Transcription of the Epstein–Barr Virus Lytic Cycle Activator BZLF-1 During Oxidative Stress Induction

Lassoued, Saloua; Gargouri, Bilel; Feki, Amal; Attia, Hammadi; Pelt, Jos van

doi:10.1007/s12011-009-8555-y

Cited by 35 publications

(29 citation statements)

References 27 publications

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“…Recent studies demonstrated that hydrogen peroxide induces reactivation of another gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) (56,98). Additionally, hydrogen peroxide has been shown to induce Z transcription (52). Here we demonstrate that induction of lytic EBV infection by inducing oxidative stress with hydrogen peroxide requires ATM kinase activation (Fig.…”

Section: Discussionsupporting

confidence: 53%

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

Hagemeier

Barlow

Qiao

et al. 2012

J Virol

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The Epstein-Barr virus (EBV) latent-to-lytic switch is mediated by the viral proteins BZLF1 (Z), BRLF1 (R), and BRRF1 (Na). Since we previously showed that DNA-damaging agents (including chemotherapy and irradiation) can induce EBV lytic reactivation and recently demonstrated that wild-type p53 contributes to lytic reactivation, we investigated the role of the ATM kinase during EBV reactivation. ATM phosphorylates and activates p53, as well as numerous other substrates involved in the cellular DNA damage response. Using an ATM inhibitor (KU55933), we found that ATM activity is required for efficient induction of EBV lytic gene expression by a variety of different stimuli, including a histone deacetylase (HDAC) inhibitor, the transforming growth factor ␤ (TGF-␤) cytokine, a demethylating agent (5-azacytidine), B cell receptor engagement with anti-IgG antibody, hydrogen peroxide, and the proteosome inhibitor bortezomib. In EBV-infected AGS (gastric) cells, knockdown of ATM, or p53, expression inhibits EBV reactivation. Conversely, treatment of these cells with nutlin-3 (which activates p53 and ATM) robustly induces lytic reactivation in a p53-and ATM-dependent manner. The ability of the EBV R and Na proteins to induce lytic reactivation in EBV-infected AGS cells is ATM dependent. However, overexpression of Z induces lytic gene expression in the presence or absence of ATM activity. Our results suggest that ATM enhances Z promoter activity in the context of the intact EBV genome and that p53 contributes to the ATM effect. Nevertheless, since we found that ATM inhibitors also reduce lytic reactivation in Burkitt lymphoma cells that have no p53, additional ATM substrates must also contribute to the ATM effect. E pstein-Barr virus (EBV) is a gammaherpesvirus that is the cause of infectious mononucleosis and is associated with a variety of epithelial and B cell cancers, including nasopharyngeal carcinoma (NPC), a subset of gastric carcinomas, Burkitt lymphoma (BL), and Hodgkin's disease (77,102). Like all herpesviruses, EBV can infect cells in either latent or lytic forms. Following infection of humans, EBV establishes long-term viral latency in the memory B cell compartment but can be reactivated to undergo the lytic form of infection following plasma cell differentiation (51). EBV infection of normal epithelial cells generally results in lytic infection (32,93,94), although EBV ϩ epithelial cell tumors such as NPCs and gastric carcinomas are primarily composed of cells with latent forms of infection (48,77). Both the latent and lytic forms of EBV infection are essential for the long-term success of the virus, and the latent-lytic switch is tightly controlled by both cellular and viral factors.The two EBV immediate-early (IE) proteins, BZLF1 (Z, also known as Zta, ZEBRA, or EB1) and BRLF1 (R), are transcription factors that activate expression of lytic viral promoters, and overexpression of either the Z or R IE protein is sufficient to reactivate the lytic form of EBV infection in many latently infected cell lines (2, ...

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Section: Discussionsupporting

confidence: 53%

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

Hagemeier

Barlow

Qiao

et al. 2012

J Virol

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“…Valko et al reported that AP-1 activity is induced in response to certain metals in the presence of H 2 O 2 as well as by several cytokines and other physical and chemical stresses [1]. In addition, in our previous study, we demonstrated that H 2 O 2 and FeSO 4 are able to activate BZLF-1 gene expression [37]. Thus, we can speculate that BZLF-1 gene expression can be directly regulated by ROS.…”

Section: Discussionsupporting

confidence: 51%

“…Qadri et al described during HCV replication an increase in SOD expression associated with activation of signalling pathways such as p38 MAPK, JNK, and AP-1, which are well-known as modulator of SOD [27]. Interesting, BZLF-1, the key molecule responsible for the reactivation of EBV, is a member of AP-1 family [34][35][36][37]. Valko et al reported that AP-1 activity is induced in response to certain metals in the presence of H 2 O 2 as well as by several cytokines and other physical and chemical stresses [1].…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Production and Antioxidant Enzyme Expression after Epstein–Barr Virus Lytic Cycle Induction in Raji Cell Line

