Mitogenic activity of Epstein–Barr virus-encoded BARF1 protein

Sall, Alhousseynou; Caserta, Sophie; Jolicœur, Pierre; Franqueville, Laure; Turenne-Tessier, Mireille de; Ooka, Tadamasa

doi:10.1038/sj.onc.1207607

Cited by 39 publications

(45 citation statements)

References 18 publications

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“…As the secreted BARF1 was shown to possess mitogenic activities, the functionally active BARF1 protein may be monomeric when analyzed by denaturing SDS-PAGE under both reducing and nonreducing conditions. This is consistent with the reported results (Sall et al, 2004;De TurenneTessier et al, 2005). However, the secreted BARF1 protein was demonstrated to be in the macromolecular state with a molecular mass in the range of 150-240 kDa under native conditions (De Turenne-Tessier et al, 2005).…”

Section: Discussionsupporting

confidence: 83%

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Biochemical and functional characterization of Epstein–Barr virus-encoded BARF1 protein: interaction with human hTid1 protein facilitates its maturation and secretion

2006

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EBV BARF1 gene encodes a secretory protein with transforming and mitogenic activities. In this report, the post-translational modification, folding, maturation and secretion of BARF1 are systematically studied by sitedirected mutagenesis and overexpression of the protein in mammalian cells using the vaccinia/T7 system. The protein was shown to be post-translationally modified by N-linked glycosylation on the asparagine 95 residue. This modification was confirmed to be essential for the maturation and secretion of the protein. Analysis of the four cysteine residues by site-directed mutagenesis demonstrated that cysteine 146 and 201 were essential for proper folding and secretion of the protein. To search for human proteins involved in the maturation process of the protein, a yeast two-hybrid screening was carried out using the BARF1 sequence from amino acids 21-221 (BARF1D) as bait, leading to the identification of human hTid1 protein as a potential interacting protein. This interaction was subsequently confirmed by coimmunoprecipitation and dual immunofluorescent labeling of cells coexpressing BARF1 and hTid1, and the interaction domain in hTid1 was mapped to amino acids 149-320. Interestingly, coexpression of BARF1 with hTid1 demonstrated that hTid1 could promote secretion of BARF1, suggesting that hTid1 may act as a chaperone to facilitate the folding, processing and maturation of BARF1.

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Section: Discussionsupporting

confidence: 83%

“…It suggests that BARF1 may be expressed as a latent gene in these carcinoma tissues. The secreted form of BARF1 can act as a growth factor in vivo (Sall et al, 2004). It could inhibit alpha-interferon secretion from mononuclear cells (Cohen and Lekstrom, 1999) and has mitogenic activity in vivo (Sall et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Biochemical and functional characterization of Epstein–Barr virus-encoded BARF1 protein: interaction with human hTid1 protein facilitates its maturation and secretion

2006

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“…Therefore, BARF1 likely plays an important role in epithelial oncogenesis. BARF1 protein, a hexamer oligomeric structure as determined by crystallography study (29), acts as a powerful mitogen (30). The BARF1 protein can complex in vitro with colony-stimulating factor 1, resulting in the inhibition of macrophage activation (31), and can also inhibit the secretion of IFN-a in EBV-infected B cells (32).…”

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confidence: 99%

A New Diagnostic Marker for Secreted Epstein-Barr Virus–Encoded LMP1 and BARF1 Oncoproteins in the Serum and Saliva of Patients with Nasopharyngeal Carcinoma

Houali

Wang

Shimizu

et al. 2007

Clinical Cancer Research

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116

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Purpose: EBV has been associated with nasopharyngeal carcinomas (NPC). In North Africa, the incidence is bimodalöthe first peak occurring at f20 years of age and the second peak occurring at f50 years. Standard diagnostic tests based on immunofluorescence using anti-IgA EBV have shown that young North African patients have a negative serology compared with older patients.We are interested in two EBV-encoded oncoproteins, LMP1and BARF1, which have thus far not been studied in terms of their potential as diagnostic markers for NPC. These two viral oncoproteins have been detected in cell culture media, so we tested whether they could be detected in the serum and saliva of patients with NPC. Experimental Design: LMP1 and BARF1 proteins were analyzed in the sera and saliva of young patients and adult patients with NPC from North Africa and China. We then examined whether the secreted proteins had biological activity by analyzing their mitogenic activity. Results: Both LMP1 and BARF1 were present in the serum and saliva from North African and Chinese patients with NPC. All young North African patients secreted both proteins, whereas 62% and 100% of adult patients secreted LMP1 and BARF1, respectively. From animal studies, the secreted LMP1was associated with exosome-like vesicles. These secreted EBV oncoproteins showed a powerful mitogenic activity in B cells. Conclusion: Both proteins will be a good diagnostic marker for NPC whereas BARF1is a particularly promising marker for all ages of patients with NPC. Their mitogenic activity suggests their implication in the oncogenic development of NPC. Nasopharyngeal carcinoma (NPC) is a human malignancyderived from the epithelium of the nasopharyngeal cavity. It is one of the most striking examples of a human malignancy that is consistently associated with a virus (1 -3). The EBV genome is contained in all malignant NPC cells and it encodes viral proteins that contribute to the malignant phenotype (4 -6). Even though infection with EBV is ubiquitous in humans, the incidence of NPC is extremely variable, depending on the geographic area. Whereas the incidence of NPCs in the Chinese population peaks at f50 years of age, there are two peaks of incidence in North Africa-one at f20 years of age and the second at f50 years of age (6). Because of the close association of EBV with NPC, detection of EBV anti-IgA, anti-EA, or anti-VCA by immunofluorescence tests in serum from patients with NPC is used in most Asian countries. However, this test is almost always negative for young North African patients (6). Recent data showed a successful diagnosis of NPC by molecular serology based on EBV-encoded proteins, DNase, thymidine kinase, and p16 VCA used as viral antigens (7 -10). Virus load in patient blood has been used as a diagnostic marker for NPC (11,12), but high levels have been reported in nonneoplastic disorders, gastrointestinal malignancies, and for lymphoproliferative disease (13,14). We therefore need a more reliable, simpler, and specific diagnostic test for NPC.Seve...

