Transcriptional regulation of UCP4 by NF-κB and its role in mediating protection against MPP+ toxicity

Jessica Wing Man Ho, Philip Wing Lok Ho, Wei Yi Zhang, Hui Fang Liu, Ken Hon Hung Kwok, David Chi Wai Yiu, Koon Ho Chan, Michelle Hiu Wai Kung, David Boyer Ramsden, Shu Leong Ho

Research output: Journal article publicationJournal articleAcademic researchpeer-review

17 Citations (Scopus)

Abstract

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 100bp 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-κB putative binding site at -507/-495. Mutation of this site significantly decreased UCP4 promoter activity. Activation of NF-κB by TNFα or cycloheximide increased, whereas its inhibition by 4-hydroxy-2-nonenal or transfection of pIκBαM suppressed, UCP4 promoter activity. NF-κB inhibition significantly suppressed the MPP+-induced increase in UCP4 expression. MPP+ increased specific binding of NF-κB protein complexes to this site in electrophoretic mobility shift assay. Both UCP4 knockdown and NF-κB inhibition exacerbated MPP+-induced cell death. We present the first direct evidence that UCP4 is regulated by NF-κB, mediated via a functional NF-κB site in its promoter region, and that UCP4 has a significant role in NF-κB prosurvival signaling, mediating its protection against MPP+ toxicity.

Original languageEnglish
Pages (from-to)192-204
Number of pages13
JournalFree Radical Biology and Medicine
Volume49
Issue number2
DOIs
Publication statusPublished - Jul 2010
Externally publishedYes

Keywords

  • Free radicals
  • Mitochondrial dysfunction
  • Nuclear factor κB
  • Oxidative stress
  • Parkinson disease
  • Promoter
  • Transcription regulation
  • UCP
  • Uncoupling protein 4

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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