Epstein-Barr Virus Latent Membrane Protein 1 Represses DNA Repair through the PI3K/Akt/FOXO3a Pathway in Human Epithelial Cells

Chen, Yiren; Liu, Ming‐Tsan; Chang, Yu-Ting; Wu, Chung-Chun; Hu, Chia-Cheng; Chen, Jen‐Yang

doi:10.1128/jvi.00430-08

Cited by 59 publications

(47 citation statements)

References 63 publications

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“…The PI3K/Akt signaling pathway is also known to be activated by LMP1 . In this analysis, gene expression profiling revealed that the PI3K/Akt pathway was activated in EBV‐infected B‐cell lines compared with EBV‐negative B‐cell lines.…”

Section: Discussionmentioning

confidence: 81%

Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

et al. 2014

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Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[−]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[−]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.

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Section: Discussionmentioning

confidence: 81%

Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

et al. 2014

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“…Several latency-associated EBV proteins have been proposed to promote genomic instability by suppressing the checkpoint machineries that safeguard genome integrity (11,12,23). However, their overall contribution to the tumor-promoting effect of EBV is likely to be limited, given that the viral proteins associated with these effects are either not expressed or expressed only in a subset of the tumors.…”

Section: Discussionmentioning

confidence: 99%

The Epstein–Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species

Gruhne

Sompallae

Marescotti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

215

189

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The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 is the only viral protein expressed in all EBV-carrying malignancies, but its contribution to oncogenesis has remained enigmatic. We show that EBNA-1 induces chromosomal aberrations, DNA double-strand breaks, and engagement of the DNA damage response (DDR). These signs of genomic instability are associated with the production of reactive oxygen species (ROS) and are reversed by antioxidants. The catalytic subunit of the leukocyte NADPH oxidase, NOX2/gp91 phox , is transcriptionally activated in EBNA-1-expressing cells, whereas inactivation of the enzyme by chemical inhibitors or RNAi halts ROS production and DDR. These findings highlight a novel function of EBNA-1 and a possible mechanism by which expression of this viral protein could contribute to malignant transformation and tumor progression.is a human gamma-herpesvirus that establishes latent infections in B lymphocytes, where only a subset of viral genes is expressed and virus replication is suppressed (1). The proteins encoded by the latency genes, including 6 EBV-encoded nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and -5) and 3 latent membrane proteins (LMP1, -2A, and -2B), induce growth transformation by capturing multiple signaling pathways that control B cell proliferation and apoptosis. It is generally assumed that the continuous expression of viral genes underlies the association of EBV with a variety of human malignancies, including Burkitt's lymphoma (BL), Hodgkin's disease (HD), nasopharyngeal carcinoma (NPC), and posttransplant lymphoproliferative disease (PTLD) (2). Some EBVpositive tumors do not express all of the latency proteins, leading to restricted forms of latency in which EBNA-1 is detected either alone (latency I, found in BL) or together with the LMPs (latency II, found in HD and NPC). Thus, EBNA-1 is the only viral protein regularly expressed in all EBV-carrying malignancies.EBNA-1 binds to the viral origin of replication (oriP) and is required for the correct partitioning of the viral episomes in proliferating cells (3). It may confer a growth advantage to BL cells (4) and protect them from apoptosis (5) but does not act as an autonomous oncogene (6) and seems to be dispensable for B cell immortalization in vitro (7). Hence, the mechanism by which EBNA-1 may contribute to malignant transformation is not understood.Genomic instability is common in malignant cells and was observed in EBV-carrying tumors (8-10). EBNA-3C (11) and LMP-1 (12) may promote this phenotype through inhibition of DNA repair or inactivation of cell cycle checkpoints, which allow the propagation of DNA damage. However, these viral proteins are not expressed in EBV-carrying BLs, and only half of HDs and NPCs express detectable levels of LMP1, suggesting a limited role in EBV oncogenesis. A possible involvement of EBNA-1 in the induction of genomic instability is suggested by a significant increase of transient chromosomal aberrations, such as dicentric chromosomes, chromosome fragments, and gaps, in EBVpositiv...

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“…LMP1 represses DNA damage repair through inactivation of FOXO3a. 68,69 EBNA1 induces DNA damage through the production of reactive oxygen species. 70 EBNA3C disrupts cell-cycle checkpoint and has oncogenic activity.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Yang

Deng

Hau

et al. 2015

Laboratory Investigation

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Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies. Epstein-Barr virus (EBV) is a gamma herpesvirus and infection with EBV is associated with a variety of epithelial and B-cell cancers. 1,2 EBV has a biphasic life cycle consisting of latent and lytic stages. The switch from latent to lytic infection is triggered by the EBV immediate-early transcription factor, BZLF1 (ZEBRA, Zta, Z, EB1). 3,4 A number of reports have demonstrated that lytic EBV activation is intimately linked to the pathogenesis of EBV-induced malignancies including the development of NPC. [5][6][7][8] The mammalian DNA damage response (DDR) network has pivotal roles in maintaining genome stability and tumor suppression. [9][10][11][12][13] In the presence of double-strand break (DSBs), the protein complex composed of MRE11-RAD50-NBS1 (MRN) recruits and activates the ataxia-telangiectasiamutated (ATM) kinase at the vicinity of DSBs, 10 which leads to the phosphorylation of the histone variant H2AX (γH2AX). γH2AX decorates chromatin domains flanking DSBs, and is directly engaged by the mediator of DNA damage checkpoint 1 (MDC1). MDC1 loading onto the damaged chromatin subsequently permits the productive accumulation of a cohort of DNA damage signaling and mediator proteins. 14,15 In particular, the RING finger ubiquitin ligase RNF8 is targeted to MDC1 via its phospho-binding forkheadassociated domain, where it initiates a cascade of chromatin ubiquitination events important for tethering of DNA damage mediator and repair proteins, including 53BP1 and BRCA1, [16][17][18][19] the dysregulation of which compromises genome stability and cont...

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Epstein-Barr Virus Latent Membrane Protein 1 Represses DNA Repair through the PI3K/Akt/FOXO3a Pathway in Human Epithelial Cells

Cited by 59 publications

References 63 publications

Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

The Epstein–Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

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