TY - JOUR
T1 - Central role of the p53 pathway in the noncoding-RNA response to oxidative stress
AU - Fuschi, Paola
AU - Carrara, Matteo
AU - Voellenkle, Christine
AU - Garcia-Manteiga, Jose Manuel
AU - Righini, Paolo
AU - Maimone, Biagina
AU - Sangalli, Elena
AU - Villa, Francesco
AU - Specchia, Claudia
AU - Picozza, Mario
AU - Nano, Giovanni
AU - Gaetano, Carlo
AU - Spinetti, Gaia
AU - Puca, Annibale A.
AU - Magenta, Alessandra
AU - Martelli, Fabio
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - Endothelium
KW - Long noncoding RNAs
KW - MicroRNAs
KW - Oxidative stress
KW - P53
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U2 - 10.18632/aging.101341
DO - 10.18632/aging.101341
M3 - Article
AN - SCOPUS:85039788493
VL - 9
SP - 2559
EP - 2586
JO - Aging
JF - Aging
SN - 1945-4589
IS - 12
ER -