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

Paola Fuschi, Matteo Carrara, Christine Voellenkle, Jose Manuel Garcia-Manteiga, Paolo Righini, Biagina Maimone, Elena Sangalli, Francesco Villa, Claudia Specchia, Mario Picozza, Giovanni Nano, Carlo Gaetano, Gaia Spinetti, Annibale A. Puca, Alessandra Magenta, Fabio Martelli

Research output: Contribution to journalArticle

13 Citations (Scopus)

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
DOIs
Publication statusPublished - Dec 1 2017

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Untranslated RNA
Cell Aging
Oxidation-Reduction
Oxidative Stress
Cell Death
Endothelial Cells
Long Noncoding RNA
RNA Sequence Analysis
Messenger RNA
Gene Expression Profiling
Computational Biology
MicroRNAs
Transcriptome
DNA Repair
Exons
Blood Cells
Cell Cycle
Protein Isoforms
Skeletal Muscle
Ischemia

Keywords

  • Endothelium
  • Long noncoding RNAs
  • MicroRNAs
  • Oxidative stress
  • P53

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

Cite this

Fuschi, P., Carrara, M., Voellenkle, C., Garcia-Manteiga, J. M., Righini, P., Maimone, B., ... Martelli, F. (2017). Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. Aging, 9(12), 2559-2586. https://doi.org/10.18632/aging.101341

Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. / Fuschi, Paola; Carrara, Matteo; Voellenkle, Christine; Garcia-Manteiga, Jose Manuel; Righini, Paolo; Maimone, Biagina; Sangalli, Elena; Villa, Francesco; Specchia, Claudia; Picozza, Mario; Nano, Giovanni; Gaetano, Carlo; Spinetti, Gaia; Puca, Annibale A.; Magenta, Alessandra; Martelli, Fabio.

In: Aging, Vol. 9, No. 12, 01.12.2017, p. 2559-2586.

Research output: Contribution to journalArticle

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, vol. 9, no. 12, pp. 2559-2586. https://doi.org/10.18632/aging.101341
Fuschi P, Carrara M, Voellenkle C, Garcia-Manteiga JM, Righini P, Maimone B et al. Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. Aging. 2017 Dec 1;9(12):2559-2586. https://doi.org/10.18632/aging.101341
Fuschi, Paola ; Carrara, Matteo ; Voellenkle, Christine ; Garcia-Manteiga, Jose Manuel ; Righini, Paolo ; Maimone, Biagina ; Sangalli, Elena ; Villa, Francesco ; Specchia, Claudia ; Picozza, Mario ; Nano, Giovanni ; Gaetano, Carlo ; Spinetti, Gaia ; Puca, Annibale A. ; Magenta, Alessandra ; Martelli, Fabio. / Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. In: Aging. 2017 ; Vol. 9, No. 12. pp. 2559-2586.
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