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“…10,15 BARF1 has transforming activity in vitro and in vivo. [16][17][18] BARF1 encodes a 33 kDa type-II membrane protein that can be cleaved after amino acid 20 to release a soluble 29 kDa fragment with mitogenic activity, whereas the remaining transmembrane domain increases bcl-2 expression, thus contributing to cell growth and survival. Recent reports further substantiated that BARF1 protein is rapidly and efficiently secreted by epithelial cells.…”

mentioning

confidence: 99%

“…Recent reports further substantiated that BARF1 protein is rapidly and efficiently secreted by epithelial cells. [19][20][21] Currently, diagnosis of WHO type III NPC requires a biopsy from the primary tumour site or metastases for histopathological assessment and demonstration of EBV involvement by in situ hybridisation for EBER1/2. Even at the early stages of NPC, patients are characterised by aberrant serological responses to EBV compared to healthy EBV-carriers.…”

mentioning

confidence: 99%

Noninvasive diagnosis of nasopharyngeal carcinoma: Nasopharyngeal brushings reveal high Epstein‐Barr virus DNA load and carcinoma‐specific viral BARF1 mRNA

Stevens

Verkuijlen

Hariwiyanto

et al. 2006

Intl Journal of Cancer

106

130

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Nasopharyngeal carcinoma (NPC) is the most prevalent ENTtumour in Indonesia. We investigated the primary diagnostic value of Epstein-Barr virus (EBV) DNA load and mRNA detection in noninvasive nasopharyngeal (NP) brushings, obtained prospectively from consecutive Indonesian ENT-patients with suspected NPC (N 5 106) and controls. A subsequent routine NP biopsy was taken for pathological examination and EBER-RISH, yielding 85 confirmed NPC and 21 non-NPC tumour patients. EBV DNA and human DNA load were quantified by real-time PCR. NP brushings from NPC patients contained extremely high EBV DNA loads compared to the 88 non-NPC controls (p < 0.0001). Using mean EBV DNA load in controls plus 3 SD as cut-off value, specificity, sensitivity, positive and negative predictive values were 98, 90, 97 and 91%, respectively. Epstein-Barr nuclear antigen 1 (EBNA1) and the carcinoma-specific BARF1 mRNA were detected by nucleic acid sequence based amplification and found in 86 and 74% of NP brushings, confirming NPC tumour cell presence. EBV RNA positivity was even higher in fresh samples stored at 280°C until RNA expression analyses (88% for both EBNA1 and BARF1). EBV RNA-negative NP brushings from proven NPC cases had the lowest EBV DNA loads, indicating erroneous sampling. No EBV mRNA was detected in NP brushings from healthy donors and non-NPC patients. In conclusion, EBV DNA load measurement combined with detection of BARF1 mRNA in simple NP brushings allows noninvasive NPC diagnosis. It reflects carcinoma-specific EBV involvement at the anatomical site of tumour development and reduces the need for invasive biopsies. This procedure may be useful for confirmatory diagnosis in large serological NPC screening programs and has potential as prognostic tool. ' 2006 Wiley-Liss, Inc.Key words: EBV; NPC; diagnosis; viral load; oncogene; carcinoma Undifferentiated nasopharyngeal carcinoma (NPC WHO type III) is virtually 100% associated with Epstein-Barr virus (EBV) and has a reported high incidence in most of South-East Asia and intermediate incidence in North-African populations and in Inuit. [1][2][3] In Indonesia, with an ethnically diverse population of 225 million people, NPC is the most common ENT tumour with high prevalence among native populations and a yearly overall incidence estimated at 6.2/100,000. 4 Extremely high incidence was recently documented in native populations living on the island of Sulawesi. 5 In Yogyakarta, Central Java, NPC is the most prevalent tumour among man and 4th most prevalent among females, with a male/female ratio of 2.4, constituting respectively 22 and 8% of all diagnosed malignancies. 4 The strong etiological link between EBV and NPC has been known for over 3 decades [1][2][3]6 and is reflected by abnormal anti-EBV antibody profiles, increased circulating EBV DNA levels and by distinct EBV gene expression in the tumour cells. 7-11 Classically, NPC is considered to have a latency type 2 EBV transcription, with expression of EBV-encoded small RNAs 1 and 2 (EBER1/2), BamHI A rightward transcript...

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Mitogenic activity of Epstein–Barr virus-encoded BARF1 protein

Cited by 39 publications

References 18 publications

Biochemical and functional characterization of Epstein–Barr virus-encoded BARF1 protein: interaction with human hTid1 protein facilitates its maturation and secretion

Biochemical and functional characterization of Epstein–Barr virus-encoded BARF1 protein: interaction with human hTid1 protein facilitates its maturation and secretion

A New Diagnostic Marker for Secreted Epstein-Barr Virus–Encoded LMP1 and BARF1 Oncoproteins in the Serum and Saliva of Patients with Nasopharyngeal Carcinoma

Noninvasive diagnosis of nasopharyngeal carcinoma: Nasopharyngeal brushings reveal high Epstein‐Barr virus DNA load and carcinoma‐specific viral BARF1 mRNA

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