Regulation of transcription by the Epstein–Barr virus nuclear antigen EBNA 2

Palermo, Richard D.; Webb, Helen; Gunnell, Andrea; West, Michelle J.

doi:10.1042/bst0360625

Cited by 14 publications

(10 citation statements)

References 48 publications

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“…The herpes simplex virus type 1 ICP22 IE viral protein also binds to cdk9 and specifically alters RNAP II phosphorylation (15,16). It has also been found that EBNA2 plays not only a role in initiation of viral transcription during EpsteinBarr virus infection but also a cdk9-dependent role in productive elongation of viral RNA synthesis (5,38). In addition, cdk9 plays an integral role in p53 phosphorylation during Kaposi's sarcoma-associated herpesvirus infection via cdk9 interaction with a virus-encoded cyclin (11).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription

Kapasi

Clark

Tran

et al. 2009

J Virol

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Human cytomegalovirus (HCMV) infection results in the formation of nuclear viral transcriptosomes, which are sites dedicated to viral immediate-early (IE) transcription. At IE times of the infection, viral and cellular factors, including several components of transcription such as cyclin-dependent kinase 9 (cdk9), localize at these sites. To determine the mechanism and requirements of specific recruitment of cdk9 to the viral transcriptosomes, infection in the presence of inhibitor drugs and infection of cell lines expressing exogenous mutant cdk9 were performed. We found that cdk9 localization to the viral transcriptosomes requires de novo protein synthesis. In addition, active transcription is required for recruitment and maintenance of cdk9 at the viral transcriptosomes. In cells infected with a recombinant IE2 HCMV (IE2 86 ⌬SX virus) in which IE2 gene expression is greatly reduced, cdk9 localization at the transcriptosome is delayed and corresponds to the kinetics of accumulation of the IE2 protein at these sites. Infection in the presence of the cdk9 inhibitors Flavopiridol and DRB (5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole) allowed cdk9 localization to the viral transcriptosomes. A kinase-inactive cdk9 (D167N) expressed during the infection also localizes to the viral transcriptosomes, indicating that kinase activity of cdk9 is not a requirement for its localization to the sites of IE transcription. Exogenous expression of additional cdk9 mutants indicates that binding of Brd4 to the cdk9 complex is not required but that efficient binding to cyclin T1 is essential.Human cytomegalovirus (HCMV) is a member of the Herpesviridae family and is of clinical concern in immunocompromised patients, organ transplant recipients, and the developing fetus (for a review, see reference 34). Congenital HCMV is the major viral cause of birth defects and can lead to permanent disabilities such as hearing and vision loss, mental disabilities, and even death. At present, there is no cure or available vaccine for treatment of HCMV.Immediately after the viral particles contact the cellular plasma membrane, many host functions are altered. It is a combination of the interactions between the virus and host that are established and the disruption of cellular functions that creates an optimal environment for viral replication (for a review, see reference 17). Viral gene expression is temporally regulated, beginning with the immediate-early (IE) genes. The IE genes do not require de novo cellular or viral protein synthesis for expression and can be classified as the set of viral transcripts that accumulate in the presence of cycloheximide (CHX). The IE gene products activate the expression of viral early genes, which in turn initiate and regulate viral DNA synthesis. After the onset of viral DNA synthesis, the late viral genes, which primarily encode structural proteins, are expressed, and that expression leads to the eventual release of virus from the cell.HCMV utilizes cellular RNA polymerase II (RNAP II) and the accompanying h...

