Hypoxia can contribute to the induction of the Epstein-Barr virus (EBV) lytic cycle

Jiang, Ju Hong; Wang, Na; Li, Ang; Liao, Wen Ting; Pan, Zhongdang; Shi, Juan; Li, Da Jiang; Zeng, Mu Sheng; Wen, Jian Ming; Zeng, Yi Xin

doi:10.1016/j.jcv.2006.06.013

Cited by 71 publications

(62 citation statements)

References 25 publications

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“…The coinvolvement of HIF-1␣ and XBP-1s may also be of significance to the life cycles of other herpesviruses. EpsteinBarr virus (EBV), the human herpesvirus most closely related to KSHV, is also induced into its lytic cycle by hypoxic treatment (24), and XBP-1s has been implicated as an EBV lytic cycle inducer, although most likely in the presence of other coactivators, such as protein kinase D (3,46). For murine herpesvirus 4, a related rhadinovirus, ORF50 is also upregulated in response to hypoxia (32), although a response to XBP-1s has not been reported.…”

Section: Discussionmentioning

confidence: 99%

X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions

Dalton-Griffin¹,

Wilson

Kellam

2009

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV), like other herpesviruses, has two stages to its life cycle: latency and lytic replication. KSHV is required for development of Kaposi's sarcoma, a tumor of endothelial origin, and is associated with the B-cell tumor primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease, all of which are characterized by predominantly latent KSHV infection. Recently, we and others have shown that the activated form of transcription factor X-box binding protein 1 (XBP-1) is a physiological trigger of KSHV lytic reactivation in PEL. Here, we show that XBP-1s transactivates the ORF50/RTA promoter though an ACGT core containing the XBP-1 response element, an element previously identified as a weakly active hypoxia response element (HRE). Hypoxia induces the KSHV lytic cycle, and active HREs that respond to hypoxia-inducible factor 1␣ are present in the ORF50/RTA promoter. Hypoxia also induces active XBP-1s, and here, we show that both transcription factors contribute to the induction of RTA expression, leading to the production of infectious KSHV under hypoxic conditions.

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Section: Discussionmentioning

confidence: 99%

X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions

Dalton-Griffin¹,

Wilson

Kellam

2009

J Virol

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“…They also sequentially activate early and late lytic genes, leading to the production of the progeny virus (8). In vitro, lytic replication can be induced by various stimuli, such as hypoxia (9), transforming growth factor beta (10)(11)(12), cross-linking of surface immunoglobulin (13), and 12-O-tetradecanoylphorbol-13-acetate (TPA) (14). In vivo, latency can be converted to a lytic cycle by triggering factors that remain unknown.…”

mentioning

confidence: 99%

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

Kim

Choi

Lee

2016

J Virol

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Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

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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.…”

mentioning

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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Hypoxia can contribute to the induction of the Epstein-Barr virus (EBV) lytic cycle

Cited by 71 publications

References 25 publications

X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions

X-Box Binding Protein 1 Contributes to Induction of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle under Hypoxic Conditions

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

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

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