Epstein-Barr Virus-Encoded Bcl-2 Homologue Functions as a Survival Factor in Wp-Restricted Burkitt Lymphoma Cell Line P3HR-1

Watanabe, Ayano; Maruo, Seiji; Ito, Taku; Ito, Miho; Katsumura, Koichi R.; Takada, Kenzo

doi:10.1128/jvi.01616-09

Cited by 33 publications

(34 citation statements)

References 46 publications

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“…uk). Notably, however, the Wp-restricted BLs are considerably more resistant to apoptosis in vitro than latency I BLs, through the effects of the BCL2 homologue BHRF1, combined with the EBNA3s and other factors acting on pro-apoptotic proteins including BIM and NOXA Kelly et al 2009;Vereide and Sugden 2011;Watanabe et al 2010;Yee et al 2011). This increased robustness of the Wp-restricted BL may have implications for treatment strategies and success, but this has not yet been tested.…”

Section: Ebna3s In B Cell Lymphomagenesismentioning

confidence: 97%

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells

Allday

Bazot

White

2015

Current Topics in Microbiology and Immunology

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Epstein-Barr virus nuclear antigens EBNA3A , EBNA3B and EBNA3C are a family of three large latency-associated proteins expressed in B cells induced to proliferate by the virus. Together with the other nuclear antigens (EBNA-LP, EBNA2 and EBNA1), they are expressed from a polycistronic transcription unit that is probably unique to B cells. However, compared with the other EBNAs, hitherto the EBNA3 proteins were relatively neglected and their roles in EBV biology rather poorly understood. In recent years, powerful new technologies have been used to show that these proteins are central to the latency of EBV in B cells, playing major roles in reprogramming the expression of host genes affecting cell proliferation, survival, differentiation and immune surveillance. This indicates that the EBNA3s are critical in EBV persistence in the B cell system and in modulating B cell lymphomagenesis. EBNA3A and EBNA3C are necessary for the efficient proliferation of EBV-infected B cells because they target important tumour suppressor pathways--so operationally they are considered oncoproteins. In contrast, it is emerging that EBNA3B restrains the oncogenic capacity of EBV, so it can be considered a tumour suppressor--to our knowledge the first to be described in a tumour virus. Here, we provide a general overview of the EBNA3 genes and proteins. In particular, we describe recent research that has highlighted the complexity of their functional interactions with each other, with specific sites on the human genome and with the molecular machinery that controls transcription and epigenetic states of diverse host genes.

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Section: Ebna3s In B Cell Lymphomagenesismentioning

confidence: 97%

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells

Allday

Bazot

White

2015

Current Topics in Microbiology and Immunology

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“…In addition to its antiapoptotic role in EBV replication, BHRF1 protein may have a role in initial cell transformation (2) or in the pathogenesis of Wp-restricted Burkitt lymphomas (28,55). The expression of BHRF1 protein has been confirmed in a subset of Burkitt lymphomas (28).…”

Section: Discussionmentioning

confidence: 87%

cis -Acting Effects on RNA Processing and Drosha Cleavage Prevent Epstein-Barr Virus Latency III BHRF1 Expression

