Co-localization of the retinoblastoma protein and the epstein-barr virus-encoded nuclear antigen EBNA-5

Jiang, Wei‐Qin; Szekeres, L.; Wendel-Hansen, Vidar; Ringertz, Nils R.; Klein, George; Rosén, Anders

doi:10.1016/0014-4827(91)90438-z

Cited by 55 publications

(36 citation statements)

References 21 publications

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“…In contrast, it was found that EBNA1 proteins were distributed diffusely in nuclei throughout the cell cycle with a fine granular pattern (Fig. 5), in line with the diffuse punctate localization in the nuclei of interphase cells reported earlier (37). As shown in Fig.…”

Section: Ebna1 Binds To the Orip Region During Lytic Replication Andsupporting

confidence: 82%

In Vivo Dynamics of EBNA1-oriP Interaction during Latent and Lytic Replication of Epstein-Barr Virus

Daikoku

Kudoh

Fujita

et al. 2004

Journal of Biological Chemistry

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The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is required for maintenance of the viral genome DNA during the latent phase of EBV replication but continues to be synthesized after the induction of viral productive replication. An EBV genome-wide chromatin immunoprecipitation assay revealed that EBNA1 constantly binds to oriP of the EBV genome during not only latent but also lytic infection. Although the total levels of EBNA1 proved constant throughout the latter, the levels of the oriP-bound form were increased as lytic infection proceeded. EBV productive DNA replication occurs at discrete sites in nuclei, called replication compartments, where viral replication proteins are clustered. Confocal laser microscopic analyses revealed that whereas EBNA1 was distributed broadly in nuclei as fine punctate dots during the latent phase of infection, the protein became redistributed to the viral replication compartments and localized as distinct spots within and/or nearby the compartments after the induction of lytic replication. Taking these findings into consideration, oriP regions of the EBV genome might be organized by EBNA1 into replication domains that may set up scaffolding for lytic replication and transcription.The Epstein-Barr virus (EBV) 1 is a human herpes virus that infects 90% of individuals. Primary EBV infection targets resting B lymphocytes, inducing their continuous proliferation. In the B lymphoblastoid cell lines, only limited numbers of viral genes are usually expressed and there is no production of virus particles, this being called latent infection. In the latent state, EBV maintains its 170-kbp genome as complete, multiple copies of plasmids. Latent phase viral replication appears to faithfully mimic cellular replicons; the EBV genomes or small EBNA1-oriP plasmids are synthesized only once in each Sphase by the host cell replication machinery, following the rules of chromosome replication (1).EBV-infected cell lines usually contain a small subpopulation of cells that have switched spontaneously from a latent stage of infection into the lytic cycle. The mechanism of switching is not fully understood, but one of the first detectable changes is expression of the BZLF1 gene product. The BZLF1 protein, together with the protein product of the BRLF1 gene, transactivates viral and certain cellular promoters (2) and leads to an ordered cascade of viral gene expression. The lytic phase of EBV DNA replication is dependent on seven viral replication proteins: BZLF1, an oriLyt-binding protein; BALF5, a DNA polymerase; BMRF1, a polymerase processivity factor; BALF2, a single-stranded DNA-binding protein; and BBLF4, BSLF1, and BBLF2/3, predicted to be helicase-, primase-, and helicase-primase-associated proteins, respectively (3). All of these proteins except for BZLF1 conceivably work together at replication forks to synthesize leading and lagging strands of the concatemeric EBV genome (4). Interestingly, viral lytic replication occurs in discrete sites in nuclei called replication compartments in which...

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Section: Ebna1 Binds To the Orip Region During Lytic Replication Andsupporting

confidence: 82%

In Vivo Dynamics of EBNA1-oriP Interaction during Latent and Lytic Replication of Epstein-Barr Virus

Daikoku

Kudoh

Fujita

et al. 2004

Journal of Biological Chemistry

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“…EBNA-LP (also known as EBNA-5) is one of the first genes to be expressed upon viral infection and cooperates with EBNA-2 to drive the resting B lymphocyte into the G1 phase of the cell cycle (Sinclair et al, 1994). Immunofluorescence analysis has shown that EBNA-LP colocalizes accurately with pRb in nuclear dots in LCLs (Jiang et al, 1991) and EBNA-LP has been shown to associate with pRb in vitro using bacterial fusion proteins or in vitro-translated material (Szekely et al, 1993). The characteristics of this association were different from the binding of other pocket-binding proteins in that binding was prevented by an HPV E7 peptide corresponding to the pocket-binding site but was not affected by a pocket mutation of pRb that prevents other pocket-binding proteins associating.…”

