The p38 Signaling Pathway Upregulates Expression of the Epstein-Barr Virus LMP1 Oncogene

Abstract

The Epstein-Barr virus (EBV)-encoded LMP1 oncogene has a role in transformation, proliferation, and metastasis of several EBV-associated tumors. Furthermore, LMP1 is critically involved in transformation and growth of EBV-immortalized B cells in vitro. The oncogenic properties of LMP1 are attributed to its ability to upregulate anti-apoptotic proteins and growth signals. The transcriptional regulation of LMP1 is dependent on the context of cellular and viral proteins present in the cell. Here, we investigated the effect of several signaling pathways on the regulation of LMP1 expression. Inhibition of p38 signaling, using p38-specific inhibitors SB203580 and SB202190, downregulated LMP1 in estrogen-induced EREB2.5 cells. Similarly, p38 inhibition decreased trichostatin A-induced LMP1 expression in P3HR1 cells. Exogenous expression of p38 in lymphoblastoid cell lines (LCLs) led to an increase in LMP1 promoter activity in reporter assays, and this activation was mediated by the previously identified CRE site in the promoter. Inhibition of p38 by SB203580 and p38-specific small interfering RNA (siRNA) also led to a modest decrease in endogenous LMP1 expression in LCLs. Chromatin immunoprecipitation indicated decreased binding of CREB-ATF1 to the CRE site in the LMP1 promoter after inhibition of the p38 pathway in EREB2.5 cells. Taken together, our results suggest that an increase in p38 activation upregulates LMP1 expression. Since p38 is activated in response to stimuli such as stress or possibly primary infection, a transient upregulation of LMP1 in response to p38 may allow the cells to escape apoptosis. Since the p38 pathway itself is activated by LMP1, our results also suggest the presence of an autoregulatory loop in LMP1 upregulation. Epstein-Barr virus (EBV) is a human B-lymphocryptovirusthat infects approximately 90% of the world's adult population and is the causative agent of infectious mononucleosis (IM). EBV is associated with several human malignancies such as Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), nasopharyngeal carcinoma (NPC), nasal T/NK lymphoma (NL), peripheral T-cell lymphoma, gastric carcinoma, and lymphoproliferative diseases in immunocompromised patients (57). EBV establishes latent infection in human B cells and transforms them in culture. The EBV-encoded LMP1 oncogene is critically involved in the EBV immortalization of B cells and their persistence in vitro, and it has the ability to transform rodent fibroblast and human cell lines in culture (4). LMP1 expression is thought to contribute to the genesis and growth of EBV-associated tumors. The oncogenic ability of LMP1 is attributed to its upregulation of anti-apoptotic proteins and growth signaling pathways (55). LMP1 transcription is regulated by both viral and cellular factors. EBV uses different programs of viral gene expression in order to drive naïve B cells into resting memory cells. These patterns of viral gene expression are referred to as latency types I, II, and III. EBV-associated tumors also exhibit similar patterns o...

Modes of infection and oncogenesis by the Epstein–Barr virus

“…EBNA2 may not be compatible with entry into the germinal center and may therefore require to be silenced [1,22,62]. In type II latency, LMP1 and LMP2 are expressed even without EBNA2, probably through the effect of signal transducers and activators of transcription (STAT), NF-κB, and CCAAT enhancer-binding protein [64,[79][80][81][82].…”

Differentiation-Dependent LMP1 Expression Is Required for Efficient Lytic Epstein-Barr Virus Reactivation in Epithelial Cells

“…Multiple layers of regulation act to ensure tight control of LMP1 transcription from both of these promoters. In addition to viral factors, such as EBNA2, EBNA-LP, EBNA3C, and microRNAs, cellular transcription factors, including RBPJ, PU.1, SpiB, IRF4, EBF1, IRF7, Pax5, Notch-1, ATF-1, CREB-1, AP-2, NF-B family members, and STAT family members, also regulate the activity of the LMP1 promoters (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). Epigenetic modifications of the viral genome, such as promoter DNA methylation, histone acetylation, and histone methylation, also regulate LMP1 expression (67).…”

Estrogen differentially regulates expression of P-38 and hemeoxygenase-1 in mouse cervix

“…The P-38/MAPK pathway is also among the many signaling pathways that are utilized by estrogen. Specifically, the P-38/ MAPK pathway has been shown to regulate the effects of estrogen on human corneal epithelial cells [18], as well as up-regulate the LMP1 oncogene [19]. Although no specific studies have implicated the P-38/MAPK pathway in estrogen action in the cervix, P-38 activity has also been demonstrated in the cervical tissue.…”