TY  - JOUR
A1  - Fuschi, Paola
A1  - Carrara, Matteo
A1  - Voellenkle, Christine
A1  - Garcia‐Manteiga, Jose Manuel
A1  - Righini, Paolo
A1  - Maimone, Biagina
A1  - Sangalli, Elena
A1  - Villa, Francesco
A1  - Specchia, Claudia
A1  - Picozza, Mario
A1  - Nano, Giovanni
A1  - Gaetano, Carlo
A1  - Spinetti, Gaia
A1  - Puca, Annibale A.
A1  - Magenta, Alessandra
A1  - Martelli, Fabio
T1  - Central role of the p53 pathway in the noncoding-RNA response to oxidative stress
T2  - Aging
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.
KW  - oxidative stress
KW  - long noncoding RNAs
KW  - microRNAs
KW  - p53
KW  - endothelium
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48647
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-486478
SN  - 1945-4589
N1  - Copyright: Fuschi et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 9
IS  - 12
SP  - 2559
EP  - 2586
PB  - Impact Journals, LLC
CY  - [s. l.]
ER  -