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.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Department of Chemistry, Center of Membrane Sciences, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Eugenio
E
Barone
Giovanna
G
Cenini
Rukhsana
R
Sultana
Fabio
F
Di Domenico
Ada
A
Fiorini
Marzia
M
Perluigi
Teresa
T
Noel
Chi
C
Wang
Cesare
C
Mancuso
Daret K
DK
St Clair
D Allan
DA
Butterfield
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D013879:Thioredoxins; D013482:Superoxide Dismutase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase