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

Paola Fuschi1, Matteo Carrara1, Christine Voellenkle1

  • 1Molecular Cardiology Laboratory, IRCCS Policlinico S. Donato, 20097, San Donato Milanese, Milan, Italy.

Aging
|December 16, 2017
PubMed

Insights

Oxidative stress impacts endothelial cells (ECs) via redox imbalance. This study reveals noncoding RNAs, regulated by p53, are key players in the EC response to oxidative stress, influencing cell death and proliferation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genomics

Background:

  • Oxidative stress and redox imbalance are implicated in numerous conditions, notably inhibiting endothelial cell (EC) growth and promoting cell death and senescence.
  • The role of noncoding RNAs in cellular responses to oxidative stress, particularly within ECs, remains incompletely understood.

Purpose of the Study:

  • To investigate the involvement of noncoding RNAs in endothelial cell phenotypes induced by oxidative stress using global transcriptome profiling.
  • To elucidate the role of the p53 signaling pathway in regulating noncoding RNA expression under oxidative stress conditions.

Main Methods:

  • Global transcriptome profiling via RNA-sequencing in human ECs exposed to hydrogen peroxide (H2O2).
  • Bioinformatic analysis and validation in p53-silenced ECs to identify p53 targets.
  • Analysis of differential exon usage to assess p53 pathway involvement.

Main Results:

  • RNA-sequencing identified significant transcriptome changes in H2O2-treated ECs, highlighting a p53-signaling dependent response.
  • Several messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs), including MALAT1 and NEAT1, were identified as p53 targets.
  • MicroRNA (miRNA) miR-192-5p was significantly induced by H2O2 in a p53-dependent manner, and its overexpression reduced EC proliferation and induced cell death.
  • p53-dependent 5'-isoforms of MDM2 and PVT1 selectively increased upon H2O2 treatment, confirming the p53 pathway's central role.
  • Similar transcriptomic alterations were observed in conditions like replicative senescence, critical limb ischemia, and in long-living individuals, suggesting a conserved role of noncoding RNAs in redox control.

Conclusions:

  • Noncoding RNAs play a prominent role in the cellular response to oxidative stress.
  • The p53 signaling pathway is a critical regulator of noncoding RNA expression during oxidative stress in endothelial cells.
  • Dysregulation of noncoding RNAs, such as miR-192-5p, contributes to endothelial cell dysfunction under oxidative stress.
Keywords:
endotheliumlong noncoding RNAsmicroRNAsoxidative stressp53

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