Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23

Abstract

Latent Epstein-Barr virus (EBV) infection and growth transformation of B lymphocytes is characterized by EBV nuclear and membrane protein expression (EBV nuclear antigen [EBNA] and latent membrane protein [LMP], respectively). LMP1 is known to be an oncogene in rodent fibroblasts and to induce B-lymphocyte activation and cellular adhesion molecules in the EBV-negative Burkitt's lymphoma cel line Louckes. EBNA-2 is required for EBV-induced growth transformation; it lowers rodent fibroblast serum dependence and specifically induces the B-lymphocyte activation antigen CD23 in Louckes cels. These initial observations are now extended through an expanded study of EBNA-and LMP1-induced phenotypic effects in a different EBV-negative B-lymphoma cell line, BJAB. LMP1 effects were also evaluated in the EBV-negative Blymphoma cel line BL41 and the EBV-positive Burkitt's lymphoma cel line, Daudi (Daudi is deleted for EBNA-2 and does not express LMP). Previously described EBNA-2-and LMPl-transfected Louckes cells were studied in parallel. EBNA-2, from EBV-1 strains but not EBV-2, induced CD23 and CD21 expression in transfected BJAB cells. In contrast, EBNA-3C induced CD21 but not CD23, while no changes were evident in vector control-, EBNA-1-, or EBNA-LP-transfected clones. EBNAs did not affect CD10, CD30, CD39, CD40, CD44, or cellular adhesion molecules. LMP1 expression in all cell lines induced growth in large clumps and expression of the cellular adhesion molecules ICAM-1, LFA-1, and LFA-3 in those cell lines which constitutively express low levels. LMP1 expression induced marked homotypic adhesion in the BJAB cell line, despite the fact that there was no significant increase in the high constitutive BJAB LFA-1 and ICAM-1 levels, suggesting that LMP1 also induces an associated functional change in these molecules. LMP1 induction of these cellular adhesion molecules was also associated with increased heterotypic adhesion to T lymphocytes. The Burkitt's lymphoma marker, CALLA (CD10), was uniformly down regulated by LMP1 in all cell lines. In contrast, LMP1 induced unique profiles of B-lymphocyte activation antigens in the various cell lines. LMP1 induced CD23 and CD39 in BJAB; CD23 in Louckes; CD39 and CD40 in BL41; and CD21, CD40, and CD44 in Daudi. In BJAB, CD23 surface and mRNA expression were markedly increased by EBNA-2 and LMP1 coexpression, compared with EBNA-2 or LMP1 alone. This cooperative effect was CD23 specific, since no such effect was observed on another marker, CD21. Si analyses revealed that BJAB cells express low levels of FcERIIa CD23 mRNA, and FceRIIb CD23 mRNA was not detectable. LMIP1 preferentially increases FceRIIb CD23 mRNA. EBNA-2 expression alone in BJAB increases the constitutively expressed FceRlla CD23 mRNA. However, when coexpressed with LMP1, EBNA-2 increases total CD23 mRNA without altering the high relative abundance of FcpRIIb to FcrRHla CD23 mRNA induced by LMP1. Thus, LMP1 likely activates the FcrRHb CD23 promoter, while EBNA-2 more likely transactivates a regulatory element common to bot...

Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II

“…The interaction between STAT6 and p100 may also provide some interesting insight related to the mechanism of EBV-mediated gene activation and transformation. EBNA2 plays an important role in EBV-mediated transformation by inducing the expression of a viral gene encoding LMP1 and cellular genes such as CD23 (Wang et al, 1990). LMP1 shows functional similarity to CD40 and directly activates the JAK/STAT pathway (Gires et al, 1999).…”

“…LMP1 shows functional similarity to CD40 and directly activates the JAK/STAT pathway (Gires et al, 1999). CD23, on the other hand, is a direct target gene for STAT6 (Tinnell et al, 1998) and the STAT6 response element of the CD23 promoter is localized within the EBNA2-responsive region (Wang et al, 1990). Interestingly, EBNA2 and LMP1 cooperatively induce CD23 expression (Wang et al, 1990).…”

Inconsistent association of Epstein‐Barr virus with CD56 (NCAM)‐positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract

“…The EBV-specific gene expressions have been investigated in EBV-transformed B-cells [66][67][68] . It is now clear that there are several different states of EBV latency, each of which is characterized by its own distinctive pattern of restricted antigen expression 69 .…”

Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival.

“…et al, 1985;Baichwal and Sugden, 1988;Moorthy and Thorley-Lawson, 1993) and blocks differentiation in epithelial cells (Dawson et al, 1990;Fahraeus et al, 1990b;Wilson et al, 1990). In Burkitt's lymphoma cell lines LMP1 induces the expression of B cell activation markers CD23 and CD40 and cell adhesion molecules ICAM1, LFA1 and LFA3 and stimulates NF-iB activity (Wang,F. et al, 1990;Hammarskjoeld and Simurda, 1992;Laherty et al, 1992;Huen et al, 1995;Mitchell and Sugden, 1995).…”