Abstract
BackgroundEBV lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor β (TGFβ), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells. To investigate the molecular mechanisms allowing EBV-infected cells to be protected, we examined the expression of viral and cellular antiapoptotic proteins as well as the activation of signal transduction pathways in BL-derived Raji cells exposed to lytic cycle inducing agents.ResultsOur data show that, following EBV activation, the latent membrane protein 1 (LMP1) and the cellular anti-apoptotic proteins MCL-1 and BCL-2 were quickly up-regulated and that Raji cells remained viable even when exposed simultaneously to P(BU)2, sodium butyrate and TGFβ. We report here that inhibition of p38 pathway, during EBV activation, led to a three fold increment of apoptosis and largely prevented lytic gene expression.ConclusionThese findings indicate that, during the switch from the latent to the lytic phase of EBV infection, p38 MAPK phosphorylation plays a key role both for protecting the host cells from apoptosis as well as for inducing viral reactivation. Because Raji cells are defective for late antigens expression, we hypothesize that the increment of LMP1 gene expression in the early phases of EBV lytic cycle might contribute to the survival of the EBV-positive cells.
Highlights
Epstein Barr Virus (EBV) lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor β (TGFβ), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells
Because Raji cells are defective for late antigens expression, we hypothesize that the increment of latent membrane protein 1 (LMP1) gene expression in the early phases of EBV lytic cycle might contribute to the survival of the EBV-positive cells
Activators of EBV lytic cycle induce apoptosis in EBVnegative Burkitt's lymphoma cells EBV lytic cycle can be induced in Burkitt's lymphoma cells by treatment with phorbol esthers, anti-immunoglobulin, sodium butyrrate or TGFβ
Summary
EBV lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor β (TGFβ), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells. LMP1 plays a prominent role in the process of EBV-associated oncogenesis This integral membrane protein can cause transformation of rodent fibroblasts and epithelial cells in vitro [4,5] and induce development of B cell lymphoma or epidermal hyperplasia in transgenic mice [6,7]. By functioning as constitutively activated member of the tumor necrosis factor receptor (TNFR) family, through the cytoplasmic carboxy terminus LMP1 triggers several signaling pathways to alter cell growth and survival [8,9] This viral oncoprotein stimulates NFkB, JNK, the JAK/STAT, PI3K/Akt, ERK1/2, and p38 mitogen activated protein kinase (MAPK) signal transduction cascades [10]; in addition, it regulates several downstream genes including anti-apoptotic genes such as bcl-2 [11,12], mcl-1 [13], A20 [14] and survivin [15]
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