Section: Introductionmentioning

confidence: 99%

Epstein--Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays

Inman

Farrell

1995

Journal of General Virology

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The EBNA-LP protein (also known as EBNA-5) of Epstein-Barr virus (EBV) has been reported previously to colocalize in the nuclei of cells with the pRb protein and to bind in vitro to pRb and to the p53 protein, suggesting a role for EBNA-LP in modulation of the function of these proteins. Here we test in transfection assays whether EBNA-LP expression has any functional consequence for repression of E2F-1 activity by pRb or p107 or for activation of transcription by the p53 protein. No significant effect could be found, although the assay systems were sensitive to the established effects of simian virus 40 large T antigen and human papillomavirus type 16 E6 protein. There was very effective repression of GAL4/E2F-1 transactivation by p107, consistent with earlier reports and indicating that p107 can interact with the E2F-1 transactivation domain, even though p107 has been reported to bind specifically to E2F complexes containing E2F-4. The results indicate that, if the associations of EBNA-LP with pRB and p53 are physiologically relevant, they most likely affect other functions of these proteins or modulate their gene regulatory functions in ways that cannot be detected by transfection into cycling transformed cells.

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“…EBNA-LP localizes to the nucleus in distinct foci now recognized as nuclear domain 10 (ND10) bodies or promyelocytic leukemia-associated protein (PML) oncogenic domains (PODs) (21,39). Several cellular proteins, including PML, hsp70, and an antigenically distinct form of RB, have been reported to be present in PODs or ND10 bodies (7,21,26,49,50,54). Although little is known about the functions of proteins present in the PODs, they appear to be involved in cellular proliferation processes.…”

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confidence: 99%

Sequence and Functional Analysis of EBNA-LP and EBNA2 Proteins from Nonhuman Primate Lymphocryptoviruses

Peng

Gordadze

Panana

et al. 2000

J Virol

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The Epstein-Barr virus (EBV) EBNA-LP and EBNA2 proteins are the first to be synthesized during establishment of latent infection in B lymphocytes. EBNA2 is a key transcriptional regulator of both viral and cellular gene expression and is essential for EBV-induced immortalization of B lymphocytes. EBNA-LP is also important for EBV-induced immortalization of B lymphocytes, but far less is known about the functional domains and cellular cofactors that mediate EBNA-LP function. While recent studies suggest that serine phosphorylation of EBNA-LP and coactivation of EBNA2-mediated transactivation are important, more detailed mutational and genetic studies are complicated by the repeat regions that comprise the majority of the EBNA-LP sequence. Therefore, we have used a comparative approach by studying the EBNA-LP homologues from baboon and rhesus macaque lymphocryptoviruses (LCVs) (baboon LCV and rhesus LCV). The predicted baboon and rhesus LCV EBNA-LP amino acid sequences are 61 and 64% identical to the EBV EBNA-LP W1 and W2 exons and 51% identical to the EBV EBNA-LP Y1 and Y2 exons. Five evolutionarily conserved regions can be defined, and four of eight potential serine residues are conserved among all three EBNA-LPs. The major internal repeat sequence also revealed a highly conserved Wp EBNA promoter with strong conservation of upstream activating sequences important for Wp transcriptional regulation. To test whether transcriptional coactivating properties were common to the rhesus LCV EBNA-LP, a rhesus LCV EBNA2 homologue was cloned and expressed. The rhesus LCV EBNA2 transcriptionally transactivates EBNA2-responsive promoters through a CBF1-dependent mechanism. The rhesus LCV EBNA-LP was able to further enhance rhesus LCV or EBV EBNA2 transactivation 5-to 12-fold. Thus, there is strong structural and functional conservation among the simian EBNA-LP homologues. Identification of evolutionarily conserved serine residues and regions in EBNA-LP homologues provides important clues for identifying the cellular cofactors and molecular mechanisms mediating these conserved viral functions.Epstein-Barr virus (EBV) is a gammaherpesvirus and a preeminent tumor virus in humans. EBV is associated with a variety of cancers, including endemic Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and lymphoma in the immunosuppressed (40). Consistent with its association with human malignancy, EBV also immortalizes human B lymphocytes with high efficiency in vitro (35). Efficient immortalization of B lymphocytes requires expression of only a subset of viral genes (22). These genes include several EBV nuclear antigens (EBNAs), EBNA1, EBNA2, EBNA3A and -C, and EBNA-LP, and an integral latent membrane protein, LMP-1. EBNA-LP is the first protein along with EBNA2 made during infection of lymphocytes by EBV (1). Despite a growing body of knowledge on the molecular mechanisms of latent protein functions, the role of EBNA-LP for EBV-induced immortalization remains enigmatic.The EBNA-LP protein (also referred to as EBNA-5 or E...

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Co-localization of the retinoblastoma protein and the epstein-barr virus-encoded nuclear antigen EBNA-5

Cited by 55 publications

References 21 publications

In Vivo Dynamics of EBNA1-oriP Interaction during Latent and Lytic Replication of Epstein-Barr Virus

In Vivo Dynamics of EBNA1-oriP Interaction during Latent and Lytic Replication of Epstein-Barr Virus

Epstein--Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays

Sequence and Functional Analysis of EBNA-LP and EBNA2 Proteins from Nonhuman Primate Lymphocryptoviruses

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