Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Sivachandran, Nirojini; Dawson, Christopher W.; Young, Lawrence S.; Liu, Fei‐Fei; Middeldorp, Jaap M.; Frappier, Lori

doi:10.1128/jvi.05623-11

Cited by 86 publications

(93 citation statements)

References 46 publications

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“…The top four molecular and cellular functions enriched in this set of genes were cellular movement, cell-to-cell signaling and interaction, cell growth and proliferation, and cell death; each was highly significant with extremely low P values (Table 2). Interestingly, infection of AGS cells with EBV has been shown previously to increase cellular mobility (25), and expression of EBNA1 in AGS cells inhibits expression of promyelocytic leukemia nuclear bodies and reduces apoptosis in response to DNA damage (26). The IPA-identified categories reflect these known properties and are likely relevant to the growth in the soft agar phenotype presented here.…”

Section: Ebv Latent Infection In Ags Cells Promotes Growth In Soft Agarmentioning

confidence: 97%

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Marquitz

Mathur

Shair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Latent infection of EBV is linked to the development of multiple cancers that have distinct patterns of expression of viral proteins and microRNAs (miRNAs). In this study, we show that in vitro infection of a gastric epithelial cell line with EBV alters growth properties and induces growth in soft agar. The infected cells have high levels of expression of a large cluster of viral miRNAs, [the BamHI A rightward transcript (BART) miRNAs] and limited viral protein expression. Expression profile microarray analysis of this cell line revealed a large number of changes in cellular expression, with decreased expression of many genes. Inhibition of the traceexpressed levels of the viral oncoprotein, latent membrane protein 1, did not affect growth or alter the pattern of cellular expression. The expression changes are highly enriched for genes involved in cell motility and transformation pathways, suggesting these changes are important for the altered growth phenotype. Importantly, the transcripts decreased by microarray are significantly enriched in both experimentally and bioinformatically predicted BART miRNA targets. The absence of viral protein expression and the enrichment for viral miRNA targets in the modulated cell genes suggest that the BART miRNAs are major contributors to the transformed growth properties of the EBV-infected cells. The ability to affect cell growth through miRNA expression without viral protein expression would be a major factor in the development of cancer in individuals with functional immune systems.gastric carcinoma | oncogenesis | herpes virus

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Section: Ebv Latent Infection In Ags Cells Promotes Growth In Soft Agarmentioning

confidence: 97%

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Marquitz

Mathur

Shair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…ND10 and its organizer PML have been a hot spot for viral oncogenic studies (57)(58)(59)(60)(61). As a tumor suppressor gene, PML deficiency and subsequent ND10 loss have been observed in many cancer types, including viral-infection-related cancers.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention

Zheng

Roizman

2013

J Virol

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On entry into the nucleus, herpes simplex virus 1 (HSV-1) DNA localizes to nuclear bodies known as ND10. Gene repression imposed by ND10 is released by a viral protein, ICP0, via degradation of the ND10 constituents promyelocytic leukemia protein (PML) and Sp100 and the subsequent dispersal of ND10 bodies. In order to understand the dynamic interaction between ICP0 and ND10, we carried out deletion mapping to identify the domains of ICP0 responsible for its association with ND10. Here, we report the following. (i) An ND10 entry signal (ND10-ES), located between residues 245 and 474, is required for ICP0 to penetrate and fuse with ND10. ICP0 lacking ND10-ES adheres to the surface of ND10 but fails to enter. (ii) In the absence of ND10-ES, the E3 ubiquitin ligase of ICP0 facilitates the transient adhesion of the truncated ICP0 to the ND10 surface, whereas the presence of ND10-ES in ICP0 renders ND10 fusion regardless of the E3 ligase activity. (iii) The C terminus of ICP0 is required for retention of ICP0 in ND10 but plays no role in the recruitment process. (iv) The adverse effects of an inactive RING domain on viral replication are partially reversed by deleting either ND10-ES or the C-terminal retention domain, suggesting that additional ICP0 functions require the release of ICP0 from ND10. Based on these results, we conclude that association of ICP0 and ND10 is a dynamic process, in which three sequential steps-adhesion, fusion, and retention-are adopted to stabilize the interaction. A faithful execution of these steps defines the ultimate productivity of the virus.

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“…We have previously identified a mechanism by which the EpsteinBarr virus (EBV) protein EBNA1 induces loss of PML NBs and degradation of PML proteins in nasopharyngeal carcinoma (NPC) and gastric carcinoma, two EBV-associated cancers (Sivachandran et al, 2012a(Sivachandran et al, , 2008(Sivachandran et al, , 2010. However, little is known about the cellular ubiquitin pathway proteins that regulate PML in these cells.…”

Section: Identification Of Rnf8 and Rnf168 As Pml Regulatorsmentioning

confidence: 99%

Identification of RNF168 as a PML nuclear body regulator

Shire

Wong

Tatham

et al. 2016

Journal of Cell Science

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Promyelocytic leukemia (PML) protein forms the basis of PML nuclear bodies (PML NBs), which control many important processes. We have screened an shRNA library targeting ubiquitin pathway proteins for effects on PML NBs, and identified RNF8 and RNF168 DNAdamage response proteins as negative regulators of PML NBs. Additional studies confirmed that depletion of either RNF8 or RNF168 increased the levels of PML NBs and proteins, whereas overexpression induced loss of PML NBs. RNF168 partially localized to PML NBs through its UMI/MIU1 ubiquitin-interacting region and associated with NBs formed by any PML isoform. The association of RNF168 with PML NBs resulted in increased ubiquitylation and SUMO2 modification of PML. In addition, RNF168 was found to associate with proteins modified by SUMO2 and/or SUMO3 in a manner dependent on its ubiquitin-binding sequences, suggesting that hybrid SUMO-ubiquitin chains can be bound. In vitro assays confirmed that RNF168, preferentially, binds hybrid SUMO2-K63 ubiquitin chains compared with K63-ubiquitin chains or individual SUMO2. Our study identified previously unrecognized roles for RNF8 and RNF168 in the regulation of PML, and a so far unknown preference of RNF168 for hybrid SUMOubiquitin chains.

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Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma

Cited by 86 publications

References 46 publications

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Infection of Epstein–Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression

Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention

Identification of RNF168 as a PML nuclear body regulator

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