bZIP proteins of human gammaherpesviruses

Sinclair, Alison J.

doi:10.1099/vir.0.19112-0

Cited by 81 publications

(96 citation statements)

References 74 publications

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“…B cells from the same donor were also infected with supernatants from the B95. 1999; Lieberman & Berk, 1991Sinclair, 2003;Wu et al, 2003;Zerby et al, 1999;Zhang et al, 1994). In addition, BZLF1 expression may affect cell growth by inducing lytic infection in cells harbouring EBV.…”

Section: Discussionmentioning

confidence: 99%

“…The BZLF1 protein is a member of the basic leucine zipper (bZIP) family of transcription factors and functions as a transactivator by binding to the BZLF1-responsive element (ZRE) in its target promoters (Chang et al, 1990;Farrell et al, 1989;Feederle et al, 2000;Flemington et al, 1992;Sinclair, 2003). BZLF1 plays critical roles in the replication of the EBV genome by binding to the origin of lytic replication, as well as by inducing viral genes that function as the viral replication machinery, such as BALF5, a DNA polymerase, and BMRF1, a processivity factor (Tsurumi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, BZLF1 expression causes transcription of many viral genes and replication of the EBV genome, and results in production of progeny virus . BZLF1 also upregulates several cellular genes whose promoters contain ZRE, such as c-fos, EGR-1, DHRS9, Flemington & Speck, 1990;Hsu et al, 2008;Jones et al, 2007a;Mahot et al, 2003), and interacts with and interferes with the function of several cellular proteins, such as p53, CREB-binding protein, CEBPa and the basic transcriptional machinery (Adamson & Kenney, 1999;Lieberman & Berk, 1991Sinclair, 2003;Wu et al, 2003;Zerby et al, 1999;Zhang et al, 1994). For example, BZLF1 attenuates transactivation by p53 and transactivation by CREB (Adamson & Kenney, 1999;Zhang et al, 1994).…”

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Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Katsumura

Maruo

et al. 2009

Journal of General Virology

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The Epstein-Barr virus (EBV) immediate-early transactivator BZLF1 plays a key role in switching EBV infection from the latent to the lytic form by stimulating the expression cascade of lytic genes; it also regulates the expression of several cellular genes. Recently, we reported that BZLF1 is expressed in primary human B cells early after EBV infection. To investigate whether this BZLF1 expression early after infection plays a role in the EBV-induced growth transformation of primary B cells, we generated BZLF1-knockout EBV and quantitatively evaluated its transforming ability compared with that of wild-type EBV. We found that the 50 % transforming dose of BZLF1-knockout EBV was quite similar to that of wild-type EBV. Established lymphoblastoid cell lines (LCLs) harbouring BZLF1-knockout EBV were indistinguishable from LCLs harbouring wild-type EBV in their pattern of latent gene expression and in their growth in vitro. Furthermore, the copy numbers of EBV episomes were very similar in the LCLs harbouring BZLF1-knockout EBV and in those harbouring wild-type EBV. These data indicate that disrupting BZLF1 expression in the context of the EBV genome, and the resultant inability to enter lytic replication, have little impact on the growth of LCLs and the steady-state copy number of EBV episomes in established LCLs. INTRODUCTIONEpstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that is associated with various malignancies, including Burkitt's lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma and gastric carcinoma . EBV efficiently infects primary B lymphocytes, transforming them into indefinitely proliferating lymphoblastoid cell lines (LCLs) in vitro and causing lymphoproliferative diseases in immune-deficient individuals in vivo .LCLs harbour multiple copies of the EBV episome, from which EBV expresses latent gene products, including six nuclear proteins (EBNA1, -2, -3A, -3B, -3C and -LP), three integral membrane proteins (LMP1, -2A and -2B), two small non-polyadenylated RNAs (EBER1 and EBER2), BamHI-A rightward transcripts and microRNAs. Of these, EBNA1, -2, -3A, -3C and -LP, LMP1 and EBER2 are necessary for efficient growth transformation (Cohen et al., 1989;Hammerschmidt & Sugden, 1989;Humme et al., 2003;Kaye et al., 1993;Mannick et al., 1991;Maruo et al., 2003Maruo et al., , 2006Tomkinson et al., 1993;Wu et al., 2007;Yajima et al., 2005).The viral gene BZLF1 encodes a key protein that switches EBV infection from the latent to the lytic form (Countryman & Miller, 1985;Takada et al., 1986). The BZLF1 protein is a member of the basic leucine zipper (bZIP) family of transcription factors and functions as a transactivator by binding to the BZLF1-responsive element (ZRE) in its target promoters (Chang et al., 1990;Farrell et al., 1989;Feederle et al., 2000;Flemington et al., 1992;Sinclair, 2003). BZLF1 plays critical roles in the replication of the EBV genome by binding to the origin of lytic replication, as well as by inducing viral genes that function as the viral replication machinery, such as BALF5...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Katsumura