Gargouri

Nasr

Mansour

et al. 2011

Biol Trace Elem Res

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In a previous study, we have described oxidative stress during Epstein-Barr virus lytic cycle induction. Oxidative stress was evidenced by the observed high MDA levels and the decreased activities of antioxidant enzymes. We hypothesised that the lower activities of the antioxidant enzymes decrease were the result of either the excessive production of reactive oxygen radical species (ROS) or a negative regulation of the antioxidant enzyme gene expressions. In an attempt to clarify this situation, EBV lytic cycle was induced in Raji cell line by a non-stressing dose of 12-0-tetradecanoylphorbol-13-acetate. BZLF-1, superoxide dismutase, and catalase gene expressions were then analysed using semi-quantitative RT-PCR, simultaneously at a kinetic of 6, 12, 24, 36, and 48 h. ROS production was evaluated by chemiluminescence. A study was conducted to establish whether ROS production, BZLF-1, and the expression of antioxidant genes were inter-correlated. Induction of the lytic cycle resulted in increased expressions of the genes of superoxide dismutase and catalase, which began at 24 h (p < 0.05) and reached a peak at 48 h (p < 0.05). Significant increases of the ROS levels were observed in TPA-treated Raji cell line at 12 h, as compared with untreated cells, reaching a peak at 48 h after EBV lytic cycle induction. ROS production correlates positively with BZLF-1, SOD, and CAT gene expressions (p < 0.05; r = 0.913, r = 0.978, and r = 0.955, respectively). A positive correlation was also observed between BZLF-1 and antioxidant gene expressions (p < 0.05; r = 0.961 and r = 0.987, respectively). In conclusion, the observed increases of the SOD and CAT gene expressions eliminate the hypothesis of a repression of the respective genes during the induction of the lytic cycle. On the other hand, the observed direct correlation between the BZLF-1 gene expression and the ROS production is indicative of a role of this gene in oxidative stress.

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Section: Systematic Review Marongiumentioning

confidence: 99%

“…Increased calcium levels induced the exit from the latent cycle of the HHV-4-containing cell line Raji, although this line is characterized by the coexistence of both integrative and episomal forms of the virus [22]. Modifications of the cellular environment such as hypoxia and oxidative stress have been reported to reactivate transcriptionally silent HHV-4 proviruses [23,24].Since cells containing viral integrants are typically a minority within a tissue and, by definition, transcriptionally silent viral copies do not express mRNAs or proteins, screening assays might miss the presence of the latent oncogenic proviruses in a given sample. Likewise, the immune system is not activated due to the absence of sufficient levels of viral antigens.…”

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confidence: 99%

Proportion of Transcriptionally Active Dna Virus Integrants: A Meta-Analysis

Marongiu

2017

Future Virol.

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Oncoviruses are collectively responsible for over 1,000,000 new cases of cancer per year; some can integrate into the host's chromosomes. The present work was aimed at assessing the proportion of transcriptionally active viral integrants through a systematic review of the scientific publications present on the MedLine database. From the articles screened, 628 viral integrants overall were retrieved, of which 530.84 were transcriptionally active (84.53%); among the clinical samples, 264 of 323 integrants were active (81.73%). The causes for the silencing were not addressed in the articles analyzed. These findings might highlight a possible risk factor for the insurgence of cancer since some oncovirus integrants could be reactivated by stimuli of disparate nature. Further studies should address such possibility. About 16% of all cancer cases have been identified having an infectious aetiology [1]. Hepatitis B virus (HBV), human papilloma virus (HPV), human herpes 4 virus (HHV-4, historically known as Epstein-Barr virus [EBV]) and human herpes 8 virus (HHV-8, previously Kaposi sarcoma herpes virus) are collectively responsible for 56.2% of the incident microbial-related cancer cases, corresponding to over 1,200,000 new cases per year [2].HBV, HPV and HHV-4 share the capability of integrating into the host's chromosomes whereas HHV-8 integrants have not been observed [3]. In addition, other DNA viruses with transformation potential can integrate: Merkel cell polyomavirus (MCPV), human herpes 6 virus (HHV-6) and, in a lesser extent, adenovirus (AdV) [4][5][6]. The infection with these viruses is associated with a wide range of cancer types: HBV with hepatocarcinoma; HPV with virtually all cases of cervical cancer and in a significant proportion of other tumors, for instance in the head and neck; HHV-4 with a number of malignancies, in particular Burkitt and Hodgkin lymphomas, in both immunologically deficient and competent patients; HHV-8 DNA has been retrieved in all Kaposi sarcoma lesions even in immunocompetent hosts; MCPV is recognized as the causative agent of the Merkel cell carcinoma; HHV-6 has been involved in lymphoproliferative diseases; and AdV has been shown to transform rodent cells [1,[7][8][9].All these viruses encode for proteins that disrupt the cell cycle and DNA damage repair response to sustain the viral replication. For example, HBV X, HPV E6/E7, HHV-8 LANA and MCPV large T proteins, all hinder the function of p53, a pivotal factor of the DNA damage response, and pRb, an oncosuppressor that prevents over-replication of the cellular DNA [10][11][12][13][14]. HHV-4 encodes for a plethora of early proteins with oncogenic potential; for instance, BARF1 and BCRF1 have antiapoptotic function and the viral DNAse enzyme can cause genomic instability, therefore induction of the lytic cycle can contribute to the development of malignant phenotypes [15]. Even during the lysogenic cycle, HHV-4 encodes for proteins and interfering RNAs that have oncogenic potential [16].Integration can disrupt the transcripti...

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Transcription of the Epstein–Barr Virus Lytic Cycle Activator BZLF-1 During Oxidative Stress Induction

Cited by 35 publications

References 27 publications

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

Reactive Oxygen Species Production and Antioxidant Enzyme Expression after Epstein–Barr Virus Lytic Cycle Induction in Raji Cell Line

Proportion of Transcriptionally Active Dna Virus Integrants: A Meta-Analysis

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