Epstein-Barr Virus LMP1 Activates EGFR, STAT3, and ERK through Effects on PKCδ

Kung, Che Pei; Meckes, David G.; Raab‐Traub, Nancy

doi:10.1128/jvi.01703-10

Cited by 139 publications

(134 citation statements)

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“…Constitutive expression of pSTAT3 and survivin is a wellknown characteristic of tumor cells and cells transformed by oncogenic viruses, including KSHV and EBV (14,(26)(27)(28). Our study of VZV shows that STAT3 activation and survivin expression also support lytic herpesvirus replication not only in vitro but also in differentiated human skin cells within their tissue microenvironment in vivo.…”

Section: Discussionmentioning

confidence: 80%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.T he life cycle of varicella-zoster virus (VZV) in the human host depends on its tropism for T cells, skin, and neurons within sensory ganglia (1). As shown in the SCID mouse model of VZV pathogenesis, infected human T cells transport the virus to epidermal cells in human skin xenografts and to neural cells in dorsal root ganglia xenografts (2, 3). VZV establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster.VZV modulates several signaling pathways to replicate efficiently in vitro, and these regulatory effects are especially important in differentiated skin cells infected in vivo. VZV interferes with IFN induction and signaling via inhibition of IFN regulatory factor 3 (IRF3), NFκB, and STAT1 in vitro and in skin (4, 5). However, the pathogenesis of VZV skin infection requires a mechanism to overcome the constitutive IFNα expression by epidermal cells that accounts for the 10-to 21-d interval between VZV transfer into skin and the appearance of lesions at skin surfaces (6). How VZV overcomes this cutaneous IFN barrier and produces skin vesicles is not known.The STATs are ubiquitous transcription factors with many cellular functions and are at the junction of several cytokinesignaling pathways (7,8). Of the seven STAT family proteins, STAT3 exerts widespread effects through transcri...

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Section: Discussionmentioning

confidence: 80%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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“…Notably, overexpression of ICAM1 is generally seen in various types of EBV-related cancers such as NPC, GC and NHL [27][28][29]. Similarly, exosomal LMP1 also induced epidermal growth factor receptor (EGFR) expression [30] which is another important receptor that modulates a cascade of oncogenic signalling pathways such as mitogen-activated protein kinase (MAPK), c-Jun N terminal kinase (JNK), phosphatidylinositol 3 kinase (PI3K) and nuclear factor kappa-beta (NF-κB) in EBV cancers [31,32]. In line with of the role of exosomal LMP1 in EGFR-related pathways, Meckes and co-workers also demonstrated that exosomal LMP1…”

Section: Novel Implications Of Exosomes In Diagnosis and Treatment Ofmentioning

confidence: 99%

“…As summarized in Table 1, cumulative findings suggest that exosomal LMP1 promotes the growth and progression of EBV-associated cancers. While the cell-associated or intracellular LMP1 plays multiple roles in EBV latent infection and cancer pathogenesis particularly by modulating NF-κB, PI3K/AKT, MAPK and JAK/STAT pathways [31,32], future investigations are warranted to demonstrate whether the exosomal LMP1 similarly carries these tumorigenic functions and pathogenic effects in EBV-associated cancers.…”

Section: Novel Implications Of Exosomes In Diagnosis and Treatment Ofmentioning

confidence: 99%

Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers

Teow¹,

Peh²

2017

Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases

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Exosomes are microvesicles with sizes ranging from 50 to 150 nm. These small vesicles are known to morphologically and functionally resemble virus particles from human immunodeficiency virus type I (HIV-I) and human T-lymphotropic virus type I (HTLV-I). The function of exosomes is to mainly mediate cell-to-cell communication by exchanging various macromolecules including proteins, lipids and nucleic acids in diverse cellular processes. Due to its size and structural simplicity, the transfer of pathogenic or virulent cellular factors across the cells mediated by exosomes is more efficient, hence facilitating the dissemination of viral infections and cancer diseases. The pathogenic role of exosomes in various cancers such as lung and breast, and their potentials as biomarkers have been previously studied, yet limited information is known for Epstein-Barr virus (EBV)-associated cancers. In this chapter, we discuss current evidences that support the pathogenic roles of exosomes in EBV-related cancers and their potentials as biomarkers in cancer diagnostics and therapy response. Here, we also highlight the potential challenges in the development of exosome-based biomarkers for clinical application.

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“…EBV-encoded latent membrane proteins, LMP1, LMP2A, and 2B: LMP1 acts as a constitutively active receptor in a ligand-independent manner, mimicking CD40 (Gires et al, 1997). It activates the majority of signaling pathways that are known to be activated in HRS cells, including NF-κB, PI3K/ Akt/mTOR, and Jak/STAT pathways, thereby induces various antiapoptotic proteins and cytokines (Chen et al, 2003;Lambert and Martinez, 2007;Kung et al, 2011). Since normal germinal center B cells that lack BCR in their cell surfaces are eliminated by apoptosis, the HRS precursor cell is assumed to be rescued by LMP1 that plays a critical role in the protection of B cells from apoptotic death by up-regulating several antiapoptosis genes (Asso-Bonnet et al, 1998;Lee et al, 2003).…”

Section: Ebna1mentioning

confidence: 99%

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

Lee¹

2011

Biomolecules and Therapeutics

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Lymphoma is a type of cancer involving cells of the immune system, and has two major categories: Hodgkin lymphoma (HL) and all other lymphomas (non-HL). Although the two types may display the same symptoms, they are readily distinguishable via microscopic examination, and differ in the way they develop, spread and are treated. HL is a unique clinicopathological disorder characterized by the rare presence of malignant cells (usually accounting for 0.1% to 10% of the cells in the total tumor mass) in a background of a nonneoplastic cellular microenvironment comprising T-and Blymphocytes and other cell types (Weiss et al., 1999). In the United States, about 8,500 new cases of HL were expected to be diagnosed in 2010, and the overall incidence is increasing each year (Maggioncalda et al., 2011).Although the pathogenesis of HL is still largely unknown, the association of HL with Epstein-Barr virus (EBV) infection has been demonstrated in many reports. For examples, HL patients show elevated antibody titers to EBV antigens (Levine et al., 1971), and the risk of developing HL is increased up to three-fold in population that have experienced infectious mononucleosis caused by primary EBV infection (Gutensohn Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBVassociated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event in the development of this disease, EBV infection may play a very crucial role in the pathogenesis of HL. AbstractAccording to a population-based cohort study, the frequency of EBV associated HL among total HL cases varies from 30 to 50% (in certain cases even higher; >90% in developing and underdeveloped countries, and >95% in HIV associated cases), and most of them appear in classical Hodgkin lymphoma (cHL), the major type of HL (Herbst et al., 1991;Pallesen et al., 1991;Ambinder et al., 1993;Leoncini et al., 1996). Since EBV is an oncogenic virus that is able to subvert cellular processes supporting growth and survival, the approach to unravel the f...

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Epstein-Barr Virus LMP1 Activates EGFR, STAT3, and ERK through Effects on PKCδ

Cited by 139 publications

References 49 publications

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

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