Epstein-Barr Virus Nuclear Antigen 2
            <i>trans</i>
            -Activates the Cellular Antiapoptotic
            <i>bfl-1</i>
            Gene by a CBF1/RBPJκ-Dependent Pathway

Pegman, Pamela; Smith, Sinead; D’Souza, Brendan; Loughran, Sinéad T.; Maier, Sabine; Kempkes, Bettina; Cahill, Paul A.; Simmons, Matthew J.; Gélinas, Céline; Walls, Dermot

doi:10.1128/jvi.00278-06

Cited by 26 publications

(25 citation statements)

References 65 publications

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“…Collectively, similar to findings for Chlamydia trachomatis (20,22,79,80), these observations argue against a major role for NF-B transcriptional activation in the antiapoptotic effect of PorB in HeLa cells (which does not induce IB␣ degradation or p65/RelA nuclear translocation but induces p65 cleavage to interfere with the host inflammatory response) (37). Although the lack of NF-B activation might explain the lack of Bcl-2, Bcl-xL, and c-IAP-2 expression by PorB, induction of Bfl-1 expression might be induced via NF-B-independent transactivation of the bfl-1 gene, similar to what has been described for Burkitt's lymphoma cells with EBV nuclear antigen 2 via CBF1 (or RBP-J kappa), a nuclear component of the Notch signaling pathway (60). Regulation of Bfl-1 in epithelial cells in the absence of NF-B has not been described so far, and this regulation in response to PorB should be investigated further.…”

Section: Discussionmentioning

confidence: 88%

Meningococcal Porin PorB Prevents Cellular Apoptosis in a Toll-Like Receptor 2- and NF-κB-Independent Manner

et al. 2010

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Meningococcal porin PorB is an inhibitor of apoptosis induced via the intrinsic pathway in various cell types.This effect is attributed to prevention of mitochondrial depolarization and of subsequent release of proapoptotic mitochondrial factors. To determine whether apoptosis is globally inhibited by PorB, we compared the intrinsic and extrinsic pathways in HeLa cells. Interestingly, PorB does not prevent extrinsic apoptosis induced by tumor necrosis factor alpha plus cycloheximide, suggesting a unique mitochondrial pathway specificity.

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Section: Discussionmentioning

confidence: 88%

Meningococcal Porin PorB Prevents Cellular Apoptosis in a Toll-Like Receptor 2- and NF-κB-Independent Manner

et al. 2010

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“…EBNA-2, for example, binds to the nuclear receptor NUR77 (Nr4A1, GenBank: NP_775180) and blocks NUR77-mediated apoptosis [20], [21]. EBNA-2 transactivates the anti-apoptotic gene BFL-1 (BCL2A1, GenBank: NM_004049) in complex with RBP-Jj [22]. EBNA-2 can also inhibit the pro-apoptotic and anti-proliferative functions of the transforming growth factor beta 1 (TGFB1, GenBank: NP_000651) cytokine, as shown in the EBNA-2 inducible EREB system [23].…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes

Yenamandra

Hellman

Kempkes³

et al. 2010

Cell. Mol. Life Sci.

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Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes. The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus. In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.

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“…EBNA2 has been shown to inhibit Nurr77-induced apoptosis by directly interacting with that protein (95,96) and to also upregulate the antiapoptotic BFL-1 (97). EBNA2 expression is invariably accompanied by LMP1 during EBV infection and almost always so in EBV-associated disease settings.…”

Section: Discussionmentioning

confidence: 99%

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

Campion

Hakimjavadi

Loughran

et al. 2014

J Virol

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The Epstein-Barr virus (EBV) establishes a lifelong latent infection in humans. EBV infection of primary B cells causes cell activation and proliferation, a process driven by the viral latency III gene expression program, which includes EBV nuclear proteins (EBNAs), latent membrane proteins, and untranslated RNAs, including microRNAs. Some latently infected cells enter the long-lived memory B-cell compartment and express only EBNA1 transiently (Lat I) or no EBV protein at all (Lat 0). Targeting the molecular machinery that controls B-cell fate decisions, including the Bcl-2 family of apoptosis-regulating proteins, is crucial to the EBV cycle of infection. Here, we show that BIK (also known as NBK), which encodes a proapoptotic "sensitizer" protein, is repressed by the EBNA2-driven Lat III program but not the Lat I program. BIK repression occurred soon after infection of primary B cells by EBV but not by a recombinant EBV in which the EBNA2 gene had been knocked out. Ectopic BIK induced apoptosis in Lat III cells by a mechanism dependent on its BH3 domain and the activation of caspases. We show that EBNA2 represses BIK in EBV-negative B-cell lymphoma-derived cell lines and that this host-virus interaction can inhibit the proapoptotic effect of transforming growth factor ␤1 (TGF-␤1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-␤1-associated regulatory SMAD proteins were bound to the BIK promoter in response to EBV Lat III or ectopic EBNA2. These data are evidence of an additional mechanism used by EBV to promote Bcell survival, namely, the transcriptional repression of the BH3-only sensitizer BIK. IMPORTANCEOver 90% of adult humans are infected with the Epstein-Barr virus (EBV). EBV establishes a lifelong silent infection, with its DNA residing in small numbers of blood B cells that are a reservoir from which low-level virus reactivation and shedding in saliva intermittently occur. Importantly, EBV DNA is found in some B-cell-derived tumors in which viral genes play a key role in tumor cell emergence and progression. Here, we report for the first time that EBV can shut off a B-cell gene called BIK. When activated by a molecular signal called transforming growth factor ␤1 (TGF-␤1), BIK plays an important role in killing unwanted B cells, including those infected by viruses. We describe the key EBV-B-cell molecular interactions that lead to BIK shutoff. These findings further our knowledge of how EBV prevents the death of its host cell during infection. They are also relevant to certain posttransplant lymphomas where unregulated cell growth is caused by EBV genes. E pstein-Barr virus (EBV) is a B lymphotropic human herpesvirus with oncogenic potential (for reviews, see references 1 and 2). Following primary infection, EBV establishes a lifelong latent infection in more than 90% of all adults, with intermittent virus shedding in very low levels in saliva. EBV persists in a quiescent state in circulating, resting, memory B cells. EBV is a potent transforming virus in vitro and eff...

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Epstein-Barr Virus Nuclear Antigen 2 trans -Activates the Cellular Antiapoptotic bfl-1 Gene by a CBF1/RBPJκ-Dependent Pathway

Cited by 26 publications

References 65 publications

Meningococcal Porin PorB Prevents Cellular Apoptosis in a Toll-Like Receptor 2- and NF-κB-Independent Manner

Meningococcal Porin PorB Prevents Cellular Apoptosis in a Toll-Like Receptor 2- and NF-κB-Independent Manner

Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes

Repression of the Proapoptotic CellularBIK/NBKGene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

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