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Section: Discussionmentioning

confidence: 99%

Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription

Kapasi

Clark

Tran

et al. 2009

J Virol

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“…Similar to EBNA3C, EBNA2 also contains an acidic activation domain and can interact with a number of general transcription factors and co-activators. 102 …”

Section: Deregulation Of Cellular Pathwaysmentioning

confidence: 99%

Tumor viruses and cancer biology: Modulating signaling pathways for therapeutic intervention

Saha¹,

Kaul²,

Murakami³

et al. 2010

Cancer Biology & Therapy

109

111

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Tumor viruses have provided relatively simple genetic systems, that can be manipulated for understanding the molecular mechanisms of the cellular transformation process. A growing body of information in the tumor virology field provides several prospects for rationally targeted therapies. However, further research is needed to better understand the multiple mechanisms utilized by these viruses in cancer progression in order to develop therapeutic strategies. Initially viruses were believed to be associated with cancers as causative agents only in animals. It was almost half a century before the first human tumor virus, Epstein-Barr virus (EBV), was identified in 1964. Subsequently, several human tumor viruses have been identified including Kaposi sarcoma associated herpesvirus (KSHV), human papillomaviruses (HPV), hepatitis B virus (HBV), Hepatitis C virus (HCV), human T lymphotropic virus (HTLV-1) and recently identified Merkel cell polyomavirus (MCPyV). Tumor viruses are sub-categorized as either DNA viruses, which include EBV, KSHV, HPV, HBV and MCPyV or RNA viruses such as HCV and HTLV-1. Tumor-viruses induce oncogenesis through manipulating an array of different cellular pathways. These viruses initiate a series of cellular events, which lead to immortalization and proliferation of the infected cells by disrupting the mitotic checkpoint upon infection of the host cell. This is often accomplished by functional inhibition or proteasomal degradation of many tumor suppressor proteins by virally encoded gene products. The virally infected cells can either be eliminated via cell-mediated apoptosis or persist in a state of chronic infection. Importantly, the chronic persistence of infection by tumor viruses can lead to oncogenesis. This review discusses the major human tumor associated viruses and their ability to modulate numerous cell signaling pathways, which can be targeted for potential therapeutic approaches.

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“…EBNA2's role in transformation is essential because it acts as a transactivator for all six EBNAs as well as the LMPs. EBNA2 also interacts with the cellular DNA-binding elements RBP-J κ and PU.1 to mediate the transcription of numerous cellular genes which contribute to transformation [63, 66]. Comprehensive screening has identified 550 cellular genes that are either significantly induced or repressed by EBNA2, including MYC [67, 68].…”

Section: Burkitt Lymphoma and Transformation Of B Cellsmentioning

confidence: 99%

Burkitt Lymphoma: Pathogenesis and Immune Evasion

God

Haque

2010

Journal of Oncology

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B-cell lymphomas arise at distinct stages of cellular development and maturation, potentially influencing antigen (Ag) presentation and T-cell recognition. Burkitt lymphoma (BL) is a highly malignant B-cell tumor associated with Epstein-Barr Virus (EBV) infection. Although BL can be effectively treated in adults and children, leading to high survival rates, its ability to mask itself from the immune system makes BL an intriguing disease to study. In this paper, we will provide an overview of BL and its association with EBV and the c-myc oncogene. The contributions of EBV and c-myc to B-cell transformation, proliferation, or attenuation of cellular network and immune recognition or evasion will be summarized. We will also discuss the various pathways by which BL escapes immune detection by inhibiting both HLA class I- and II-mediated Ag presentation to T cells. Finally, we will provide an overview of recent developments suggesting the existence of BL-associated inhibitory molecules that may block HLA class II-mediated Ag presentation to CD4+ T cells, facilitating immune escape of BL.

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Regulation of transcription by the Epstein–Barr virus nuclear antigen EBNA 2

Cited by 14 publications

References 48 publications

Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription

Recruitment of cdk9 to the Immediate-Early Viral Transcriptosomes during Human Cytomegalovirus Infection Requires Efficient Binding to Cyclin T1, a Threshold Level of IE2 86, and Active Transcription

Tumor viruses and cancer biology: Modulating signaling pathways for therapeutic intervention

Burkitt Lymphoma: Pathogenesis and Immune Evasion

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