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1.
J Virol ; 89(23): 12178-88, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26401047

ABSTRACT

UNLABELLED: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus involved in the pathogenesis of Burkitt's lymphoma (BL) and various other lymphoproliferative disorders. In BL, EBV protein expression is restricted to EBV nuclear antigen 1 (EBNA1), but small noncoding RNAs such as EBV-encoded small RNAs (EBERs) and microRNAs (miRNAs) can also be detected. miRNAs play major roles in crucial processes such as proliferation, differentiation, and cell death. It has recently become clear that alterations in the expression profile of miRNAs contribute to the pathogenesis of a number of malignancies. During latent infection, EBV expresses 25 viral pre-miRNAs and modulates the expression of specific cellular miRNAs, such as miR-155 and miR-146, which potentially play a role in oncogenesis. Here, we established the small-RNA expression profiles of three BL cell lines. Using large-scale sequencing coupled to Northern blotting and real-time reverse transcription-PCR (RT-PCR) analysis validation, we demonstrated the differential expression of some cellular and viral miRNAs. High-level expression of the miR-183-96-182 cluster and EBV miR-BamHI A rightward transcript (miR-BART) cluster was significantly associated with EBV type I latency. This expression was not affected by viral reactivation since transforming growth factor ß1 (TGF-ß1) stimulation did not significantly change the miRNA profiles. However, using several approaches, including de novo infection with a mutant virus, we present evidence that the expression of latent membrane protein 1 (LMP-1) triggered downregulation of the expression of the miR-183-96-182 cluster. We further show that this effect involves the Akt signaling pathway. IMPORTANCE: In addition to expressing their own miRNAs, herpesviruses also impact the expression levels of cellular miRNAs. This regulation can be either positive or negative and usually results in the perturbation of pathways to create a cellular environment that is more "virus-friendly." For example, EBV induces the expression of miR-155, a well-characterized oncomiR, which leads to increased cell proliferation and decreased cell death. Here, we show that EBV-encoded LMP-1 is also involved in the downregulation of a cluster of three miRNAs, miR-183, -96, and -182, which are known to be also repressed in several cancers. We therefore identify yet another potential player in EBV-induced oncogenesis.


Subject(s)
Gene Expression Regulation/genetics , MicroRNAs/metabolism , Multigene Family/genetics , Viral Matrix Proteins/genetics , Base Sequence , Blotting, Northern , Cloning, Molecular , DNA Primers/genetics , Gene Expression Profiling , Gene Knockout Techniques , Humans , MicroRNAs/genetics , Molecular Sequence Data , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, RNA
2.
J Virol ; 85(13): 6502-12, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21507981

ABSTRACT

Transforming growth factor beta 1 (TGF-ß1) signal transduction has been implicated in many second-messenger pathways, including the NF-κB pathway. We provide evidence of a novel TGF-ß1-mediated pathway that leads to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, which in turn induces expression of an Epstein-Barr virus (EBV) protein, ZEBRA, that is responsible for the induction of the viral lytic cycle. This pathway includes two unexpected steps, both of which are required to control ERK 1/2 phosphorylation: first, a quick and transient activation of NF-κB, and second, downregulation of inducible nitric oxide synthase (iNOS) activity that requires the participation of NF-κB activity. Although necessary, NF-κB alone is not sufficient to produce downregulation of iNOS, suggesting that another uncharacterized event(s) is involved in this pathway. Dissection of the steps involved in the switch from the EBV latent cycle to the lytic cycle will be important to understand how virus-host relationships modulate the innate immune system.


Subject(s)
Down-Regulation , Herpesvirus 4, Human/physiology , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Transforming Growth Factor beta1/metabolism , Virus Activation , B-Lymphocytes/virology , Cell Line , Cell Line, Transformed , Gene Expression Regulation , Gene Expression Regulation, Viral , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Humans , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/genetics , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/genetics , Trans-Activators/genetics , Trans-Activators/metabolism
3.
Cancer Lett ; 305(2): 144-9, 2011 Jun 28.
Article in English | MEDLINE | ID: mdl-21172728

ABSTRACT

Epstein-Barr virus (EBV) a ubiquitous gamma herpesvirus persists for life, generally without health consequences. However, it is associated with several well-recognized malignancies, such as Burkitt's lymphoma and nasopharyngeal carcinoma. A growing list of malignancies has been proposed to be EBV-associated: most of which are consistently EBV-positive whereas others show inconsistent results. The possible contribution of EBV to the development and/or progression of different "non-classical" tumors is discussed in terms of putative "non-traditional'' infection in EBV-related tumors.


