Disease relevance of BZLF1

• Also EBV BZLF1/Zta and HHV-8 ORF57 induced PLHV-1 transactivation, but at lower levels [1].
• Expression of EA-D, BZLF1, and BHRF1 was increased in response to both, SAH- and 14-3-3 zeta/PLA2 overexpression indicating the initiation of the EBV lytic cycle [2].
• We found that low concentrations of epigenetic modifying agents, 5-aza-2'-deoxycytidine (5-aza-CdR) or trichostatin A (TSA), induced the expression of BMRF1, BZLF1, and BRLF1 genes, which are found in the lytic form of the virus, in an EBV-positive gastric cancer cell line [3].
• Using gene transfers into Burkitt lymphoma cells, we now demonstrate that rearranged sequences juxtaposed to BZLF1 in het DNA facilitate expression of ZEBRA protein [4].
• Nuclear localization of the immediate early and early gene products BZLF1, BHRF1, BRLF1, and BMLF1 was limited to oral hairy leukoplakia in human immunodeficiency virus-seropositive patients and revealed a codistribution with the virus capsid antigen [5].

High impact information on BZLF1

• DNA methylation promotes gene silencing, yet the Epstein-Barr virus immediate-early protein, BZLF1 (Z), converts the virus from the latent to the lytic form of infection even when the viral genome is highly methylated [6].
• To investigate the factors that control peptide immunogenicity, we have examined the cytotoxic T lymphocyte (CTL) response to a previously undefined epitope ((77)APQPAPENAY(86)) from the BZLF1 protein of Epstein-Barr virus (EBV) [7].
• Here we show that a large fraction of T cells infiltrating affected joints from a patient with chronic rheumatoid arthritis recognizes two EBV transactivators (BZLF1 and BMLF1) in a major histocompatibility complex-restricted fashion [8].
• This work shows that BRLF1 and BZLF1 harbor distinct but complementary functions that influence all stages of viral production [9].
• Whereas the upstream component contains several DNA-binding motifs for the viral activator protein BZLF1, the downstream component is known to be the binding site of several cellular proteins [10].

Chemical compound and disease context of BZLF1

• LY294002 markedly down regulated expression of EBV lytic gene BRLF1 protein Rta, BMRF1 protein EA-D, but not BZLF1 protein ZEBRA [11].
• Using the SNU-719 gastric cancer cell line, which is naturally infected with Epstein-Barr virus, we found that the chemotherapeutic agents, such as 5-fluorouracil, cis-platinum and taxol, induced the expressions of BMRF1, BZLF1 and BRLF1 proteins that are usually found in the lytic form of the virus [12].
• Retinoic acid is a negative regulator of the Epstein-Barr virus protein (BZLF1) that mediates disruption of latent infection [13].
• When Jijoye cells are infected with the BZLF1 or BRLF1 adenovirus vectors in the presence of GCV, viral reactivation is induced, but virus replication is inhibited (thus preventing the release of infectious EBV particles); yet cells are still efficiently killed [14].
• GCV enhanced cell killing by gemcitabine or doxorubicin in lymphoblastoid cells transformed with wild-type EBV, but not in lymphoblastoid cells transformed by a mutant virus (with a deletion in the BZLF1 immediate-early gene) that is unable to enter the lytic form of infection [15].

Biological context of BZLF1

• ZEBRA, the product of the Epstein-Barr virus gene bzlf1, and a member of the AP-1 subfamily of basic zipper (bZIP) transcription factors, is necessary and sufficient to disrupt viral latency and to initiate the viral lytic cycle [16].
• To understand the contribution of cis- and transacting elements involved in DNA replication of oriLyt, a detailed mutational analysis was undertaken which defined BZLF1, a viral transcriptional activator, as an essential replication factor [17].
• One of them, the BZLF1 open reading frame (ORF)-encoded product EB1, is able to induce the productive cycle in infected B cells [18].
• This correlates with the ability of CsA to inhibit Ca2+-dependent transcription of the lytic cycle switch gene BZLF1 [19].
• Gel retardation and DNase footprinting assays using these proteins show that BZLF1 is a sequence specific DNA binding protein capable of binding to a target sequence which contains a consensus AP-1 site [20].

Anatomical context of BZLF1

• The cellular oncogene c-myb can interact synergistically with the Epstein-Barr virus BZLF1 transactivator in lymphoid cells [21].
• Overexpression of ZEBRA, the product of BZLF1, is sufficient to disrupt latency in B lymphocytes and epithelial cells by stimulating expression of lytic cycle genes, including BRLF1 [22].
• Cell cycle analysis revealed that while BZLF1 dramatically blocked G(1)/S progression in normal human fibroblasts, it did not significantly affect cell cycle progression in primary human tonsil keratinocytes [23].
• We demonstrate that supernatants from early-passage LCLs infected with BZLF1-deleted virus (Z-KO LCLs) are highly impaired in promoting endothelial cell tube formation in vitro compared to wild-type (WT) LCL supernatants [24].
• Here we demonstrate that BZLF1 induces both a G(2) block and a mitotic block in HeLa cells and inhibits chromosome condensation [25].

