Is Epstein-Barr virus transmitted sexually?
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Cervix Uteri↗
Biomedical subjects
Joseph S Pagano
Publications and source records attributed to Joseph S Pagano.
MUC1 induced by Epstein-Barr virus latent membrane protein 1 causes dissociation of the cell-matrix interaction and cellular invasiveness via STAT signaling.
Disruption of cellular adhesion is an essential pathobiologic step leading to tumor dissemination. Mucin 1 (MUC1) is a mucinous glycoprotein expressed at the surfaces of epithelial cells in many tissues and their carcinomas. MUC1 plays crucial roles in tumor invasion and metastasis, especially in opposing cell adhesion. We have shown that virus infection, specifically by the human tumor virus Epstein-Barr virus (EBV) induces a spectrum of cellular invasiveness and metastasis factors. Here we show that expression of MUC1 is increased in diverse latently EBV-infected cell lines that express latent membrane protein 1 (LMP1), the main viral oncoprotein, and that the level of MUC1 was suppressed by expression of a dominant-negative mutant of LMP1. Expression of LMP1 in EBV-negative nasopharyngeal cell lines induces expression of MUC1 through activation of the MUC1 promoter via binding of STAT1 and STAT3. Finally, LMP1 reduces cell adhesion ability, which is restored by inhibition of MUC1 expression with MUC1 small interfering RNA (siRNA). In addition, LMP1 increases cell invasiveness, which is suppressed by MUC1 siRNA. Thus, LMP1 induces MUC1, a factor important in an early step of detachment and release of tumor cells, which along with induction of other invasiveness and angiogenic factors may combine to act in a complex sequential process that culminates in metastasis of EBV-infected tumor cells.
Antigens, Neoplasm↗
EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells.
Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit alpha. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1alpha and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1alpha activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1alpha for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1alpha complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1alpha and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1.
Breast Neoplasms↗
cdc2/cyclin B1-dependent phosphorylation of EBNA2 at Ser243 regulates its function in mitosis.
Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) transactivates EBV genes in latently infected B cells. We have shown that mitotic hyperphosphorylation of EBNA2 suppresses its ability to transactivate the latent membrane protein 1 (LMP1) promoter. In this follow-up study, we identify EBNA2 Ser243 as a phosphorylation site for mitotic cdc2/cyclin B1 kinase. Mutation at Ser243, which mimics constitutive phosphorylation of the protein, decreases endogenous levels of both LMP1 and EBNA2. Moreover, mutation at Ser243 reduces the ability of EBNA2 to transactivate Cp, the promoter for all six EBV EBNA genes. Our data implicate EBNA2 Ser243 as a cdc2/cyclin B1 site of phosphorylation important for EBNA2's cotranscriptional function in mitosis.
Amino Acid Substitution↗
Up-regulation of beta-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells.
The protein levels of beta-catenin are tightly regulated by the ubiquitin/proteasome system. We provide evidence that two distinct ubiquitin-dependent degradation pathways for beta-catenin are active in the same Burkitt's lymphoma cells: Along with the classical glycogen-synthase kinase 3beta-dependent destruction machinery, degradation of beta-catenin through seven in absentia homolog 1 (Siah-1) ubiquitin ligase is functional in these cells. We show that inhibition of endogenous Siah-1 stabilizes and activates beta-catenin in B cells. The principal Epstein-Barr virus oncoprotein, latent membrane protein 1, is involved in beta-catenin up-regulation, and expression of latent membrane protein 1 in B lymphoma cells is associated with decreased Siah-1 RNA and protein levels. Thus, we demonstrate the significance of the endogenous Siah-1-dependent ubiquitin/proteasome pathway for beta-catenin degradation in malignant human cells and its regulation by a viral oncogene.
Cell Line↗
Ribonucleotide reductase inhibitors enhance cidofovir-induced apoptosis in EBV-positive nasopharyngeal carcinoma xenografts.
In nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV) infection is mainly latent, and the tumor cells contain episomal viral DNA. We have shown that the acyclic nucleoside phosphonate analog, cidofovir [(S)-1-(3-hydroxy-2-(phosphonylmethoxypropyl))cytosine] (HPMPC), inhibits growth of NPC xenografts in nude mice by causing apoptosis. The ribonucleotide reductase (RR) inhibitors, hydroxyurea and didox (3,4-dihydroxybenzohydroxamic acid), have been demonstrated to inhibit neoplastic growth and are used as antiviral and anticancer agents. Here we show that RR inhibitors enhance the antitumor effect of cidofovir in EBV-transformed epithelial cells. MTT assays indicate that hydroxyurea and didox enhance cidofovir-induced cell toxicity in NPC-KT cells, an EBV-positive epithelial cell line derived from NPC. The effect is due to enhancement of apoptosis through the caspase cascade as shown by pronounced cleavage of poly(ADP-ribose) polymerase. Finally, hydroxyurea strikingly enhanced the cidofovir-induced growth-inhibitory effect on NPC grown in athymic mice. The results suggest that RR inhibitors should enhance the antitumor effect of acyclic nucleoside phosphonate analogs on NPC.
