This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eliopoulos, A. G.
Right arrow Articles by Young, L. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eliopoulos, A. G.
Right arrow Articles by Young, L. S.

 Previous Article  |  Next Article 

Journal of Virology, May 2002, p. 4567-4579, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4567-4579.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Oncogenic Protein Kinase Tpl-2/Cot Contributes to Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1-Induced NF-{kappa}B Signaling Downstream of TRAF2

Aristides G. Eliopoulos,1,2* Clare Davies,1 Sarah S. M. Blake,1 Paul Murray,1,3 Sohrab Najafipour,1,3 Philip N. Tsichlis,4 and Lawrence S. Young1,2

The Cancer Research UK Institute for Cancer Studies,1 MRC Center for Immune Regulation,2 Department of Pathology, The University of Birmingham Medical School, Birmingham B15 2TA, England,3 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 191074

Received 31 July 2001/ Accepted 4 February 2002

The Epstein-Barr virus-encoded latent infection membrane protein 1 (LMP1) is a pleiotropic protein, the activities of which include effects on cell transformation and phenotype, growth, and survival. The ability of LMP1 to mediate at least some of these phenomena could be attributed to the activation of the transcription factor NF-{kappa}B. LMP1 promotes NF-{kappa}B activation through the recruitment of the adapter protein TRAF2 and the formation of a dynamic multiprotein complex that includes the NF-{kappa}B kinase, the I{kappa}B kinases, and their downstream targets, I{kappa}Bs and p105. In this study, we have identified the oncogenic kinase Tpl-2/Cot as a novel component of LMP1-induced NF-{kappa}B signaling. We show that Tpl-2 is expressed in primary biopsies from patients with nasopharyngeal carcinoma and Hodgkin's disease, where LMP1 is also found. Inducible expression of LMP1 promotes the activation of Tpl-2, and a catalytically inactive Tpl-2 mutant suppresses LMP1-induced NF-{kappa}B signaling. In colocalization and coimmunoprecipitation experiments, Tpl-2 and TRAF2 were found to interact with Tpl-2 functioning downstream of TRAF2. Consistent with this observation, catalytically inactive Tpl-2 also blocked CD40-mediated NF-{kappa}B activation, which largely depends on TRAF2. The ability of Tpl-2 to influence LMP1-induced NF-{kappa}B occurs through modulation of both I{kappa}B{alpha} and p105 functions. Furthermore, Tpl-2 was found to influence the expression of angiogenic mediators, such as COX-2 in LMP1-transfected cells. These data identify Tpl-2 as a component of LMP1 signaling downstream of TRAF2 and as a modulator of LMP1-mediated effects.

* Corresponding author. Mailing address: Cancer Research UK Institute of Cancer Studies, The University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44 (121) 414 2801. Fax: 44 (121) 414 3263. E-mail: A.G.Eliopoulos{at}bham.ac.uk.

Journal of Virology, May 2002, p. 4567-4579, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4567-4579.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Faumont, N., Le Clorennec, C., Teira, P., Goormachtigh, G., Coll, J., Canitrot, Y., Cazaux, C., Hoffmann, J.-S., Brousset, P., Delsol, G., Feuillard, J., Meggetto, F. (2009). Regulation of DNA Polymerase {beta} by the LMP1 Oncoprotein of EBV through the Nuclear Factor-{kappa}B Pathway. Cancer Res. 69: 5177-5185 [Abstract] [Full Text]  
  • Dawson, C. W., Laverick, L., Morris, M. A., Tramoutanis, G., Young, L. S. (2008). Epstein-Barr Virus-Encoded LMP1 Regulates Epithelial Cell Motility and Invasion via the ERK-MAPK Pathway. J. Virol. 82: 3654-3664 [Abstract] [Full Text]  
  • Eliopoulos, A. G., Das, S., Tsichlis, P. N. (2006). The Tyrosine Kinase Syk Regulates TPL2 Activation Signals. J. Biol. Chem. 281: 1371-1380 [Abstract] [Full Text]  
  • Das, S., Cho, J., Lambertz, I., Kelliher, M. A., Eliopoulos, A. G., Du, K., Tsichlis, P. N. (2005). Tpl2/Cot Signals Activate ERK, JNK, and NF-{kappa}B in a Cell-type and Stimulus-specific Manner. J. Biol. Chem. 280: 23748-23757 [Abstract] [Full Text]  
  • Caivano, M., Rodriguez, C., Cohen, P., Alemany, S. (2003). 15-Deoxy-{Delta}12,14-prostaglandin J2 Regulates Endogenous Cot MAPK Kinase Kinase 1 Activity Induced by Lipopolysaccharide. J. Biol. Chem. 278: 52124-52130 [Abstract] [Full Text]  
  • Saito, N., Courtois, G., Chiba, A., Yamamoto, N., Nitta, T., Hironaka, N., Rowe, M., Yamamoto, N., Yamaoka, S. (2003). Two Carboxyl-terminal Activation Regions of Epstein-Barr Virus Latent Membrane Protein 1 Activate NF-{kappa}B through Distinct Signaling Pathways in Fibroblast Cell Lines. J. Biol. Chem. 278: 46565-46575 [Abstract] [Full Text]  
  • Gandara, M. L., Lopez, P., Hernando, R., Castano, J. G., Alemany, S. (2003). The COOH-Terminal Domain of Wild-Type Cot Regulates Its Stability and Kinase Specific Activity. Mol. Cell. Biol. 23: 7377-7390 [Abstract] [Full Text]  
  • Kurland, J. F., Voehringer, D. W., Meyn, R. E. (2003). The MEK/ERK Pathway Acts Upstream of NF{kappa}B1 (p50) Homodimer Activity and Bcl-2 Expression in a Murine B-Cell Lymphoma Cell Line: MEK INHIBITION RESTORES RADIATION-INDUCED APOPTOSIS. J. Biol. Chem. 278: 32465-32470 [Abstract] [Full Text]  
  • Dawson, C. W., Tramountanis, G., Eliopoulos, A. G., Young, L. S. (2003). Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) Activates the Phosphatidylinositol 3-Kinase/Akt Pathway to Promote Cell Survival and Induce Actin Filament Remodeling. J. Biol. Chem. 278: 3694-3704 [Abstract] [Full Text]  
  • Kontoyiannis, D., Boulougouris, G., Manoloukos, M., Armaka, M., Apostolaki, M., Pizarro, T., Kotlyarov, A., Forster, I., Flavell, R., Gaestel, M., Tsichlis, P., Cominelli, F., Kollias, G. (2002). Genetic Dissection of the Cellular Pathways and Signaling Mechanisms in Modeled Tumor Necrosis Factor-induced Crohn's-like Inflammatory Bowel Disease. JEM 196: 1563-1574 [Abstract] [Full Text]  
  • Gius, D., Coleman, C. N. (2002). Treatment of Nasopharyngeal Cancer: Raising the "Barr". JNCI J Natl Cancer Inst 94: 1594-1595 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»