scholarly journals Modulation of the Cell Growth Regulator mTOR by Epstein-Barr Virus-Encoded LMP2A

2005 ◽  
Vol 79 (9) ◽  
pp. 5499-5506 ◽  
Author(s):  
Cary A. Moody ◽  
Rona S. Scott ◽  
Nazanin Amirghahari ◽  
Cherie-Ann Nathan ◽  
Lawrence S. Young ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Mammalian Target Of Rapamycin ◽  
Human Tumor ◽  
Protein Translation ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Barr Virus ◽  
Eukaryotic Initiation Factor 4E ◽  
Tumor Virus ◽  
Epstein Barr

ABSTRACT Control of translation initiation is one means by which cells regulate growth and proliferation, with components of the protein-synthesizing machinery having oncogenic potential. Expression of latency protein LMP2A by the human tumor virus Epstein-Barr virus (EBV) activates phosphatidylinositol 3-kinase/Akt located upstream of an essential mediator of growth signals, mTOR (mammalian target of rapamycin). We show that mTOR is activated by expression of LMP2A in carcinoma cells, leading to wortmannin- and rapamycin-sensitive inhibition of the negative regulator of translation, eukaryotic initiation factor 4E-binding protein 1, and increased c-Myc protein translation. Intervention by this DNA tumor virus in cellular translational controls is likely to be an integral component of EBV tumorigenesis.

EBV+ Lymphoproliferative Diseases: Opportunities for leveraging EBV as a Therapeutic Target

Blood ◽  
2021 ◽  
Author(s):  
Keri Toner ◽  
Catherine M. Bollard
Keyword(s):  
Proliferative Response ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Lymphoproliferative Disease ◽  
Lymphoproliferative Diseases ◽  
Malignant Lymphomas ◽  
Barr Virus ◽  
Immune Therapies ◽  
Tumor Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell based immune therapies. In this review, we will describe the EBV-associated lymphoproliferative diseases and will particularly focus on the therapies that target EBV.

scholarly journals Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Yonggang Pei ◽  
Josiah Hiu-yuen Wong ◽  
Hem Chandra Jha ◽  
Tian Tian ◽  
Zhi Wei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Population ◽  
Regulatory Networks ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Human Tumor ◽  
Barr Virus ◽  
Repressor Complex ◽  
Tumor Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) was discovered as the first human tumor virus more than 50 years ago. EBV infects more than 90% of the human population worldwide and is associated with numerous hematologic malignancies and epithelial malignancies. EBV establishes latent infection in B cells, which is the typical program seen in lymphomagenesis. Understanding EBV-mediated transcription regulatory networks is one of the current challenges that will uncover new insights into the mechanism of viral-mediated lymphomagenesis. Here, we describe the regulatory profiles of several cellular factors (E2F6, E2F1, Rb, HDAC1, and HDAC2) together with EBV latent nuclear antigens using next-generation sequencing (NGS) analysis. Our results show that the E2F-Rb-HDAC complex exhibits similar distributions in genomic regions of EBV-positive cells and is associated with oncogenic super-enhancers involving long-range regulatory regions. Furthermore, EBV latent antigens cooperatively hijack this complex to bind at KLFs gene loci and facilitate KLF14 gene expression in lymphoblastoid cell lines (LCLs). These results demonstrate that EBV latent antigens can function as master regulators of this multisubunit repressor complex (E2F-Rb-HDAC) to reverse its suppressive activities and facilitate downstream gene expression that can contribute to viral-induced lymphomagenesis. These results provide novel insights into targets for the development of new therapeutic interventions for treating EBV-associated lymphomas. IMPORTANCE Epstein-Barr virus (EBV), as the first human tumor virus, infects more than 90% of the human population worldwide and is associated with numerous human cancers. Exploring EBV-mediated transcription regulatory networks is critical to understand viral-associated lymphomagenesis. However, the detailed mechanism is not fully explored. Now we describe the regulatory profiles of the E2F-Rb-HDAC complex together with EBV latent antigens, and we found that EBV latent antigens cooperatively facilitate KLF14 expression by antagonizing this multisubunit repressor complex in EBV-positive cells. This provides potential therapeutic targets for the treatment of EBV-associated cancers.

scholarly journals Study On the Mechanism of LMP2A Maintaining Epstein-barr Virus Latency Infection Through Interaction With CXCR4

2021 ◽  
Author(s):  
Ni Qin ◽  
Yan Zhang ◽  
Lin Xu ◽  
Wen Liu ◽  
Bing Luo
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Signal Pathways ◽  
Barr Virus ◽  
Virus Latency ◽  
Early Protein ◽  
Tumor Virus ◽  
Epstein Barr ◽  
And Migration

