Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, and histone deacetylase inhibitor (HDACi). We have discovered that protein kinase C delta (PKC␦) is required specifically for EBV reactivation by HDACi. Overexpression of PKC␦ is sufficient to induce the activity of the Zta promoter (Zp) but not of the Rta promoter (Rp). Deletion analysis revealed that the ZID element of Zp is important for PKC␦ activation. Moreover, the Sp1 putative sequence on ZID is essential for PKC␦-induced Zp activity, and the physiological binding of Sp1 on ZID has been confirmed. After HDACi treatment, activated PKC␦ can phosphorylate Sp1 at serine residues and might result in dissociation of the HDAC2 repressor from ZID. HDACi-mediated HDAC2-Sp1 dissociation can be inhibited by the PKC␦ inhibitor, Rotterlin. Furthermore, overexpression of HDAC2 can suppress the HDACi-induced Zp activity. Consequently, we hypothesize that HDACi induces PKC␦ activation, causing phosphorylation of Sp1, and that the interplay between PKC␦ and Sp1 results in the release of HDAC2 repressor from Zp and initiation of Zta expression.Epstein-Barr virus (EBV), a human oncogenic virus, infects two types of human cells predominantly, B lymphocytes and epithelial cells, and EBV infection also is associated with an array of malignancies derived from these two cell types, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma (49). Being a human gammaherpesvirus, EBV undergoes two cycles: latency and lytic replication. Although most latent products are important for its ability to immortalize cells, and the virus is present in a latent form in most EBV-associated cancer tissues, serological studies revealed that elevated antibody titers against some lytic antigens, or increased viral DNA load in serum, are risk factors for tumor development (8,33). In addition, experiments using the SCID mouse model suggested that Zta, an EBV lytic transactivator, is crucial for tumor formation (43). In vitro, experimental approaches also revealed that EBV lytic products may contribute to the pathogenesis of EBV-associated diseases, via upregulation of cytokines, cell growth factors or antiapoptotic proteins (5, 48, 50). Thus, the reactivation of EBV not only leads to the production of viral progeny but also facilitates viral pathogenesis.In vitro, EBV persists predominantly in a latent form in host cells. However, lytic replication can be elicited conditionally by many different chemicals and physical stimuli or by ectopic transfection with two transactivators, Zta or Rta (49). These inducing agents provide the best available models for the study of essential factors involved in the switch of EBV from latency to lytic replication. Tetradecanoyl phorbol acetate (TPA) and anti-Ig are...
IntroductionPrimary EBV infection usually is asymptomatic but persists, so that more than 90% of adults worldwide are persistently infected with EBV. 1 However, as the first human tumor virus identified, EBV is associated with several disorders of lymphocytes, including infectious mononucleosis, Burkitt lymphoma, Hodgkin lymphoma, T-cell lymphoma, NK-cell lymphoma, AIDS-associated lymphoma, and posttransplantation lymphoproliferative disorder (PTLD). 1 Being an oncogenic virus, EBV can immortalize primary B cells into lymphoblastoid cell lines (LCLs). EBV-immortalized LCLs are characterized by several features, including aberrant production of cytokines and chemokines, unlimited proliferation, clumping morphology, and display of an EBV latency III phenotype, characteristics similar to those of PTLD. 2 Indeed, LCLs are good in vitro models to understand the pathogenesis of, and to discover novel therapeutic targets for, PTLD.EBV encodes several proteins which mimic or associate with host cellular factors and these factors are well documented in B-cell survival, differentiation, proliferation, and immortalization. 1 (1) The latent membrane protein 1 (LMP1) acts as a constitutively activated CD40 receptor, which provides signals of survival and differentiation in B cells. In LMP1 transgenic mice, constitutively activated LMP1 drives B-cell lymphoma formation, suggesting that LMP1 acts as an oncogene and plays an important role in EBV-mediated tumorigenesis. 1,3 (2) The latent membrane protein 2A (LMP2A) mimics a functional B-cell receptor (BCR). It interacts with Syk and Lyn tyrosine kinases to deliver survival signals through PKC and intracellular calcium. In LMP2A transgenic mice, LMP2A can rescue BCR-lacking B cells from apoptosis, suggesting that the BCR-driven survival signals can be replaced by LMP2A. 4 (3) The Epstein-Barr nuclear antigen 2 (EBNA2) mimics Notch signaling. It interacts with the DNAbinding protein RBPJ/CBP to interfere with Notch-mediated inhibition of B-cell proliferation and differentiation. 1 (4) Zta, a transactivator, mimics a functional and structural AP-1 protein. It plays an important role in regulating cytokine expression by immune cells, such as IL-13. 5 (5) BCRF-1, which is an IL-10 homologue, serves as a growth factor for B cells and suppresses antiviral immune responses. 6 So, we wondered whether any other specific cellular genes are involved in EBV-mediated immortalization. In this study, tyrosine kinases are our target.Among the proteins encoded by the huge human genome, about ninety protein tyrosine kinases (PTKs) have been defined. 7 PTKs are tightly regulated in cells because they play vital roles in crucial biologic functions, such as survival, proliferation, differentiation, and development. 8 Dysregulation of PTK activity is one of the most common mechanisms leading to cellular transformation and cancer formation. 7 Of note, the discovery of PTKs stemmed from the study of an oncogenic virus, Rous sarcoma virus encoding v-src. 9 Generally, viruses can activate PTKs to transf...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.