Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation

Robert, Valentine; Dawson, Christopher W.; Hu, Chunfang; Shah, K.; Owen, Thomas J.; Date, Kathryn; Maia, Sonia P; Shao, Jian Yong; Arrand, John R.; Young, Lawrence S.; O’Neil, John D.

doi:10.1186/1476-4598-9-1

Cited by 197 publications

(204 citation statements)

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“…The human adenocarcinoma cell line AGS has been described previously (39). AGS-EBNA1 cells stably expressing EBNA1 were generated as described by Valentine et al (39). AGS-EBV was generated by coculturing AGS cells with Akata Burkitt's lymphoma cells carrying recombinant neomycin-resistant EBV as described previously (34).…”

Section: Methodsmentioning

confidence: 99%

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Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Sivachandran

Dawson

Young

et al. 2012

J Virol

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Approximately 10% of gastric carcinomas (GC) are comprised of cells latently infected with Epstein-Barr virus (EBV); however, the mechanism by which EBV contributes to the development of this malignancy is unclear. We have investigated the cellular effects of the only EBV nuclear protein expressed in GC, EBNA1, focusing on promyelocytic leukemia (PML) nuclear bodies (NBs), which play important roles in apoptosis, p53 activation, and tumor suppression. AGS GC cells infected with EBV were found to contain fewer PML NBs and less PML protein than the parental EBV-negative AGS cells, and these levels were restored by silencing EBNA1. Conversely, EBNA1 expression was sufficient to induce the loss of PML NBs and proteins in AGS cells. Consistent with PML functions, EBNA1 expression decreased p53 activation and apoptosis in response to DNA damage and resulted in increased cell survival. In addition, EBNA1 mutants unable to bind CK2 kinase or ubiquitin-specific protease 7 had decreased ability to induce PML loss and to interfere with p53 activation. PML levels in EBV-positive and EBV-negative GC biopsy specimens were then compared by immunohistochemistry. Consistent with the results in the AGS cells, EBV-positive tumors had significantly lower PML levels than EBV-negative tumors. The results indicate that EBV infection of GC cells leads to loss of PML NBs through the action of EBNA1, resulting in impaired responses to DNA damage and promotion of cell survival. Therefore, PML disruption by EBNA1 is one mechanism by which EBV may contribute to the development of gastric cancer.

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Section: Methodsmentioning

confidence: 99%

“…The human adenocarcinoma cell line AGS has been described previously (39). AGS-EBNA1 cells stably expressing EBNA1 were generated as described by Valentine et al (39).…”

Section: Methodsmentioning

confidence: 99%

Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Sivachandran

Dawson

Young

et al. 2012

J Virol

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“…For example, EBNA1 counter-acts the stabilization of p53 by USP7 and induces the loss of PML nuclear bodies through the degradation of PML proteins, both of which contribute to the ability of EBNA1 to interfere with apoptosis and DNA repair (20,21). EBNA1 has also been found to inhibit transforming growth factor ␤ and NF-B signaling and to induce oxidative stress (22)(23)(24)(25). EBNA1 may also be able to transactivate the expression of some cellular genes.…”

mentioning

confidence: 99%

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

Mansouri

Pan

Blencowe

et al. 2014

J Virol

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The EBNA1 protein of Epstein-Barr virus (EBV) plays multiple roles in EBV latent infection, including altering cellular pathways relevant for cancer. Here we used microRNA (miRNA) cloning coupled with high-throughput sequencing to identify the effects of EBNA1 on cellular miRNAs in two nasopharyngeal carcinoma cell lines. EBNA1 affected a small percentage of cellular miRNAs in both cell lines, in particular, upregulating multiple let-7 family miRNAs, including let-7a. The effects of EBNA1 on let-7a were verified by demonstrating that EBNA1 silencing in multiple EBV-positive carcinomas downregulated let-7a. Accordingly, the let-7a target, Dicer, was found to be partially downregulated by EBNA1 expression (at the mRNA and protein levels) and upregulated by EBNA1 silencing in EBV-positive cells. Reporter assays based on the Dicer 3= untranslated region with and without let-7a target sites indicated that the effects of EBNA1 on Dicer were mediated by let-7a. EBNA1 was also found to induce the expression of let-7a primary RNAs in a manner dependent on the EBNA1 transcriptional activation region, suggesting that EBNA1 induces let-7a by transactivating the expression of its primary transcripts. Consistent with previous reports that Dicer promotes EBV reactivation, we found that a let-7a mimic inhibited EBV reactivation to the lytic cycle, while a let-7 sponge increased reactivation. The results provide a mechanism by which EBNA1 could promote EBV latency by inducing let-7 miRNAs. IMPORTANCE The EBNA1 protein of Epstein-Barr virus (EBV) contributes in multiple ways to the latent mode of EBV infection that leads to lifelong infection.In this study, we identify a mechanism by which EBNA1 helps to maintain EBV infection in a latent state. This involves induction of a family of microRNAs (let-7 miRNAs) that in turn decreases the level of the cellular protein Dicer. We demonstrate that let-7 miRNAs inhibit the reactivation of latent EBV, providing an explanation for our previous observation that EBNA1 promotes latency. In addition, since decreased levels of Dicer have been associated with metastatic potential, EBNA1 may increase metastases by downregulating Dicer. E pstein-Barr virus (EBV) is a gammaherpesvirus that infects most people worldwide and is associated with several types of B-cell lymphomas, as well as nasopharyngeal carcinoma (NPC) and gastric carcinoma (1, 2). The EBV life cycle consists of both latent and lytic modes of infection in B lymphocytes and epithelial cells. Although EBV mainly exists in a latent mode of infection in B cells, it occasionally reactivates to the lytic state for cell-to-cell spread. In addition, lytic reactivation of EBV in epithelial cells of the orthopharynx is necessary for the production of viral particles required for host-to-host transmission of the virus. Lytic infection begins with the expression of BZLF1 (or Zta), followed by the expression of BRLF1 (or Rta). Together these proteins activate the cascade of subsequent lytic gene expression and enable the generation of lin...

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“…Moreover, the key latent antigen called EBNA1 is also shown to inhibit the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. The reduction of both IκBα and p65 phosphorylation lead to decreased amount of p65 within the nuclear NF-κB complexes (Valentine et al, 2010). In the EBV-infected lymphoma cells, EBNA2 is specifically associated with upregulation of the two chemokines CCL3 and CCL4, which enhance Btk and NF-κB phosphorylation, and contribute to doxorubicin resistance of B lymphoma cells (Kim et al, 2016).…”

Section: Phosphorylation-mediated Viral Inhibition Of Nf-κb and Inflamentioning

confidence: 99%

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

et al. 2017

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Activation of specific sets of protein kinases by intracellular signal molecules has become more and more apparent in the past decade. Phosphorylation, one of key posttranslational modification events, is activated by kinase or regulatory protein and is vital for controlling many physiological functions of eukaryotic cells such as cell proliferation, differentiation, malignant transformation, and signal transduction mediated by external stimuli. Moreovers, the reversible modification of phosphorylation and dephosphorylation can result in different features of the target substrate molecules including DNA binding, protein-protein interaction, subcellular location and enzymatic activity, and is often hijacked by viral infection. Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), two human oncogenic gamma-herpesviruses, are shown to tightly associate with many malignancies. In this review, we summarize the recent progresses on understanding of molecular properties and regulatory modes of cellular and viral proteins phosphorylation influenced by these two tumor viruses, and highlight the potential therapeutic targets and strategies against their related cancers.

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Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation

Cited by 197 publications

References 39 publications

Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

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