Animals↗
Epstein-Barr virus infections: prospects for treatment.
Epstein-Barr virus (EBV) causes infectious mononucleosis and oral hairy leucoplakia, and is associated with a number of malignancies. There are, however, no regulatory agency-approved treatments for EBV-related diseases. Several antiviral drugs inhibit replication of EBV in cell culture including acyclic nucleoside and nucleotide analogues and pyrophosphate analogues, all of which inhibit the EBV DNA polymerase. Despite their potency in vitro, these drugs have limited use in vivo for treatment of acute primary EBV infection as well as EBV-associated malignancies for several reasons. Here we discuss novel anti-EBV compounds, including maribavir, potentially useful for the treatment of acute EBV infections. A number of experimental approaches for treatment of EBV-related malignancies that are not susceptible to conventional antiviral drug treatment are also discussed.
Antiviral Agents↗
Epstein-Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: enhanced susceptibility to nasopharyngeal carcinoma.
The Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1) has a significant role in several malignancies, including nasopharyngeal carcinoma (NPC). LMP1 is the principal oncoprotein, and we have shown that it also induces a set of factors that mediates invasion, angiogenesis and metastasis. Matrix metalloproteinase-1 (MMP1) is also involved in several malignancies. A single guanine insertion polymorphism (2G) in the MMP1 promoter creates an Ets binding site that causes high levels of transcription and correlates with risk for some malignancies. Here, we evaluate the impact of this 2G insertion type on NPC. We genotyped 44 Japanese and 39 Taiwanese NPC patients, as well as 58 Japanese and 23 Taiwanese healthy controls. The proportion of 2G homozygotes was higher in the NPC groups than in controls (Japanese: p = 0.02, odds ratio (OR) = 2.49; Taiwanese: p = 0.02, OR = 3.66). An analysis of overall survival rates in the patients with NPC, and the 1G/1G genotype disclosed a favorable prognosis (5-year survival rate = 100%, p = 0.04). Multivariate analysis showed that 1G/1G has independent prognostic significance. We also examined whether LMP1 enhances MMP1 expression in epithelial cells in culture. LMP1-transfected cells with 2G/2G genotype expressed MMP1, which was abolished by activator protein-1 (AP1) dominant-negative (DN) and Ets-DN. LMP1 also induced active MMP3, which can cleave latent MMP1, and AP1-DN and Ets-DN suppressed the MMP3 expression. These results suggest that LMP1-induced MMP1 and MMP3 are closely linked and show that LMP1 activates MMP1 via an Ets binding site formed by 2G, which is a candidate marker for both risk and prognosis of NPC.
Carcinoma, Squamous Cell↗
Regulation of the transcriptional activity of the IRF7 promoter by a pathway independent of interferon signaling.
Genes containing an interferon (IFN)-stimulated response element (ISRE) can be divided into two groups according to their inducibility by IFN and virus infection: one induced only by IFN and the other induced by both IFN and virus infection. Although it is now clear that IFN regulatory factor 7 (IRF7) is a multifunctional gene essential for induction of type I IFNs, regulation of the IRF7 promoter (IRF7p) is poorly understood. The IRF7 gene includes two IFN responsive elements, an IRF-binding element (IRFE) in the promoter region and an ISRE in the first intron, and is induced by the IFN-triggered Jak-STAT pathway by binding of the IFN-stimulated gene factor 3 (ISGF3) complex to the ISRE. In this study, we demonstrate that IRF3 and IRF7, which with the coactivators CREB-binding protein and P300 form the virus-activated factor (VAF) complex upon Sendai virus infection, bind to the IRF7 ISRE and IRFE and can directly activate IRF7 transcription. Promoter reporter assays show that both the ISRE and IRFE are responsive to activation by IRF7 and IRF3. In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection. Studies with Jak1 kinase inactive 293 cells that were stably transfected with a Jak1 kinase dead dominant negative construct, and the mutant cell lines SAN (IFNalpha-/beta-), U2A (IRF9-), U4A (Jak1-), and DKO (IRF1-/IRF2-) show that the IRF7 transcription activated directly by VAF is distinct from and independent of the IFN signaling pathway. Thus, IRF7 transcription is autoregulated by binding of the IRF7-containing VAF to its own ISRE and IRFE. The results show two distinct mechanisms for the activation of the IRF7 promoter, by IFN and by virus infection. A regulatory network between type I IFNs and IRF7 is proposed. The distinct pathways may reflect special roles for an efficient antiviral response at different stages of virus infection.
