Amino-acid change in the Epstein-Barr-virus zebra protein in undifferentiated nasopharyngeal carcinomas from Europe and North Africa

Grunewald, Virginie; Bonnet, Mathilde; Boutin, Sylvie; Yip, Timothy T. C.; Louzir, Hechmi; Levrero, Massimo; Seigneurin, J.M.; Raphaël, Martine; Robert, Thomas; Martel-Renoir, Dominique; Cochet, C; Durandy, Anne; André, Patrice; Lau, W.S.; Zeng, Yi; Joab, Irène

doi:10.1002/(sici)1097-0215(19980209)75:4<497::aid-ijc2>3.0.co;2-o

Cited by 30 publications

(22 citation statements)

References 21 publications

(15 reference statements)

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“…Control DNA from two biopsy specimens of nasopharyngeal carcinoma and five pellets of peripheral blood cells was taken from the study described by Grunewald et al (12).…”

Section: Methodsmentioning

confidence: 99%

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol)

Arbach

Víglaský

Lefeu

et al. 2006

J Virol

102

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The Epstein-Barr virus (EBV) has been detected in subsets of breast cancers. In order to elaborate on these observations, we quantified by real-time PCR (Q-PCR) the EBV genome in biopsy specimens of breast cancer tissue as well as in tumor cells isolated by microdissection. Our findings show that EBV genomes can be detected by Q-PCR in about half of tumor specimens, usually in low copy numbers. However, we also found that the viral load is highly variable from tumor to tumor. Moreover, EBV genomes are heterogeneously distributed in morphologically identical tumor cells, with some clusters of isolated tumor cells containing relatively high genome numbers while other tumor cells isolated from the same specimen may be negative for EBV DNA. Using reverse transcription-PCR, we detected EBV gene transcripts: EBNA-1 in almost all of the EBV-positive tumors and RNA of the EBV oncoprotein LMP-1 in a smaller subset of the tissues analyzed. Moreover, BARF-1 RNA was detected in half of the cases studied. Furthermore, we observed that in vitro EBV infection of breast carcinoma cells confers resistance to paclitaxel (taxol) and provokes overexpression of a multidrug resistance gene (MDR1). Consequently, even if a small number of breast cancer cells are EBV infected, the impact of EBV infection on the efficiency of anticancer treatment might be of importance.The Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, is associated with the development of different epithelial malignancies (28), including nasopharyngeal carcinoma (NPC). It has also been linked with subsets of other types of carcinomas, including gastric carcinoma and lymphoepithelioma-like carcinoma in salivary glands and thymus (32,44). Several laboratories have reported detection of EBV in a subset of breast tumors (3,10,19,23). However, negative results have also been reported (6,9,14,27). Nevertheless, in most of the studies, a low viral load was detected in breast cancer biopsy specimens but the infected cells were not clearly identified. In the study presented here, we used real-time PCR (Q-PCR) to quantify the copy numbers of the EBV genome in biopsy specimens as well as in microdissected tumor cells. The results show that breast cancer cells harbor the viral genome. However, through microdissection and isolation of pure tumor cells, we now find that even in EBV-positive tumor samples, many tumor cells do not contain EBV genomes and that the breast carcinomas are highly heterogeneous in terms of genome content and distribution. Moreover, using reverse transcription-PCR (RT-PCR), we detected EBNA-1 and BARF-1 transcripts in almost all of the EBV-positive tumors and LMP-1 RNA in 3 of the 15 cases studied. The findings raise the possibility that although EBV is unlikely to have an etiologic role in the genesis of breast cancer, the virus might contribute to tumor progression. Finally, the potential impact of EBV in breast cancer progression was evaluated by estimation of resistance to chemotherapeutic agents on in vitro-infected MDA-MB-231 cells. The resul...

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“…Control DNA from two biopsy specimens of nasopharyngeal carcinoma and five pellets of peripheral blood cells was taken from the study described by Grunewald et al (12).…”

Section: Methodsmentioning

confidence: 99%

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol)

Arbach

Víglaský

Lefeu

et al. 2006

J Virol

102

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“…Previous analyses have focused on the BZLF1 sequence deduced from the B95-8 isolate of EBV (1); using this as a reference sequence, the two variants are A205S (19) and A206S (10). In this study, we sought to determine whether further variants of the multimerization region occur in natural isolates of EBV before exploring biophysically whether BZLF1 is indeed able to form multimers through a coiled-coil interface.…”

mentioning

confidence: 99%

Biophysical Analysis of Natural Variants of the Multimerization Region of Epstein-Barr Virus Lytic-Switch Protein BZLF1