Abstract Epstein-Barr virus (EBV) belongs to the γ-herpesvirus subfamily and is the first human tumor virus to be discovered. The global adult infection rate exceeds 90%. EBV can participate in the regulation of multiple genes and multiple signal pathways through its latent genes. Many studies have reported that CXCR4 is involved in the development of gastric cancer, but there are few studies on the specific mechanism of its role in EBV-associated gastric cancer (EBVaGC). In this study, we explored the mechanism by which EBV-encoded products maintain EBV latent infection through interaction with CXCR4, and the role of CXCR4 in EBV positive cells. The results show that there is a positive feedback between the EBV-encoded products and CXCR4, and LMP2A can activate CXCR4 through the NF-κB pathway. In addition, CXCR4 can be fed back to LMP2A and EBNA1 through the ERK signaling pathway. At the same time, CXCR4 can promote the proliferation and migration of EBV-positive cells, reduce the expression of the immediate early protein BZLF1, and play an important role in maintaining the incubation period of EBV infection. These findings are conducive to the further targeted therapy of EBVaGC.

scholarly journals Immune Escape by Non-coding RNAs of the Epstein Barr Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian Münz
Keyword(s):  
Epstein Barr Virus ◽  
Vaccine Development ◽  
Immune Escape ◽  
Human Tumor ◽  
Experimental Models ◽  
Cytotoxic Lymphocytes ◽  
Barr Virus ◽  
Tumor Virus ◽  
Non Coding Rnas ◽  
Epstein Barr

Epstein Barr virus (EBV) is one of the most successful pathogens of humans, persistently colonizing more than 95% of the adult human population. At the same time EBV encodes oncogenes that can readily transform human B cells in culture and threaten healthy virus carriers with lymphomagenesis. Cytotoxic lymphocytes have been identified in experimental models and by primary immunodeficiencies as the main protective immune compartments controlling EBV. EBV has reached a stalemate with these cytotoxic T and innate lymphocytes to ensure persistence in most infected humans. Recent evidence suggests that the non-coding RNAs of the virus contribute to viral immune escape to prevent immune eradication. This knowledge might be used in the future to attenuate EBV for vaccine development against this human tumor virus that was discovered more than 55 years ago.

scholarly journals Epstein-Barr virus reprograms human B-lymphocytes immediately in the pre-latent phase of infection

2018 ◽  
Author(s):  
Paulina Mrozek-Gorska ◽  
Alexander Buschle ◽  
Dagmar Pich ◽  
Thomas Schwarzmayr ◽  
Ron Fechtner ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Metabolic Pathways ◽  
Epstein Barr Virus ◽  
Human Tumor ◽  
Time Resolved ◽  
Barr Virus ◽  
Tumor Virus ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B-lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV’s oncogenic potential in vivo. This seminal finding was made 50 years ago, but how EBV activates primary human B-lymphocytes and how lymphoblastoid cell lines (LCLs) evolve from the EBV-infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B-lymphocytes. EBV reprograms these human cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 hours of infection and precede any metabolic and phenotypic changes. Within the next 48 hours, the virus activates the cells, changes their phenotypes with respect to cell size, RNA and protein content and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day three post infection. The transcriptional program that EBV initiates consists of three waves of clearly discernable clusters of cellular genes that peak on day one, two, or three and regulate RNA synthesis, metabolic pathways and cell division, respectively. Upon the onset of cell doublings on day four the cellular transcriptome appears to be completely reprogrammed to support the activated and proliferating cell, but three additional clusters of EBV regulated genes adjust the infected immune cells to fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 98 % of the 13,000 expressed genes in B-lymphocytes are regulated upon infection demonstrating that EBV governs the entire biology of its target cell.

scholarly journals Promoter-Proximal Regulatory Elements Involved in oriP-EBNA1-Independent and -Dependent Activation of the Epstein-Barr Virus C Promoter in B-Lymphoid Cell Lines

2001 ◽  
Vol 75 (13) ◽  
pp. 5796-5811 ◽  
Author(s):  
Tina Nilsson ◽  
Henrik Zetterberg ◽  
Yuyan Camilla Wang ◽  
Lars Rymo
Keyword(s):  
Transcription Factor ◽  
Epstein Barr Virus ◽  
Regulatory Elements ◽  
Negative Regulator ◽  
Regulatory Sequences ◽  
Barr Virus ◽  
Group I ◽  
Epstein Barr ◽  
B Lymphoid ◽  
Virus C

ABSTRACT The identification of the cellular factors that control the transcription regulatory activity of the Epstein-Barr virus C promoter (Cp) is fundamental to the understanding of the molecular mechanisms that control virus latent gene expression. Using transient transfection of reporter plasmids in group I phenotype B-lymphoid cells, we have previously shown that the −248 to −55 region (−248/−55 region) of Cp contains elements that are essential fororiPI-EBNA1-dependent as well asoriPI-EBNA1-independent activation of the promoter. We now establish the importance of this region by a detailed mutational analysis of reporter plasmids carrying Cp regulatory sequences together with or without oriPI. The reporter plasmids were transfected into group I phenotype Rael cells and group III phenotype cbc-Rael cells, and the Cp activity measured was correlated with the binding of candidate transcription factors in electrophoretic mobility shift assays and further assessed in cotransfection experiments. We show that the NF-Y transcription factor interacts with the previously identified CCAAT box in the −71/−63 Cp region (M. T. Puglielli, M. Woisetschlaeger, and S. H. Speck, J. Virol. 70:5758–5768, 1996). We also show that members of the C/EBP transcription factor family interact with a C/EBP consensus sequence in the −119/−112 region of Cp and that this interaction is important for promoter activity. A central finding is the identification of a GC-rich sequence in the −99/−91 Cp region that is essential fororiPI-EBNA1-independent as well asoriPI-EBNA1-dependent activity of the promoter. This region contains overlapping binding sites for Sp1 and Egr-1, and our results suggest that Sp1 is a positive and Egr-1 is a negative regulator of Cp activity. Furthermore, we demonstrate that a reporter plasmid that in addition to oriPI contains only the −111/+76 region of Cp still retains the ability to be activated by EBNA1.

