The NPC derived C15 LMP1 protein confers enhanced activation of NF-κB and induction of the EGFR in epithelial cells

Abstract

The Epstein ± Barr Virus (EBV) LMP1 protein is frequently expressed in nasopharyngeal carcinoma and is essential for the transforming eects of EBV. Analysis of LMP1 genes isolated from tumor biopsies has revealed considerable sequence variation including deletion of amino acids 343 ± 352. Several studies have suggested that this sequence variation could enhance the transforming potential of LMP1. LMP1 has profound eects on cellular gene expression mediated in part through activation of the NF-kB transcription factor. In addition, LMP1 engages the TRAF signaling pathway resulting in the induction of EGFR expression. In this study, the LMP1 proteins derived from the laboratory strain B95-8 and the NPC strain C15 were analysed for their ability to activate NF-kB and also to induce expression of the EGFR. The data suggest that the C15-LMP1 protein activates NF-kB more eciently and induces higher levels of the EGFR. Analysis of chimeric LMP1 proteins indicates that the amino terminal 181 amino acids of C15-LMP1 confer this increased signaling capability, and that deletion of amino acids 343 ± 352 does not aect these properties. Finally, these data provide evidence that ®ve amino acid changes within the transmembrane domain in the C15-LMP1 protein lead to enhanced NF-kB activation and EGFR induction.

Hairy Leukoplakia: an Unusual Combination of Transforming and Permissive Epstein-Barr Virus Infections

“…6C and D). The LMP1-TRAF association is known to activate the transcription factor NF-B; in epithelial cells, three distinct NF-B complexes have been detected, with the major complex containing p52-p65 heterodimers (7,22,25,26,31). To determine if NF-B is activated in HLP, antibodies specific for the p65 nuclear localization signal were used to detect the activated form of the transcription factor by immunohistochemistry.…”

LMP1 Promotes Expression of Insulin-Like Growth Factor 1 (IGF1) To Selectively Activate IGF1 Receptor and Drive Cell Proliferation

“…To confirm that the transfected cell lines expressed LMP1 at physiologically relevant levels, the expression of LMP1 in transfected cells was compared to LMP1 expression in C15 xenograft tumors. C15 tumors are serially passaged in vivo models of NPC that contain the EBV genome and consistently express LMP1 (35) (Fig. 1B).…”

Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression

“…Expression of LMP1 in B lymphocytes induces the transcription of many genes, including those encoding activation antigens such as CD23 and CD40, adhesion molecules such as ICAM-1, LFA-1, and LFA-3, and molecules which inhibit programmed cell death such as Bcl-2, Mch-1, and A20 (16,22,33,35,36,(62)(63)(64). Expression of LMP1 in epithelial cells induces expression of the genes encoding the epidermal growth factor receptor (EGFR) and the A20 molecule (38)(39)(40). Induction of these genes is likely to play an important role in the transformation of epithelial cells by LMP1.…”