Associations of BZLF1 with chemical compounds

• BZLF1 protein and gp350/250 immunoreactivity was absent in all instances [26].
• Despite differences between PY motif mutant LCLs and wild-type LCLs, the PY motif mutants still exhibited a block in B-cell receptor (BCR) signal transduction as measured by the induction of tyrosine phosphorylation and BZLF1 expression following BCR activation [27].
• The BZLF1-induced changes in promoter-directed chloramphenicol acetyltransferase activity occur in EBV-negative as well as EBV-positive cell lines and are accompanied by a similar change in chloramphenicol acetyltransferase mRNA [28].
• Gemcitabine and doxorubicin both activated transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBV-negative B cells [15].
• In transcriptional reporter assays, S186 is essential for the activation of BZLF1 by TPA [29].

Physical interactions of BZLF1

• This effect required the EGR-1 motif in the BRLF1 promoter and the CRE (ZII) and MEF-2D (ZI) binding sites in the BZLF1 promoter [15].
• In cells in which EBV was lytically replicating, BFRF3 protein was coimmunoprecipitated together with ZEBRA by a rabbit antiserum directed against amino acids 197 to 245 of BZLF1 [30].
• (iv) BZLF1 was specifically coimmunoprecipitated with BGLF4 in 12-O-tetradecanoylphorbol-13-acetate-treated B95-8 cells and in COS-1 cells transiently expressing both of these viral proteins [31].

Enzymatic interactions of BZLF1

• Epstein-Barr virus protein kinase BGLF4 is a virion tegument protein that dissociates from virions in a phosphorylation-dependent process and phosphorylates the viral immediate-early protein BZLF1 [31].

Regulatory relationships of BZLF1

• Induction of the Epstein-Barr virus lytic cycle is mediated through the immediate-early BZLF1 gene and the coordinately regulated BRLF1 gene [32].
• In contrast, BZLF1-induced activation of the BMRF1 promoter is inhibited in the presence of the BMRF1 gene product [33].
• A few EBV-infected B cells expressed BZLF1 (an EBV immediate-early gene product) while none expressed EBNA-2 or latent membrane protein 1 [34].
• Tyrosine phosphorylation, calcium mobilization, and induction of BZLF1 expression were no longer blocked in the LMP2A ITAM mutant LCLs following BCR cross-linking [35].

Other interactions of BZLF1

• IgA antibodies in primary infection were directed against the Bam Z Epstein-Barr replication activator (ZEBRA) (BZLF1) and diffuse EA (BMRF1) EAs [36].
• Furthermore, we detected transcripts for BZLF1 in 72% and for BALF2 in 16% of peripheral B lymphocytes of healthy seropositive donors [37].
• RESULTS: BZLF1 (ZEBRA) or early gene products (EA-R and EA-D/BHLF1/NotI) were detected in a small proportion (< 0.01-5%) of tumour cells in eight of these 17 cases by immunohistochemistry and in situ hybridization [38].
• The rabbit antiserum to amino acids 197 to 245 of BZLF1 was found to detect the same epitope at the carboxy end of BFRF3 as was recognized by rabbit antiserum to BFRF3 itself [30].
• The detection of BZLF1, BALF2, and BcLF1 mRNA expression suggests that the lytic cycle is initiated at early time points postinfection [39].

Analytical, diagnostic and therapeutic context of BZLF1

• The Epstein-Barr virus (EBV) immediate early gene product BZLF1 was localized by indirect immunofluorescence to the cytoplasm of the basal epithelial layer at the lateral border and dorsum of tongue in human immunodeficiency virus-infected and -seronegative patients [5].
• By immunohistochemistry, two cases were positive for EBV nuclear antigen (EBNA)-1 (5%), one was positive for the transactivating immediate early BZLF1 (ZEBRA) (2%), and none was positive for latent membrane protein-1 [40].
• Site-directed mutagenesis of this DNA target suggests that BZLF1 may work partly by overcoming a cellular repressor of viral transcription [41].
• However, induction of only Fos by BZLF1 was observed in a gel mobility shift assay using an oligonucleotide probe containing the TRE sequence and the antibody against Fos protein [42].
• We found that transfection of the EBV BZLF1 gene causes the disappearance of EBNA proteins on Western blots (immunoblots) [43].

References