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Article: Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH 2-terminal kinase signaling

TitleActivation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH 2-terminal kinase signaling
Authors
Issue Date2006
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2006, v. 66 n. 24, p. 11668-11676 How to Cite?
AbstractEBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH2-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IκB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor-associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor κB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. ©2006 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/149668
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTsai, CLen_US
dc.contributor.authorLi, HPen_US
dc.contributor.authorLu, YJen_US
dc.contributor.authorHsueh, Cen_US
dc.contributor.authorLiang, Yen_US
dc.contributor.authorChen, CLen_US
dc.contributor.authorTsao, SWen_US
dc.contributor.authorTse, KPen_US
dc.contributor.authorYu, JSen_US
dc.contributor.authorChang, YSen_US
dc.date.accessioned2012-06-26T05:56:48Z-
dc.date.available2012-06-26T05:56:48Z-
dc.date.issued2006en_US
dc.identifier.citationCancer Research, 2006, v. 66 n. 24, p. 11668-11676en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/149668-
dc.description.abstractEBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH2-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IκB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor-associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor κB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. ©2006 American Association for Cancer Research.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshCadherins - Geneticsen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshDna (Cytosine-5-)-Methyltransferase - Metabolismen_US
dc.subject.meshGenes, Reporteren_US
dc.subject.meshHumansen_US
dc.subject.meshJnk Mitogen-Activated Protein Kinases - Genetics - Physiologyen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.subject.meshRna, Small Interfering - Geneticsen_US
dc.subject.meshRecombinant Proteins - Metabolismen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshSignal Transduction - Physiologyen_US
dc.subject.meshTransfectionen_US
dc.subject.meshViral Matrix Proteins - Genetics - Metabolismen_US
dc.titleActivation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH 2-terminal kinase signalingen_US
dc.typeArticleen_US
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_US
dc.identifier.authorityTsao, SW=rp00399en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-06-2194en_US
dc.identifier.pmid17178861-
dc.identifier.scopuseid_2-s2.0-33846227472en_US
dc.identifier.hkuros138255-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33846227472&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume66en_US
dc.identifier.issue24en_US
dc.identifier.spage11668en_US
dc.identifier.epage11676en_US
dc.identifier.isiWOS:000242915600021-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridTsai, CL=15836191600en_US
dc.identifier.scopusauthoridLi, HP=9276641400en_US
dc.identifier.scopusauthoridLu, YJ=35074503400en_US
dc.identifier.scopusauthoridHsueh, C=7102910897en_US
dc.identifier.scopusauthoridLiang, Y=36072856600en_US
dc.identifier.scopusauthoridChen, CL=7501965241en_US
dc.identifier.scopusauthoridTsao, SW=7102813116en_US
dc.identifier.scopusauthoridTse, KP=7102609861en_US
dc.identifier.scopusauthoridYu, JS=7405530632en_US
dc.identifier.scopusauthoridChang, YS=7501842414en_US

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