Abstract
Latent membrane protein 1 (LMP1) is a major oncogene encoded by Epstein–Barr virus (EBV) and is essential for immortalization of B cells by the virus. Previous studies suggested that several transcription factors, such as PU.1, RBP-Jκ, NFκB, EBF1, AP-2 and STAT, are involved in LMP1 induction; however, the means by which the oncogene is negatively regulated remains unclear. Here, we introduced short mutations into the proximal LMP1 promoter that includes recognition sites for the E-box and Ikaros transcription factors in the context of EBV-bacterial artificial chromosome. Upon infection, the mutant exhibited increased LMP1 expression and EBV-mediated immortalization of B cells. However, single mutations of either the E-box or Ikaros sites had limited effects on LMP1 expression and transformation. Our results suggest that this region contains a suppressive cis-regulatory element, but other transcriptional repressors (apart from the E-box and Ikaros transcription factors) may remain to be discovered.
Highlights
The Epstein–Barr virus (EBV) is a gamma-herpesvirus that infects humans
It was later confirmed that this region contains a binding motif for enhancer box (E-box) transcription factors, and subsequently, it was suggested that this sequence contained a recognition motif for the Ikaros transcription factor (Jansson et al, 2007)
To evaluate the importance of these motifs, we first carried out luciferase assays (Figure 1). pLMP1/ED-L1-FLuc was generated by inserting the proximal latent membrane protein 1 (LMP1) promoter sequence into pGL4.10 (Promega)
Summary
The Epstein–Barr virus (EBV) is a gamma-herpesvirus that infects humans. The virus principally infects B cells, establishing latent infections in such cells, but can infect other cell types, including epithelial cells and other types of lymphocytes, such as T cells and natural killer (NK) cells. EBV infection has been implicated in infectious mononucleosis and a variety of malignancies, such as Burkitt lymphoma, NK/T cell lymphoma and nasopharyngeal carcinoma (NPC). The expression pattern of viral latent genes is dependent largely on the tissue of origin and the state of the tumor (Murata et al, 2014). EBV in Burkitt lymphoma or gastric carcinoma exhibits type I latency, in which only EBV-encoded small RNAs (EBERs) and EBV nuclear antigen 1 (EBNA1) are expressed. In type II latency (some Hodgkin lymphomas, NPC, and NK/T cell lymphoma), the genes encoding latent membrane protein 1 (LMP1) and LMP2 are expressed in addition to the EBERs and EBNA1. EBV produces EBNA2, EBNA3 and EBNA-LP, as well as EBERs, EBNA1, LMP1 and LMP2 in immunosuppression-related lymphoma or lymphoblastoid cell lines (LCLs) (type III latency). LMP1 constitutively activates cellular signaling through NFκB, MAPK, JAK/STAT, and AKT and is believed to be a major oncogene encoded by EBV (Kilger et al, 1998; Lam and Sugden, 2003; Shair et al, 2007; Kieser and Sterz, 2015)
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