scholarly journals Unexpected Absence of the Epstein-Barr Virus (EBV) lyLMP-1 Open Reading Frame in Tumor Virus Isolates: Lack of Correlation between Met129 Status and EBV Strain Identity

2003 ◽  
Vol 77 (7) ◽  
pp. 4415-4422 ◽  
Author(s):  
Kimberly D. Erickson ◽  
Christoph Berger ◽  
William F. Coffin ◽  
Edwin Schiff ◽  
Dennis M. Walling ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Open Reading Frame ◽  
Lytic Cycle ◽  
Reading Frame ◽  
Barr Virus ◽  
Tumor Virus ◽  
Epstein Barr ◽  
Virus Isolates ◽  
Codon 129

ABSTRACT The lytic cycle-associated lytic latent membrane protein-1 (lyLMP-1) of Epstein-Barr virus (EBV) is an amino-terminally truncated form of the oncogenic LMP-1. Although lyLMP-1 shares none of LMP-1's transforming and signal transducing activities, we recently reported that lyLMP-1 can negatively regulate LMP-1-stimulated NF-κB activation. The lyLMP-1 protein encoded by the B95-8 strain of EBV initiates from methionine 129 (Met129) of the LMP-1 open reading frame (ORF). The recent report that Met129 in the B95-8 LMP-1 ORF is not conserved in the Akata strain of EBV prompted us to screen a panel of EBV-positive cell lines for conservation of Met129 and lyLMP-1 expression. We found that 15 out of 16 tumor-associated virus isolates sequenced encoded an ATT or ACC codon in place of ATG in the LMP-1 ORF at position 129, and tumor cell lines harboring isolates lacking an ATG at codon 129 did not express the lyLMP-1 protein. In contrast, we found that EBV DNA from 22 out of 37 healthy seropositive donors retained the Met129 codon. Finally, the lyLMP-1 initiator occurs variably within distinct EBV strains and its presence cannot be predicted by EBV strain identity. Thus, Met129 is not peculiar to the B95-8 strain of EBV, but rather can be found in the background of several evolutionarily distinct EBV strains. Its absence from EBV isolates from tumors raises the possibility of selective pressure on Met129 in EBV-dependent tumors.

Interferon-γ–Dependent Inducible Expression of the Human Interleukin-12 p35 Gene in Monocytes Initiates From a TATA-Containing Promoter Distinct From the CpG-Rich Promoter Active in Epstein-Barr Virus-Transformed Lymphoblastoid Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4645-4651 ◽  
Author(s):  
Mark P. Hayes ◽  
Finbarr J. Murphy ◽  
Parris R. Burd
Keyword(s):  
Epstein Barr Virus ◽  
Protein Translation ◽  
Interferon Γ ◽  
Tata Box ◽  
Interleukin 12 ◽  
Limiting Factor ◽  
Rnase Protection ◽  
Barr Virus ◽  
P35 Gene ◽  
Epstein Barr

Abstract Interleukin-12 (IL-12) production by human monocytes is stringently regulated through the inducibility of both subunits, p35 and p40, and expression of p35 mRNA is the limiting factor for the secretion of the bioactive IL-12 p70 heterodimer. Optimal induction of p35 mRNA requires priming of the monocytes by interferon-γ (IFN-γ), followed by brief exposure to lipopolysaccharide or other bacterial products. To investigate control of p35 gene expression, we isolated genomic clones containing the human p35 gene and determined the 5′ end of the mRNA expressed in monocytes. We discovered that a unique p35 transcript is induced in monocytes that begins downstream of a consensus TATA box that lies within the 5′ end of the cDNA originally cloned from Epstein-Barr virus (EBV)-transformed B cells. Analysis of p35 mRNA by Northern blotting showed that the message from monocytes is approximately 200 bases shorter than message derived from the EBV-transformed B-cell line VDS. The initiation sites downstream from the TATA box were confirmed by RNase protection and 5′ RACE. The data indicate that p35 transcription can initiate from different sites depending on the cell type and that the shorter inducible transcript in monocytes is the one that accumulates after stimulation. Protein translation of these two forms may result in proteins of different sizes with potential implications for the regulation of IL-12 secretion and function.

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