TY - JOUR
T1 - 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
AU - Barone, Eugenio
AU - Cenini, Giovanna
AU - Sultana, Rukhsana
AU - Di Domenico, Fabio
AU - Fiorini, Ada
AU - Perluigi, Marzia
AU - Noel, Teresa
AU - Wang, Chi
AU - Mancuso, Cesare
AU - St. Clair, Daret K.
AU - Butterfield, D. Allan
PY - 2012/6/15
Y1 - 2012/6/15
N2 - 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.
AB - 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.
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U2 - 10.1089/ars.2011.4124
DO - 10.1089/ars.2011.4124
M3 - Article
C2 - 22229939
AN - SCOPUS:84860206827
SN - 1523-0864
VL - 16
SP - 1407
EP - 1420
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 12
ER -