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Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling.
Cancer Res. 2006 Dec 15; 66(24):11668-76.CR

Abstract

EBV 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 NH(2)-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IkappaB, 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 kappaB 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.

Authors+Show Affiliations

Graduate Institute of Basic Medical Sciences and Pathology Core, Chang-Gung Molecular Medicine Research Center, Chang-Gung University, Taiwan, Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17178861

Citation

Tsai, Chia-Lung, et al. "Activation of DNA Methyltransferase 1 By EBV LMP1 Involves c-Jun NH(2)-terminal Kinase Signaling." Cancer Research, vol. 66, no. 24, 2006, pp. 11668-76.
Tsai CL, Li HP, Lu YJ, et al. Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Res. 2006;66(24):11668-76.
Tsai, C. L., Li, H. P., Lu, Y. J., Hsueh, C., Liang, Y., Chen, C. L., Tsao, S. W., Tse, K. P., Yu, J. S., & Chang, Y. S. (2006). Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Research, 66(24), 11668-76.
Tsai CL, et al. Activation of DNA Methyltransferase 1 By EBV LMP1 Involves c-Jun NH(2)-terminal Kinase Signaling. Cancer Res. 2006 Dec 15;66(24):11668-76. PubMed PMID: 17178861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. AU - Tsai,Chia-Lung, AU - Li,Hsin-Pai, AU - Lu,Yen-Jung, AU - Hsueh,Chuen, AU - Liang,Ying, AU - Chen,Chi-Long, AU - Tsao,Sai Wah, AU - Tse,Ka-Po, AU - Yu,Jau-Song, AU - Chang,Yu-Sun, PY - 2006/12/21/pubmed PY - 2007/1/26/medline PY - 2006/12/21/entrez SP - 11668 EP - 76 JF - Cancer research JO - Cancer Res VL - 66 IS - 24 N2 - EBV 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 NH(2)-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IkappaB, 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 kappaB 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/17178861/Activation_of_DNA_methyltransferase_1_by_EBV_LMP1_Involves_c_Jun_NH_2__terminal_kinase_signaling_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17178861 DB - PRIME DP - Unbound Medicine ER -