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Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1).
Oncogene. 1998 Apr 02; 16(13):1731-42.O

Abstract

Expression of the oncogenic Epstein-Barr virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) activates signalling on the NF-kappaB axis through two distinct domains in the cytoplasmic C-terminus of the protein, namely CTAR1 (aa 187-231) and CTAR2 (aa 351-386). Whilst this effect is responsible for some of the functional consequences of LMP1 expression, additional LMP1-mediated signalling pathways may exist which contribute to the pleiotropic activities of this protein. In this study we provide evidence of a kinase cascade being activated by LMP1. Thus, we demonstrate that stable or transient expression of the LMP1 prototype from B95.8 in cells of epithelial or B cell origin activates the c-Jun N-terminal kinase (JNK, also known as the stress-activated protein kinase, SAPK) pathway, an effect which was found to be mediated through CTAR2 but not CTAR1. LMP1 from the Cao viral strain or LMP1 homologues from the simian EBV naturally infecting baboons and rhesus monkeys were also able to activate JNK. This phenomenon translates to induction of AP-1, a transcription factor which is readily activated by growth factors and mitogens. Interestingly, an LMP1/ CD40 chimaera comprising of the N-terminus and transmembrane domain of LMP1 and the cytoplasmic tail of CD40 which shares a common TRAF binding motif with CTAR1, effectively induced JNK. As NF-kappaB and JNK are co-activated in LMP1-expressing cells, we investigated whether the two pathways are overlapping or independent. We have found that inhibition of NF-kappaB by metabolic inhibitors or a constitutively active mutated IkappaBalpha does not impair the ability of LMP1 to signal on the JNK axis. Conversely, whilst a dominant negative mutated SEK (JNKK) inhibited LMP1-induced JNK activation, it did not affect NF-kappa-B suggesting that these two LMP1-mediated pathways are divergent.

Authors+Show Affiliations

CRC Institute for Cancer Studies, The University of Birmingham Medical School, UK.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

9582021

Citation

Eliopoulos, A G., and L S. Young. "Activation of the cJun N-terminal Kinase (JNK) Pathway By the Epstein-Barr Virus-encoded Latent Membrane Protein 1 (LMP1)." Oncogene, vol. 16, no. 13, 1998, pp. 1731-42.
Eliopoulos AG, Young LS. Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene. 1998;16(13):1731-42.
Eliopoulos, A. G., & Young, L. S. (1998). Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene, 16(13), 1731-42.
Eliopoulos AG, Young LS. Activation of the cJun N-terminal Kinase (JNK) Pathway By the Epstein-Barr Virus-encoded Latent Membrane Protein 1 (LMP1). Oncogene. 1998 Apr 2;16(13):1731-42. PubMed PMID: 9582021.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). AU - Eliopoulos,A G, AU - Young,L S, PY - 1998/5/15/pubmed PY - 1998/5/15/medline PY - 1998/5/15/entrez SP - 1731 EP - 42 JF - Oncogene JO - Oncogene VL - 16 IS - 13 N2 - Expression of the oncogenic Epstein-Barr virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) activates signalling on the NF-kappaB axis through two distinct domains in the cytoplasmic C-terminus of the protein, namely CTAR1 (aa 187-231) and CTAR2 (aa 351-386). Whilst this effect is responsible for some of the functional consequences of LMP1 expression, additional LMP1-mediated signalling pathways may exist which contribute to the pleiotropic activities of this protein. In this study we provide evidence of a kinase cascade being activated by LMP1. Thus, we demonstrate that stable or transient expression of the LMP1 prototype from B95.8 in cells of epithelial or B cell origin activates the c-Jun N-terminal kinase (JNK, also known as the stress-activated protein kinase, SAPK) pathway, an effect which was found to be mediated through CTAR2 but not CTAR1. LMP1 from the Cao viral strain or LMP1 homologues from the simian EBV naturally infecting baboons and rhesus monkeys were also able to activate JNK. This phenomenon translates to induction of AP-1, a transcription factor which is readily activated by growth factors and mitogens. Interestingly, an LMP1/ CD40 chimaera comprising of the N-terminus and transmembrane domain of LMP1 and the cytoplasmic tail of CD40 which shares a common TRAF binding motif with CTAR1, effectively induced JNK. As NF-kappaB and JNK are co-activated in LMP1-expressing cells, we investigated whether the two pathways are overlapping or independent. We have found that inhibition of NF-kappaB by metabolic inhibitors or a constitutively active mutated IkappaBalpha does not impair the ability of LMP1 to signal on the JNK axis. Conversely, whilst a dominant negative mutated SEK (JNKK) inhibited LMP1-induced JNK activation, it did not affect NF-kappa-B suggesting that these two LMP1-mediated pathways are divergent. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/9582021/Activation_of_the_cJun_N_terminal_kinase__JNK__pathway_by_the_Epstein_Barr_virus_encoded_latent_membrane_protein_1__LMP1__ L2 - https://doi.org/10.1038/sj.onc.1201694 DB - PRIME DP - Unbound Medicine ER -