Epstein-Ban virus induction of recombinaseactivatina cenes RAG1 and RAG2

Department of Infectious Diseases and Virology, St. Jude's Children's Research Hospital, Memphis, Tennessee 38101-0318, USA.
Journal of Virology (Impact Factor: 4.44). 01/1996; 69(12):8155-8.
Source: PubMed


In experimental B-cell infections, Epstein-Barr virus induced sustained expression of V(D)J recombinase-activating genes RAG1 and RAG2, whose aberrant activity has been implicated in chromosomal translocations in B-cell neoplasms. In cell lines in which RAG1 and RAG2 were detected, virus integrated into cellular DNA rather than assumed the configuration of extrachromosomal episomes. Expression of the Epstein-Barr virus nuclear antigen 1 in transient transfection assays was sufficient to induce both recombinase-activating genes.

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    • "There are EBNA1 binding sites in the human genome and, as EBNA1 can bind both RNA and DNA, it could influence the expression of viral or cellular genes [75], possibly by eliciting demethylation and subsequent activation or dysfunction of cellular functions [59]. EBNA1 can up regulate the recombinase-activating genes which mediate V-D-J combination and are usually only expressed in immature lymphoid cells [76]. EBNA1 is indispensable for B cell transformation and can enhance B cell immortalization several thousandfold [77]. "
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    ABSTRACT: Certain infectious agents are associated with lymphomas, but the strength of the association varies geographically, suggesting that local environmental factors make important contributions to lymphomagenesis. Endemic Burkitt's Lymphoma has well-defined environmental requirements making it particularly suitable for research into local environmental factors. The Epstein-Barr virus and holoendemic Malaria are recognized as important cofactors in endemic Burkitt's Lymphoma and their contributions are discussed. Additionally, infection with Chikungunya Fever, a potentially oncogenic arbovirus, was associated with the onset of endemic Burkitt's Lymphoma in one study and also with space-time case clusters of the lymphoma. Chikungunya Virus has several characteristics typical of oncogenic viruses. The Flavivirus, Hepatitis C, a Class 1 Human Carcinogen, closely related to the arboviruses, Yellow Fever, and Dengue, is also more distantly related to Chikungunya Virus. The mechanisms of oncogenesis believed to operate in Hepatitis C lymphomagenesis are discussed, as is their potential applicability to Chikungunya Virus.
    Advances in Hematology 01/2012; 2012:494758. DOI:10.1155/2012/494758
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    • "EBNA1 has been shown to bind to their promoters (O'Neil et al., 2008). In addition, EBNA1 increases expression of the V(D)J recombinases RAG1 and RAG2 (Srinivas and Sixbey, 1995). These findings suggest that EBNA1 might facilitate recombination events and could thereby contribute to the c-myc (Ig) locus translocation that is crucial for the development of BL. "
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    ABSTRACT: Epstein-Barr virus (EBV) is widely spread in the human population. EBV nuclear antigen 1 (EBNA1) is a transcription factor that activates viral genes and is necessary for viral replication and partitioning, which binds the EBV genome cooperatively. We identify similar EBNA1 repeat binding sites in the human genome using a nearest-neighbor positional weight matrix. Previously experimentally verified EBNA1 sites in the human genome are successfully recovered by our approach. Most importantly, 40 novel regions are identified in the human genome, constituted of tandemly repeated binding sites for EBNA1. Genes located in the vicinity of these regions are presented as possible targets for EBNA1-mediated regulation. Among these, four are discussed in more detail: IQCB1, IMPG1, IRF2BP2 and TPO. Incorporating the cooperative actions of EBNA1 is essential when identifying regulatory regions in the human genome and we believe the findings presented here are highly valuable for the understanding of EBV-induced phenotypic changes.
    Virology 09/2010; 405(2):524-9. DOI:10.1016/j.virol.2010.06.040 · 3.32 Impact Factor
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    • "However, in support of a role for EBNA1 in carcinogenesis we and others have demonstrated that EBNA1's transcription factor-like functions are not confined to the regulation of viral genes but also extend to the regulation of host cell gene expression. This has been demonstrated in the context of B-cells where EBNA1 has been shown to induce the expression of CD25, RAG1, RAG2 and CCL20 [10-12] whilst in epithelial cells we have established that expression of EBNA1 results in the differential regulation of cellular genes involved in translation, transcription and cell signalling [13,14]. We have documented that EBNA1 enhances STAT1 expression which sensitises cells to interferon-induced STAT1 activation, modulates signalling in the TGFβ1 pathway, and increases AP-1 activity resulting in the enhancement of host cell mechanisms involved in angiogenesis and metastasis [13,14]. "
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    ABSTRACT: The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-kappaB. In this report we demonstrate that EBNA1 inhibits the canonical NF-kappaB pathway in carcinoma lines by inhibiting the phosphorylation of IKKalpha/beta. In agreement with this observation we find a reduction in the phosphorylation of IkappaBalpha and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-kappaB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-kappaB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-kappaB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied. Inhibition of p65 NF-kappaB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-kappaB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-kappaB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC.
    Molecular Cancer 01/2010; 9(1):1. DOI:10.1186/1476-4598-9-1 · 4.26 Impact Factor
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