Subject(s)
Breast Neoplasms/virology , Liver Neoplasms/virology , Lymphatic Vessel Tumors/virology , Breast Neoplasms/complications , Carcinoma/complications , Carcinoma/virology , Disease Progression , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/immunology , Humans , Liver Neoplasms/complications , Lymphatic Vessel Tumors/complications , Models, Biological , Salivary Gland Neoplasms/complications , Salivary Gland Neoplasms/virology , Stomach Neoplasms/complications , Stomach Neoplasms/virology , Uterine Cervical Neoplasms/complications , Uterine Cervical Neoplasms/virology
4.
J Biol Chem ; 284(36): 23912-24, 2009 Sep 04.
Article in English | MEDLINE | ID: mdl-19589780

ABSTRACT

Epstein-Barr virus, a ubiquitous human herpesvirus, is associated with the development of carcinomas and lymphomas. We previously showed that transforming growth factor beta1 (TGF-beta1) mediated the virus to enter the lytic cycle, which is triggered by expression of Z Epstein-Barr virus replication activator (ZEBRA), through the ERK 1/2 MAPK signaling pathway. We report here that Akt, activated downstream from ERK 1/2, was required for TGF-beta1-induced ZEBRA expression and enabled Smad3, a mediator of TGF-beta1 signaling, to be acetylated by direct interaction with the co-activator CREB-binding protein and then to regulate TGF-beta1-induced ZEBRA expression.


Subject(s)
CREB-Binding Protein/metabolism , Herpesvirus 4, Human/physiology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism , Viral Proteins/metabolism , Virus Activation/physiology , Acetylation/drug effects , Cell Line, Tumor , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/physiology , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Trans-Activators , Transforming Growth Factor beta1/pharmacology , Virus Activation/drug effects
5.
Virology ; 387(1): 41-9, 2009 Apr 25.
Article in English | MEDLINE | ID: mdl-19254802

ABSTRACT

The Epstein-Barr virus (EBV) generally latently infects its target cells with expression of genes conferring resistance to apoptosis. However, the modulation of apoptotic signals during lytic cycle remains poorly understood. We show here that resulting from viral reactivation in the EBV-positive Mutu-I and Akata Burkitt's lymphoma cell lines, a two steps proteasome-dependent downregulation of expression of the proapoptotic protein BimEL occurs. The first drop might be EBV-independent, is ERK 1/2 dependent, and BimEL is phosphorylated on Ser69. A second dramatic drop of the BimEL level observed during the lytic cycle is dependent of EBV-late-gene expression, ERK 1/2 independent, and no further phosphorylation of BimEL on Ser69 occurred. These results demonstrate for the first time, that the lytic cycle contributes to downregulation of BimEL and then could add to protection against apoptosis.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Down-Regulation , Herpesvirus 4, Human/physiology , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Virus Activation , Apoptosis , Bcl-2-Like Protein 11 , Boronic Acids/pharmacology , Burkitt Lymphoma , Butadienes/pharmacology , Cell Line, Tumor , Enzyme Inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Viral/drug effects , Herpesvirus 4, Human/genetics , Humans , Nitriles/pharmacology , Phosphorylation
6.
BMC Infect Dis ; 7: 123, 2007 Oct 25.
Article in English | MEDLINE | ID: mdl-17961236

ABSTRACT

BACKGROUND: Human parvovirus B19 is the etiologic agent of erythema infectiosum in children. It is also associated with other clinical manifestations in different target groups. Patients with chronic hemolytic anemia are at high risk of developing acute erythroblastopenia following infection by the virus. They usually become highly viremic and pose an increased risk of virus transmission. Close monitoring of such high risk groups is required for epidemiologic surveillance and disease prevention activities. Here we report a molecular epidemiological study on B19 virus infection in Tunisian patients with chronic hemolytic anemia. METHODS: This study was conducted on 92 young chronic hemolytic anemia patients who attended the same ward at the National Bone Marrow Transplantation Center of Tunis and 46 controls from a different hospital. Screening for IgM and IgG anti-B19 antibodies was performed using commercially available enzyme immunoassays and B19 DNA was detected by nested PCR in the overlapping VP1/VP2 region. DNA was sequenced using dideoxy-terminator cycle sequencing technology. RESULTS: Anti-parvovirus B19 IgG antibodies were detected in 26 of 46 sickle-cell anemia patients, 18 of 46 beta-thalassemia and 7 of 46 controls. Anti-parvovirus B19 IgM antibodies were detected only in 4 of the sickle-cell anemia patients: two siblings and two unrelated who presented with acute erythroblastopenia at the time of blood collection for this study and had no history of past transfusion. B19 DNA was detected only in sera of these four patients and the corresponding 288 bp nested DNA amplicons were sequenced. The sequences obtained were all identical and phylogenetic analysis showed that they belonged to a new B19 virus strain of Genotype1. CONCLUSION: A new parvovirus B19 strain of genotype1 was detected in four Tunisian patients with sickle-cell anemia. Virus transmission appeared to be nosocomial and resulted in acute erythroblastopenia in the four patients. The possibility of independent transmission of this B19 variant to the patients is unlikely in light of the present epidemiological data. However this possibility cannot be ruled out because of the low genetic variability of the virus.


Subject(s)
Anemia, Sickle Cell/complications , Parvoviridae Infections/epidemiology , Parvovirus B19, Human/isolation & purification , Red-Cell Aplasia, Pure/virology , Adolescent , Adult , Base Sequence , Child , Cross Infection/complications , Cross Infection/epidemiology , Cross Infection/virology , DNA, Viral/chemistry , Erythroblasts/cytology , Humans , Male , Molecular Sequence Data , Parvoviridae Infections/complications , Parvoviridae Infections/virology , Parvovirus B19, Human/classification , Parvovirus B19, Human/genetics , Phylogeny , Sequence Alignment , Tunisia/epidemiology
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