The Epstein-Barr virus (EBV) is associated with the development of several human tumors, including Hodgkin's lymphoma (HL) and EBV-positive undifferentiated nasopharyngeal carcinoma (NPC).1 In HL, the malignant Hodgkin's and Reed-Sternberg (HRS) cells constitute only a minority of the total tumor mass, and are surrounded by variable proportions of nonmalignant reactive cells. In approximately onehalf of HL, EBV can be detected in HRS cells, where the virus expresses a limited subset of genes; these include the Epstein-Barr nuclear antigen-1 (EBNA1) and the latent membrane proteins, LMP1 and LMP2.2 Although EBV-specific cytotoxic T cells (CTLs) can be detected in HL and NPC and have been shown to kill LMP1-and LMP2-expressing cells in vitro, they are unable to eliminate EBV-infected tumor cells in vivo. [3][4][5] This failure may be because of increased recruitment of regulatory T cells
The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the 'canonical' NF-jB pathway that involves the phosphorylation and degradation of IjBa downstream of the IjB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-jB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-jB subunits. LMP1-induced NF-jB transactivation is reduced in nf-kb2 À/À mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-jB transcriptional effects. This pathway is likely to operate in vivo, as the expression of LMP1 in primary EBV-positive Hodgkin's lymphoma and nasopharyngeal carcinoma biopsies correlates with the nuclear accumulation of p52. Interestingly, while the ability of LMP1 to activate the canonical NF-jB pathway is impaired in cells lacking IKKc/NEMO, the regulatory subunit of the IKK complex, p100 processing remains unaffected. As a result, nuclear translocation of p52, but not p65, occurs in the absence of IKKc. These data point to the existence of a novel signalling pathway that regulates NF-jB in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.
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