Cell Phenotype-Dependent Control of Epstein-Barr Virus Latent Membrane Protein 1 Gene Regulatory Sequences

Lee

et al. 2004

J Virol

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is a transforming protein that affects multiple cell signaling pathways and contributes to EBV-associated oncogenesis. LMP1 can be expressed in some states of EBV latency, and significant induction of full-length LMP1 is also observed frequently during virus reactivation into the lytic cycle. It is still unknown how LMP1 expression is regulated during the lytic stage and whether any EBV lytic protein is involved in the induction of LMP1. In this study, we first identified that LMP1 expression is associated with the spontaneous virus reactivation in EBV-infected 293 cells and that its expression is a downstream event of the lytic cycle. We further found that

Section: Fig 2 Lmp1 Expression Is a Downstream Event Of Spontaneoussupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Induction of Epstein-Barr Virus Latent Membrane Protein 1 by a Lytic Transactivator Rta

Lee

et al. 2004

J Virol

Journal of General Virology

“…Ghosh & Kieff (1990) defined two positive cis-activating LMP promoter regulatory components ( -155 to -147 and -2 3 4 to -205). An EBNA-2-responsive element has also been mapped to the -2 1 4 to -144 LMP promoter region (Fahraeus et al, 1993). Thus far there have been no DNA binding data published concerning the LMP1 promoter region.…”

Section: Methodsmentioning

confidence: 99%

DNA-binding Studies of the Epstein--Barr Virus Nuclear Antigen 2 (EBNA-2): Evidence for Complex Formation by Latent Membrane Protein Gene Promoter-binding Proteins in EBNA-2-positive Cell Lines

Sauder

Haiss

Grässer

et al. 1994

The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA-2) protein is essential for the immortalization of human primary B cells by EBV. EBNA-2 trans-activates cellular and viral genes like CD23, c-fgr, latent membrane protein 1 (LMP1) and terminal protein 1 (TP1). Transactivation of the TP1 promoter and of the BamHI C promoter has already been investigated in detail and appears to be mediated via protein-protein interactions and not by direct binding of EBNA-2 type A (of EBV type l) to the DNA. EBNA-2 is able to trans-activate the expression of the LMP gene in several cell lines. Various reports have delineated the cis-acting elements of the LMP promoter through which EBNA-2 mediates transactivation. To determine whether EBNA-2 also transactivates the LMP promoter by protein-protein interactions, we performed a series of gel retardation assays and competition experiments with LMP promoter fragments of different sizes. We determined that the protein-binding region on the LMP promoter was within a 42 bp fragment encompassing nucleotides -135 to -176 relative to the LMP transcriptional start site. None of the DNA fragments investigated indicated interaction of EBNA-2 with the DNA via proteinprotein interactions. No significant differences between EBNA-2-positive and EBNA-2-negative nuclear extracts could be seen in the gel retardation assay under conditions that clearly showed binding of EBNA-2A to the TP 1 promoter. However, analysis of sucrose gradient fractions in the gel retardation assay provided evidence that the LMP promoter-binding proteins form a complex of higher Mr in EBNA-2-positive cell extracts. These complexes were destroyed by detergent. We deduce from these results that EBNA-2-positive cells might indeed contain specific complexes bound to the LMP promoter which are, however, too labile to be detected in a standard gel retardation assay.

“…By contrast with pLMP1, TR-L1 activation does not require EBNA2 but could be due to action of cellular Sp1/Sp3 (57) or STAT3 (7) transcription factors. Importantly, some of the regulation mechanisms are cell type specific, as exemplified by the lack of pLMP1 transactivation by EBNA2 in epithelial cells (17,63).…”

mentioning

confidence: 99%

Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Goormachtigh

Ouk

Mougel

et al. 2006

J Virol

Epstein-Barr virus (EBV)is associated with several human malignancies where it expresses limited subsets of latent proteins. Of the latent proteins, latent membrane protein 1 (LMP1) is a potent transforming protein that constitutively induces multiple cell signaling pathways and contributes to EBV-associated oncogenesis. Regulation of LMP1 expression has been extensively described during the type III latency of EBV. Nevertheless, in the majority of EBV-associated tumors, the virus is commonly found to display a type II latency program in which it is still unknown which viral or cellular protein is really involved in maintaining LMP1 expression. Here, we demonstrate that LMP1 activates its own promoter pLMP1 through the JNK signaling pathway emerging from the TES2 domain. Our results also reveal that this activation is tightly controlled by LMP1, since pLMP1 is inhibited by LMP1-activated NF-B signaling pathway. By using our physiological models of EBV-infected cells displaying type II latency as well as lymphoblastoid cell lines expressing a type III latency, we also demonstrate that this balanced autoregulation of LMP1 is shared by both latency programs. Finally, we show that this autoactivation is the most important mechanism to maintain LMP1 expression during the type II latency program of EBV.Epstein-Barr virus (EBV) is a widespread herpesvirus, found in more than 90% of healthy adults and persisting, in the vast majority of individuals, as a lifelong and asymptomatic infection. EBV classically infects B cells, causing sometimes a benign disease (infectious mononucleosis) but also malignant disorders, such as B-lymphoproliferative diseases, in patients with severe immunodeficiency. In immunocompetent hosts, EBV is also associated with other malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, peripheral or nasal NK/T-cell lymphomas, and gastric, breast, and hepatocellular adenocarcinomas (46,50). In all EBV-associated tumors, the virus displays mainly a latency program of infection with a restricted pattern of gene expression, which can be classified in three types. Type I latency, during which only the EBV-encoded nuclear antigen 1 (EBNA1) is expressed, is found in Burkitt's lymphoma. Type II latency is characterized by coexpression of EBNA1 and latent membrane proteins LMP1, LMP2A, and LMP2B and is found in nasopharyngeal carcinoma, Hodgkin's disease, NK/T-cell lymphomas, and AIDS-related non-Hodgkin's lymphomas. Type III latency with expression of the five EBNAs and three latent membrane proteins is restricted to B lymphomas of immunodeficient patients (50).Cellular models allowing investigation of the roles of LMP1 during type II and type III latencies have been developed. In vitro, EBV can infect and immortalize resting B cells to yield permanent growth of lymphoblastoid cell lines (LCLs) displaying a full latency III program (27). We previously showed that EBV can also infect and transform T cells and monocytes. We have described and extensively characterized two cel...