Cell Line↗
Targeting of host-cell ubiquitin pathways by viruses.
The ability of viruses to co-opt cell signalling pathways has, over millions of years of co-evolution, come to pervade nearly every facet of cellular functions. Recognition of the extent to which the ubiquitin-proteasome system can be directed or subverted by viruses is relatively recent. Viral products interact with, and adjust, the ubiquitin-proteasome machinery precisely and at many levels, and they do so at distinct stages of viral life-cycles. The implications for both cells and viruses are fundamental, and understanding viral strategies in this context opens up fascinating new areas for research that span from basic cell biology to therapeutic interventions against both viruses and malignancies.
Animals↗
Interferon regulatory factor 7 is negatively regulated by the Epstein-Barr virus immediate-early gene, BZLF-1.
Virus infection stimulates potent antiviral responses; specifically, Epstein-Barr virus (EBV) infection induces and activates interferon regulatory factor 7 (IRF-7), which is essential for production of alpha/beta interferons (IFN-alpha/beta) and upregulates expression of Tap-2. Here we present evidence that during cytolytic viral replication the immediate-early EBV protein BZLF-1 counteracts effects of IRF-7 that are central to host antiviral responses. We initiated these studies by examining IRF-7 protein expression in vivo in lesions of hairy leukoplakia (HLP) in which there is abundant EBV replication but the expected inflammatory infiltrate is absent. This absence might predict that factors involved in the antiviral response are absent or inactive. First, we detected significant levels of IRF-7 in the nucleus, as well as in the cytoplasm, of cells in HLP lesions. IRF-7 activity in cell lines during cytolytic viral replication was examined by assay of the IRF-7-responsive promoters, IFN-alpha4, IFN-beta, and Tap-2, as well as of an IFN-stimulated response element (ISRE)-containing reporter construct. These reporter constructs showed consistent reduction of activity during lytic replication. Both endogenous and transiently expressed IRF-7 and EBV BZLF-1 proteins physically associate in cell culture, although BZLF-1 had no effect on the nuclear localization of IRF-7. However, IRF-7-dependent activity of the IFN-alpha4, IFN-beta, and Tap-2 promoters, as well as an ISRE promoter construct, was inhibited by BZLF-1. This inhibition occurred in the absence of other EBV proteins and was independent of IFN signaling. Expression of BZLF-1 also inhibited activation of IRF-7 by double-stranded RNA, as well as the activity of a constitutively active mutant form of IRF-7. Negative regulation of IRF-7 by BZLF-1 required the activation domain but not the DNA-binding domain of BZLF-1. Thus, EBV may subvert cellular antiviral responses and immune detection by blocking the activation of IFN-alpha4, IFN-beta, and Tap-2 by IRF-7 through the medium of BZLF-1 as a negative regulator.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit.
We have reported evidence for a positive regulatory circuit between interferon regulatory factor 7 (IRF7) and the Epstein-Barr virus (EBV) oncoprotein 1 (LMP1) (S. Ning, A. M. Hahn, and J. S. Pagano, J. Virol. 77:9359-9368, 2003). To explore a possible braking mechanism for this circuit, several type II EBV-infected cell lines that express different levels of LMP1 and IRF7 proteins and therefore are convenient for studying modulation of expression of LMP1 were analyzed. Endogenous levels of IRF7 and LMP1 were directly correlated. Transient expression of an IRF7 dominant-negative mutant decreased LMP1 levels. Endogenous IRF5 and IRF7 proteins were shown to physically associate in EBV-positive cells. Transient expression of IRF5 decreased activation of the LMP1 promoter by IRF7 in a dose-dependent manner. Finally, transfection of either an IRF5 dominant-negative construct or IRF5 small interfering RNA in these cells resulted in increases in endogenous levels of LMP1. These results indicate that IRF5 can downregulate IRF7's induction of expression of LMP1 most likely by interacting with IRF7 and provide a means of modulating a regulatory circuit between IRF7 and LMP1.
