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UCP4 is a target effector of the NF-κB c-Rel prosurvival pathway against oxidative stress.

Division of Neurology, University Department of Medicine, University of Hong Kong, Hong Kong, People's Republic of China.
Free Radical Biology & Medicine (Impact Factor: 5.27). 05/2012; 53(2):383-94. DOI: 10.1016/j.freeradbiomed.2012.05.002
Source: PubMed

ABSTRACT Mitochondrial uncoupling protein-4 (UCP4) enhances neuronal survival in 1-methyl-4-phenylpyridinium (MPP(+)) toxicity by suppressing oxidative stress and preserving intracellular ATP and mitochondrial membrane potential (MMP). NF-κB regulates neuronal viability via its complexes, p65 mediating cell death and c-Rel promoting cell survival. We reported previously that NF-κB mediates UCP4 neuroprotection against MPP(+) toxicity. Here, we investigated its link with the NF-κB c-Rel prosurvival pathway in alleviating mitochondrial dysfunction and oxidative stress. We overexpressed a c-Rel-encoding plasmid in SH-SY5Y cells and showed that c-Rel overexpression induced NF-κB activity without affecting p65 level. Overexpression of c-Rel increased UCP4 promoter activity and protein expression. Electrophoretic mobility shift assay showed that H(2)O(2) increased NF-κB binding to the UCP4 promoter and that NF-κB complexes were composed of p50/p50 and p50/c-Rel dimers. Under H(2)O(2)-induced oxidative stress, UCP4 knockdown significantly increased superoxide levels, decreased reduced glutathione (GSH) levels, and increased oxidized glutathione levels, compared to controls. UCP4 expression induced by c-Rel overexpression significantly decreased superoxide levels and preserved GSH levels and MMP under similar stress. These protective effects of c-Rel overexpression in H(2)O(2)-induced oxidative stress were significantly reduced after UCP4 knockdown, indicating that UCP4 is a target effector gene of the NF-κB c-Rel prosurvival pathway to mitigate the effects of oxidative stress.

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Aug 19, 2014

Philip Wing Lok Ho