Maruo

et al. 2009

Journal of General Virology

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“…Routes by which Zta activates gene expression have been documented for both viral and host promoters. Many promoters are targeted by the interaction of the sequence-specific DNA-binding domain of Zta with sequence-specific 7 nt DNA elements, termed ZREs (Adamson & Kenney, 1999;Bergbauer et al, 2010;Bhende et al, 2004Bhende et al, , 2005Broderick et al, 2009;Dickerson et al, 2009;Flower et al, 2011;Holley-Guthrie et al, 1990;Kalla et al, 2012Kalla et al, , 2010Karlsson et al, 2008;Kenney et al, 1989;Ramasubramanyan et al, 2012a, b;Sinclair, 2003;Sinclair et al, 1991;Woellmer et al, 2012). At least 32 distinct ZRE sequence variants are specifically recognized by Zta (Flower et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Repression of CIITA by the Epstein–Barr virus transcription factor Zta is independent of its dimerization and DNA binding

Balan

Osborn

Sinclair

2016

Journal of General Virology

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Repression of the cellular CIITA gene is part of the immune evasion strategy of the cherpes virus Epstein-Barr virus (EBV) during its lytic replication cycle in B-cells. In part, this is mediated through downregulation of MHC class II gene expression via the targeted repression of CIITA, the cellular master regulator of MHC class II gene expression. This repression is achieved through a reduction in CIITA promoter activity, initiated by the EBV transcription and replication factor, Zta (BZLF1, EB1, ZEBRA). Zta is the earliest gene expressed during the lytic replication cycle. Zta interacts with sequence-specific elements in promoters, enhancers and the replication origin (ZREs), and also modulates gene expression through interaction with cellular transcription factors and co-activators. Here, we explore the requirements for Zta-mediated repression of the CIITA promoter. We find that repression by Zta is specific for the CIITA promoter and can be achieved in the absence of other EBV genes. Surprisingly, we find that the dimerization region of Zta is not required to mediate repression. This contrasts with an obligate requirement of this region to correctly orientate the DNA contact regions of Zta to mediate activation of gene expression through ZREs. Additional support for the model that Zta represses the CIITA promoter without direct DNA binding comes from promoter mapping that shows that repression does not require the presence of a ZRE in the CIITA promoter.

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“…In some microenvironments, EBNA1 is thought to suppress cell death (Kennedy et al, 2003). BARF1 and BZLF1, encoding viral transcription factors, switch the infection from latent to lytic phase (Feederle et al, 2000;Sinclair, 2003). EBV-expressed microRNAs (miRNAs) play a crucial role in development, the cell cycle, and immunity and contribute to cancerassociated pathology (Lee and Dutta, 2009;Forte and Luftig, 2011).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Mao

2013

J. Zhejiang Univ. Sci. B

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Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world's population, is associated with malignant tumors such as Burkitt's lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

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bZIP proteins of human gammaherpesviruses

Cited by 81 publications

References 74 publications

Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Repression of CIITA by the Epstein–Barr virus transcription factor Zta is independent of its dimerization and DNA binding

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

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