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

TitleTranscriptional regulation of UCP4 by NF-κB and its role in mediating protection against MPP+ toxicity
Authors
KeywordsFree radicals
Mitochondrial dysfunction
Nuclear factor κB
Oxidative stress
Parkinson disease
Promoter
Transcription regulation
UCP
Uncoupling protein 4
Issue Date2010
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomed
Citation
Free Radical Biology And Medicine, 2010, v. 49 n. 2, p. 192-204 How to Cite?
AbstractMitochondrial 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. © 2010 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/77820
ISSN
2015 Impact Factor: 5.784
2015 SCImago Journal Rankings: 2.468
ISI Accession Number ID
Funding AgencyGrant Number
Henry G. Leong Professorship in Neurology
Research Grants Council, Hong KongHKU 7661/07M
Donation Fund for Neurology Research
Seed Funding for Basic Research, Committee on Research and ConferenceHKU 200901159008
Research Assistant Professorship
University of Hong Kong
Funding Information:

We gratefully acknowledge support from the Henry G. Leong Professorship in Neurology (S.L.H.), the Research Grants Council, Hong Kong (HKU 7661/07M; S.L.H), the Donation Fund for Neurology Research (S.L.H.), and Seed Funding for Basic Research, Committee on Research and Conference Grants (HKU 200901159008; P.W.L.H.). P.W.L. Ho is supported by a Research Assistant Professorship, W.Y. Zhang by a Postdoctoral Fellowship, and H.F. Liu, D.C.W. Yiu, and J.W.M. Ho by Ph.D. Studentships from the University of Hong Kong. K.H.H. Kwok's Ph.D. Studentship is fully supported by the Donation Fund for Neurology Research (S.L.H.).

References

 

DC FieldValueLanguage
dc.contributor.authorHo, JWMen_HK
dc.contributor.authorHo, PWLen_HK
dc.contributor.authorZhang, WYen_HK
dc.contributor.authorLiu, HFen_HK
dc.contributor.authorKwok, KHHen_HK
dc.contributor.authorYiu, DCWen_HK
dc.contributor.authorChan, KHen_HK
dc.contributor.authorKung, MHWen_HK
dc.contributor.authorRamsden, DBen_HK
dc.contributor.authorHo, SLen_HK
dc.date.accessioned2010-09-06T07:36:05Z-
dc.date.available2010-09-06T07:36:05Z-
dc.date.issued2010en_HK
dc.identifier.citationFree Radical Biology And Medicine, 2010, v. 49 n. 2, p. 192-204en_HK
dc.identifier.issn0891-5849en_HK
dc.identifier.urihttp://hdl.handle.net/10722/77820-
dc.description.abstractMitochondrial 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. © 2010 Elsevier Inc.en_HK
dc.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomeden_HK
dc.relation.ispartofFree Radical Biology and Medicineen_HK
dc.rightsFree Radical Biology & Medicine. Copyright © Elsevier Inc.en_HK
dc.subjectFree radicalsen_HK
dc.subjectMitochondrial dysfunctionen_HK
dc.subjectNuclear factor κBen_HK
dc.subjectOxidative stressen_HK
dc.subjectParkinson diseaseen_HK
dc.subjectPromoteren_HK
dc.subjectTranscription regulationen_HK
dc.subjectUCPen_HK
dc.subjectUncoupling protein 4en_HK
dc.titleTranscriptional regulation of UCP4 by NF-κB and its role in mediating protection against MPP+ toxicityen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0891-5849&volume=49&issue=2&spage=192&epage=204&date=2010&atitle=Transcriptional+regulation+of+UCP4+by+NF-κB+and+its+role+in+mediating+protection+against+MPP(+)+toxicityen_HK
dc.identifier.emailHo, PWL:hwl2002@hku.hken_HK
dc.identifier.emailHo, SL:slho@hku.hken_HK
dc.identifier.authorityHo, PWL=rp00259en_HK
dc.identifier.authorityHo, SL=rp00240en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.freeradbiomed.2010.04.002en_HK
dc.identifier.pmid20385226-
dc.identifier.scopuseid_2-s2.0-77953544163en_HK
dc.identifier.hkuros169720en_HK
dc.identifier.hkuros229823-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77953544163&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume49en_HK
dc.identifier.issue2en_HK
dc.identifier.spage192en_HK
dc.identifier.epage204en_HK
dc.identifier.isiWOS:000279017800009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridHo, JWM=8685214100en_HK
dc.identifier.scopusauthoridHo, PWL=25027612100en_HK
dc.identifier.scopusauthoridZhang, WY=7409424869en_HK
dc.identifier.scopusauthoridLiu, HF=27170235100en_HK
dc.identifier.scopusauthoridKwok, KHH=7102194193en_HK
dc.identifier.scopusauthoridYiu, DCW=36674071000en_HK
dc.identifier.scopusauthoridChan, KH=7406034963en_HK
dc.identifier.scopusauthoridKung, MHW=36336960300en_HK
dc.identifier.scopusauthoridRamsden, DB=7102612805en_HK
dc.identifier.scopusauthoridHo, SL=25959633500en_HK
dc.identifier.citeulike7018276-

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