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Journal of Virology, January 2003, p. 1316-1328, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1316-1328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

TRAF1 Is a Critical Regulator of JNK Signaling by the TRAF-Binding Domain of the Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1 but Not CD40

Aristides G. Eliopoulos,1,2* Elyse R. Waites,3 Sarah M. S. Blake,1 Clare Davies,1 Paul Murray,3 and Lawrence S. Young1,2

Cancer Research UK Institute for Cancer Studies,1 MRC Centre for Immune Regulation,2 Department of Pathology, The University of Birmingham Medical School, Birmingham B15 2TA, United Kingdom3

Received 22 July 2002/ Accepted 7 October 2002

The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-{kappa}B, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type- dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.

* Corresponding author. Mailing address: Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Vincent Dr., Edgbaston, Birmingham B15 2TA, United Kingdom. Phone: 44-121-414-2801. Fax: 44-121-414-3236. E-mail: A.G.Eliopoulos{at}bham.ac.uk.

Journal of Virology, January 2003, p. 1316-1328, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1316-1328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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