Xing¹,

Kieff²

2011

J Virol

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In Epstein-Barr virus (EBV) latency III (LTIII) infection, BHRF1 encodes three microRNAs (miRNAs).Herein we report that Drosha cleavage of LTIII BHRF1 RNA and cis-acting splicing effects inhibit splicing and inhibit BHRF1 RNA and protein expression. Evidence shown here supports the view that Drosha cleavage to generate mature miRNAs and cis-acting sequences that prevent mRNA maturation are independent processes that prevent LTIII BHRF1 expression in lymphoblastoid cell lines.Eukaryotic RNA polymerase II (RNAP II) synthesizes premessenger RNAs (pre-mRNAs), which usually contain multiple exons and introns. Pre-mRNAs undergo processing steps, including 5Ј capping, 3Ј polyadenylation, and splicing to remove introns in the nucleus prior to transport to the cytoplasm for translation. These RNA-processing steps are coordinated and coupled to RNAP II transcription (37,40,45).MicroRNAs (miRNAs) are a class of approximately 22-nucleotide (nt) small noncoding RNAs which regulate protein expression in eukaryotes (5,9,20,30). Mature miRNA is processed largely from RNAP II 5Ј-capped and 3Ј-polyadenylated primary RNA (pri-miRNA) (6, 36). The pri-miRNA is cleaved in the nucleus by an RNase III enzyme, Drosha, and other interacting proteins, such as DGCR8 (23,35), to release an approximately 70-nt hairpin pre-miRNA, which is exported into the cytoplasm and processed by the RNase III enzyme Dicer complex (11,25) to produce an approximately 22-nt duplex (16). In addition to canonical pre-mRNA processing in the nucleus, Drosha cleavage occurs on pre-mRNAs that encode miRNA as well as protein. This noncanonical processing occurs on transcripts encoding miRNAs in introns or on the independently transcribed miRNA-coding transcripts (4,19,31,42). However, for RNA transcripts that encode miRNAs in exons, the correlation of Drosha cleavage with canonical premRNA processing steps, mRNA accumulation, and encoded protein expression is not clear.Epstein-Barr virus (EBV), a human gammaherpesvirus, establishes latency III (LTIII) infection in B lymphocytes (29), causing infected cell proliferation into lymphoblastoid cell lines (LCLs) in vitro or lymphoproliferative diseases in vivo (29,50). In LTIII infection, EBV expresses LTIII BHRF1 RNA that encodes three BHRF1 miRNAs (miR-BHRF1-1, miR-BHRF1-2, and miR-BHRF1-3) (7, 47). LTIII BHRF1 RNA is distinct from the EBV replication-associated 1.4-kb BHRF1 mRNA that is fully spliced and initiated by the virus replication-activated BHRF1 promoter (15). LTIII BHRF1 RNA has a long 5Ј-untranslated region (UTR) and is not spliced (3,44,48). Transcripts from the Cp or Wp promoter initiate alternatively spliced EBNA transcripts in LTIII infection and can be polyadenylated after the BHRF1 3Ј-UTR to produce LTIII BHRF1 RNAs (29). miR-BHRF1-1 is in the 5Ј-UTR of the LTIII BHRF1 mRNA and overlaps the TATA box of the EBV replication-activated BHRF1 promoter (15), whereas miR-BHRF1-2 and miR-BHRF1-3 are located in the 3Ј-UTR. While the BHRF1 miRNAs are produced in LTIII infection (57), BHRF1 protein has not been ...

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“…8 This led to the discovery that BHRF1 is expressed at low levels in wild-type EBV-infected, latent Burkitt lymphoma cells and is important in preventing apoptosis triggered by aberrant cell proliferation signals from constitutive c-myc expression. 8,9 The function of KSBcl-2, the KSHV viral Bcl-2, in oncogenesis or infection is less clear, but this protein may also act to counteract apoptosis driven by cell proliferation signals, in this case by a viral cyclin. 10,11 KSBcl-2 has been shown to be important for the initial stages of lytic reactivation from latent infection.…”

Section: Introductionmentioning

confidence: 99%

Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins

Foight

Keating

2015

Journal of Molecular Biology

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Viral homologs of the anti-apoptotic Bcl-2 proteins are highly diverged from their mammalian counterparts, yet they perform overlapping functions by binding and inhibiting BH3 motif-containing proteins. We investigated the BH3 binding properties of the herpesvirus Bcl-2 homologs KSBcl-2, BHRF1, and M11, as they relate to those of the human Bcl-2 homologs Mcl-1, Bfl-1, Bcl-w, Bcl-xL, and Bcl-2. Analysis of the sequence and structure of the BH3 binding grooves showed that, despite low sequence identity, M11 has structural similarities to Bcl-xL, Bcl-2, and Bcl-w. BHRF1 and KSBcl-2 are more structurally similar to Mcl-1 than to the other human proteins. Binding to human BH3-like peptides showed that KSBcl-2 has similar specificity to Mcl-1, and BHRF1 has a restricted binding profile; M11 binding preferences are distinct from those of Bcl-xL, Bcl-2 and Bcl-w. Because KSBcl-2 and BHRF1 are from human herpesviruses associated with malignancies, we screened computationally designed BH3 peptide libraries using bacterial surface display to identify selective binders of KSBcl-2 or BHRF1. The resulting peptides bound to KSBcl-2 and BHRF1 in preference to Bfl-1, Bcl-w, Bcl-xL, and Bcl-2, but showed only modest specificity over Mcl-1. Rational mutagenesis increased specificity against Mcl-1, resulting in a peptide with a dissociation constant of 2.9 nM for binding to KSBcl-2 and >1000-fold specificity over human Bcl-2 proteins, and a peptide with >70-fold specificity for BHRF1. In addition to providing new insights into viral Bcl-2 binding specificity, this study will inform future work analyzing the interaction properties of homologous binding domains and designing specific protein interaction partners.

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Epstein-Barr Virus-Encoded Bcl-2 Homologue Functions as a Survival Factor in Wp-Restricted Burkitt Lymphoma Cell Line P3HR-1

Abstract: Burkitt lymphoma (BL) is etiologically associated with Epstein-Barr virus (EBV).

Cited by 33 publications

References 46 publications

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells

cis -Acting Effects on RNA Processing and Drosha Cleavage Prevent Epstein-Barr Virus Latency III BHRF1 Expression

Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins

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