Hicks

Balesaria²,

Medina-Palazon³

et al. 2001

J Virol

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BZLF1 plays a key role in the induction of Epstein-Barr virus (EBV) replication. On the basis of limited sequence homology and mutagenesis experiments, BZLF1 has been described as a member of the bZip family of transcription factors, but this prospect has not been rigorously tested to date. Here, we present biophysical analysis of the multimerization domain of BZLF1, from three natural variants of EBV, and demonstrate for the first time that the region between amino acids 196 and 227 is sufficient to direct folding as a coiled-coil dimer in vitro.BZLF1 (also known as Zebra, Zta, Z, and EB1) is a key component of the machinery that induces the lytic replicative cycle of Epstein-Barr virus (EBV) (3,4,6,22,27). Increased expression of BZLF1 is one of the first events that can be detected following the induction of the lytic cycle in EBVharboring B lymphocytes, and the enforced expression of BZLF1 is sufficient to induce the lytic cycle in cells containing EBV genomes. BZLF1 functions as a transcription factor and activates its own expression and that of a subset of EBV and cellular genes through sequence-specific BZLF1 response elements within their respective promoters. Furthermore, BZLF1 also acts as a replication factor by interacting specifically with the viral lytic origin of replication (23), again through specific BZLF1 response elements (reviewed in references 21 and 24-26). BZLF1 has been previously described as a member of the bZip family (2, 5, 7, 13-15, 20, 25, 28). In support of this conjecture, it has been shown that BZLF1 contains adjacent DNA-binding (approximately residues 175 to 195) and multimerization (approximately residues 196 to 245) regions, and the protein interacts with specific DNA sequence elements (2,5,8,13,15,20,28,30) as a multimer (2,8,15). By analogy with other members of the bZip family, multimerization has been assumed to occur through the folding of a coiled-coil interface within this region (i.e., residues 196 to 245). The analysis of deletion mutants of BZLF1 and mutants containing one or more amino acid substitutions at residues within the proposed coiled-coil interface provided some support for this model (2, 5, 7, 13-15, 20, 25, 28), although there has been disagreement about the influence of some residues (Y200 and L225, for example) on the ability to multimerize (7,12). Therefore, while the results of numerous studies have been consistent with the existence of a coiled-coil interface on BZLF1, the studies have fallen short of rigorously testing the model.To date, three naturally occurring sequence variants within the multimerization domain of BZLF1 have been described. Previous analyses have focused on the BZLF1 sequence deduced from the B95-8 isolate of EBV (1); using this as a reference sequence, the two variants are A205S (19) and A206S (10). In this study, we sought to determine whether further variants of the multimerization region occur in natural isolates of EBV before exploring biophysically whether BZLF1 is indeed able to form multimers through a coiled-coil inte...

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“…This variant carries an L to V mutation in amino acid 88 and a no mutation in amino acid 79 (79V88V variant); thus contributing to the tumorigenesis (80). The BZLF1 gene, which encodes the ZEBRA protein, has been reported to have a serine in place of alanine at the amino acid position 206 in NPC tissues (78). This may again explain the association of EBV with NPC.…”

Section: Ebv Infection In Npcmentioning

confidence: 92%

“…Other studies have shown a higher proportion of LMP1 30-bp deletion is much more common in Inuit population (68%) rather than Chinese (30%) or Caucasians (20%). Distinct variations in C terminal, N terminal and transmembrane region in LMP-1 have been reported using molecular plylogenetic analysis of large panels of EBV isolated from southeast Asia, Papua New Guinea, Africa, and Australia where NPC is not endemic (78,79). The BHRF1 gene, which is a homolog of the bcl-2 oncogene, has been reported to express a particular variant of protein in NPC.…”

Section: Ebv Infection In Npcmentioning

confidence: 99%

Higher incidence of nasopharyngeal carcinoma in some regions in the world confers for interplay between genetic factors and external stimuli

Chattopadhyay

Das

Chatterjee³

et al. 2017

DD&T

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Amino-acid change in the Epstein-Barr-virus zebra protein in undifferentiated nasopharyngeal carcinomas from Europe and North Africa

Cited by 30 publications

References 21 publications

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol)

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol)

Biophysical Analysis of Natural Variants of the Multimerization Region of Epstein-Barr Virus Lytic-Switch Protein BZLF1

Higher incidence of nasopharyngeal carcinoma in some regions in the world confers for interplay between genetic factors and external stimuli

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