Lack of p53 decreases basal oxidative stress levels in the brain through upregulation of thioredoxin-1, biliverdin reductase-A, manganese superoxide dismutase, and nuclear factor kappa-B

Eugenio Barone, Giovanna Cenini, Rukhsana Sultana, Fabio Di Domenico, Ada Fiorini, Marzia Perluigi, Teresa Noel, Chi Wang, Cesare Mancuso, Daret K. St. Clair, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Aims: The basal oxidative and nitrosative stress levels measured in cytosol, mitochondria, and nuclei as well as in the whole homogenate obtained from the brain of wild type (wt) and p53 knockout [p53 (-/-)] mice were evaluated. We hypothesized that the loss of p53 could trigger the activation of several protective mechanisms such as those involving thioredoxin-1 (Thio-1), the heme-oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system, manganese superoxide dismutase (MnSOD), the IkB kinase type β (IKKβ)/nuclear factor kappa-B (NF-kB), and the nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf-2). Results: A decrease of protein carbonyls, protein-bound 4-hydroxy-2-nonenal (HNE), and 3-nitrotyrosine (3-NT) was observed in the brain from p53 (-/-) mice compared with wt. Furthermore, we observed a significant increase of the expression levels of Thio-1, BVR-A, MnSOD, IKKβ, and NF-kB. Conversely a significant decrease of Nrf-2 protein levels was observed in the nuclear fraction isolated from p53 (-/-) mice. No changes were found for HO-1. Innovation: This is the first study of basal oxidative/nitrosative stress in in vivo conditions of brain obtained from p53 (-/-) mice. New insights into the role of p53 in oxidative stress have been gained. Conclusion: We demonstrated, for the first time, that the lack of p53 reduces basal oxidative stress levels in mice brain. Due to the pivotal role that p53 plays during cellular stress response our results provide new insights into novel therapeutic strategies to modulate protein oxidation and lipid peroxidation having p53 as a target. The implications of this work are profound, particularly for neurodegenerative disorders.

Original languageEnglish
Pages (from-to)1407-1420
Number of pages14
JournalAntioxidants and Redox Signaling
Volume16
Issue number12
DOIs
StatePublished - Jun 15 2012

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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