Antigens, Viral↗
Hyperphosphorylation of EBNA2 by Epstein-Barr virus protein kinase suppresses transactivation of the LMP1 promoter.
The Epstein-Barr virus (EBV) BGLF4 gene encodes a serine/threonine protein kinase (PK) that is expressed in the cytolytic cycle. EBV nuclear antigen 2 (EBNA2) is a key latency gene essential for immortalization of B lymphocytes and transactivation of viral and cellular promoters. Here we report that EBV PK phosphorylates EBNA2 at Ser-243 and that these two proteins physically associate. PK suppresses EBNA2's ability to transactivate the LMP1 promoter, and Ser-243 of EBNA2 is involved in this suppression. Moreover, EBNA2 is hyperphosphorylated during EBV reactivation in latently infected B cells, which is associated with decreased LMP1 protein levels. This is the first report about the effect of EBV PK on the function of one of its target proteins and regulation of EBNA2 phosphorylation during the EBV lytic cycle.
Down-Regulation↗
Multiple signal transducers and activators of transcription are induced by EBV LMP-1.
Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) is required for EBV immortalization of primary B cells in vitro. Signal transducers and activators of transcription (STATs) play a pivotal role in the initiation and maintenance of certain cancers. STAT proteins, especially STAT-1, -3, and -5, are persistently tyrosine phosphorylated or activated in many cancers. We show here that EBV-infected type III latency cells, in which the EBV oncoprotein, LMP-1 is expressed, express high levels of four STATs (STAT-1, -2, -3, and -5A) and that LMP-1 is responsible for the induction of three (STAT-1, -2, and -3). In addition, the C-terminal activator region 1 (CTAR-1) and CTAR-2 of LMP-1 cooperatively induced the expression of STAT-1. The cooperativity was evident when CTAR-1 and CTAR-2 were present in cis, but not in trans. Furthermore, NF-kappaB is an essential factor involved in the induction of STAT-1. Most of the induced STATs were not phosphorylated at the critical tyrosine residue activated by many cytokines. However, the induced STATs, at least STAT-1, were functional because it could be activated by interferon (IFN) and could upregulate an IFN-inducible gene. Finally, expression of STAT-1, but not STAT-2 and -3, is associated with EBV transformation. The association of the expression of STAT-1, -2, -3, and -5A with EBV type III latency and the expression of STAT-1 in the EBV transformation process may be part of the viral programming that regulates viral latency and cellular transformation.
B-Lymphocytes↗
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors.
Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) has been linked to Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. In addition to endothelial cells and B lymphocytes, KSHV also has been shown to infect epithelial cells and keratinocytes. The transmembrane glycoprotein K1, encoded by the first open reading frame of KSHV, is a signaling protein capable of eliciting B-cell activation. We show that KSHV K1 can induce expression and secretion of vascular endothelial growth factor (VEGF) in epithelial and endothelial cells. Up-regulation of VEGF was mediated at the transcriptional level because expression of K1 resulted in VEGF promoter activation. We also show that K1 induces expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. Additional analyses with K1 mutant proteins revealed that the SH2 binding motifs present in the K1 cytoplasmic tail are necessary for VEGF secretion and MMP-9 induction. These results indicate that K1 signaling may contribute to KSHV-associated pathogenesis through a paracrine mechanism by promoting the secretion of VEGF and MMP-9 into the surrounding matrix.
Cells, Cultured↗
Infectious agents and cancer: criteria for a causal relation.
Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas); hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias); and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor (Burkitt's lymphoma-EBV; mesothelioma - SV(40)). For others the association is inconsistent (Hodgkin's Disease, gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious agents will continue to illuminate molecular oncogenic processes.
Animals↗
Effects of maribavir and selected indolocarbazoles on Epstein-Barr virus protein kinase BGLF4 and on viral lytic replication.
The human cytomegalovirus (HCMV) homolog of the Epstein-Barr virus (EBV) protein kinase (PK), UL97, is inhibited by maribavir (1263W94) and selected indolocarbazoles. Here we show that only one of these indolocarbazoles (K252a), but not maribavir, inhibits autophosphorylation of the EBV PK, BGLF4. However, maribavir and another indolocarbazole, NGIC-I, do inhibit EBV DNA synthesis, suggesting that although these last compounds inhibit both HCMV and EBV, they seem to operate through differ-ent pathways.
Benzimidazoles↗
Interferon regulatory factor 7 is associated with Epstein-Barr virus-transformed central nervous system lymphoma and has oncogenic properties.
Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas.
Adult↗