, AA Puca, A Magenta, F Martelli

Research output: Contribution to journalArticle

Abstract

Oxidative stress plays a fundamental role in many conditions. Specifically, redox imbalance inhibits endothelial cell (EC) growth, inducing cell death and senescence. We used global transcriptome profiling to investigate the involvement of noncoding-RNAs in these phenotypes. By RNA-sequencing, transcriptome changes were analyzed in human ECs exposed to H2O2, highlighting a pivotal role of p53-signaling. Bioinformatic analysis and validation in p53-silenced ECs, identified several p53-targets among both mRNAs and long noncoding-RNAs (lncRNAs), including MALAT1 and NEAT1. Among microRNAs (miRNAs), miR-192-5p was the most induced by H2O2 treatment, in a p53-dependent manner. Down-modulated mRNA-targets of miR-192-5p were involved in cell cycle, DNA repair and stress response. Accordingly, miR-192-5p overexpression significantly decreased EC proliferation, inducing cell death. A central role of the p53-pathway was also confirmed by the analysis of differential exon usage: Upon H2O2 treatment, the expression of p53-dependent 5'-isoforms of MDM2 and PVT1 increased selectively. The transcriptomic alterations identified in H2O2-treated ECs were also observed in other physiological and pathological conditions where redox control plays a fundamental role, such as ECs undergoing replicative senescence, skeletal muscles of critical limb-ischemia patients and the peripheral-blood mononuclear cells of long-living individuals. Collectively, these findings indicate a prominent role of noncoding-RNAs in oxidative stress response.
Original languageEnglish
Pages (from-to)2559-2586
Number of pages28
JournalAging
Volume9
Issue number12
Publication statusPublished - 2017

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    Fuschi, P., Carrara, M., Voellenkle, C., Garcia-Manteiga, JM., Righini, P., Maimone, B., Sangalli, E., Villa, F., Specchia, C., Picozza, M., Nano, G., Gaetano, C., Spinetti, G., Puca, AA., Magenta, A., & Martelli, F. (2017). Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. Aging, 9(12), 2559-2586. http://www.scopus.com/inward/record.url?scp=85039788493&partnerID=8YFLogxK