Transcriptional regulation of UCP4 by NF-kappa B and its role in mediating protection against MPP+ toxicity
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Mitochondrial uncoupling protein-4 (UCP4) enhances neuronal cell survival in MPP+-induced toxicity by suppressing oxidative stress and preserving intracellular ATP and mitochondrial membrane potential. UCP4 expression is increased by MPP+, but its regulation is unknown. Using serial human UCP4 promoter-luciferase reporter gene constructs, we identified and characterized several cis-acting elements that can regulate UCP4 expression. Core promoter activity exists within 100 bp upstream of the transcription initiation site (TIS = + 1). Both CAAT box (-33/-27) and Sp1 (62/-49) elements are crucial and act synergistically in its transcription. We identified a NF-kappa B putative binding site at -507/-495. Mutation of this site significantly decreased UCP4 promoter activity. Activation of NF-kappa B by TNF alpha or cycloheximide increased, whereas its inhibition by 4-hydroxy-2-nonenal or transfection of pI kappa B alpha M suppressed, UCP4 promoter activity. NF-kappa B inhibition significantly suppressed the MPP+-induced increase in UCP4 expression. MPP+ increased specific binding of NF-kappa B protein complexes to this site in electrophoretic mobility shift assay. Both UCP4 knockdown and NF-kappa B inhibition exacerbated MPP+-induced cell death. We present the first direct evidence that UCP4 is regulated by NF-kappa B, mediated via a functional NF-kappa B site in its promoter region, and that UCP4 has a significant role in NF-kappa B prosurvival signaling, mediating its protection against MPP+ toxicity. (C) 2010 Elsevier Inc. All rights reserved.
|Number of pages||13|
|Journal||Free Radical Biology and Medicine|
|Publication status||Published - 1 Jul 2010|
- UCP, Parkinson disease, Nuclear factor kappa B, Promoter, Oxidative stress, Free radicals, Uncoupling protein 4, Transcription regulation, Mitochondrial dysfunction