The Epstein-Barr Virus Protein BRLF1 Activates S Phase Entry through E2F1 Induction

Swenson, Jennifer J.; Mauser, Amy; Kaufmann, William K.; Kenney, Shannon C.

doi:10.1128/jvi.73.8.6540-6550.1999

Cited by 56 publications

(13 citation statements)

References 68 publications

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“…environment for virus replication can be maintained (DiMaio & Coen, 2001;Flemington, 2001;Op De Beeck & Caillet-Fauquet, 1997). Indeed, accumulating evidence indicates that Zta and Rta seem to have evolved diverse mechanisms in perturbation of cell cycle progression (Chen et al, 2009;Guo et al, 2010;Swenson et al, 1999;Wu et al, 2003). Because Rta is an evolutionarily conserved master switch in all gamma herpesviruses, we chose Rta as a working model for further in-depth investigation.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, the role of Rta in cell cycle control has received less attention. In one report, adenovirus vector expressing Rta increased the levels of E2F1, p53 and p21 in fibroblasts, leading to apoptotic cell death (Swenson et al, 1999). Recently, we re-examined the roles of Rta in cell cycle regulation by establishing Tet-on Rta inducible systems in NPC, 293 and HEp-2 cells.…”

Section: Introductionmentioning

confidence: 99%

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Epstein–Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity

Huang

Hsieh

Chen

et al. 2012

Journal of General Virology

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Many herpesviral immediate-early proteins promote their robust lytic phase replications by hijacking the cell cycle machinery. Previously, lytic replication of Epstein-Barr virus (EBV) was found to be concurrent with host cell cycle arrest. In this study, we showed that ectopic expression of EBV immediate-early protein Rta in HEp-2 cells resulted in increased G1/S population, hypophosphorylation of pRb and decreased incorporation of 5-bromo-29-deoxyuridine. In addition, EBV Rta transcriptionally upregulates the expressions of p21 and 14-3-3s in HEp-2 cells, 293 cells and nasopharyngeal carcinoma TW01 cells. Although p21 and 14-3-3s are known targets for p53, Rta-mediated p21 and 14-3-3s transactivation can be detected in the absence of p53. In addition, results from luciferase reporter assays indicated that direct binding of Rta to either promoter sequences is not required for activation. On the other hand, a special class of Sp1-responsive elements was involved in Rta-mediated transcriptional activation on both promoters. Finally, Rta-induced p21 expression diminished the activity of CDK2/cyclin E complex, and, Rta-induced 14-3-3s expression sequestered CDK1 and CDK2 in the cytoplasm. Based on these results, we hypothesize that through the disruption of CDK1 and CDK2 activities, EBV Rta might contribute to cell cycle arrest in EBV-infected epithelial cells during viral reactivation. INTRODUCTIONEpstein-Barr virus (EBV) is classified as a member of the gamma herpesvirinae with a dsDNA genome of 172 kbp. EBV infection is associated with various human malignancies of lymphoid and epithelial cell origin (Crawford et al., 1979;Epstein et al., 1964;Henle & Henle, 1976;Imai et al., 1994;Niedobitek & Young, 1994). Generally, EBV maintains itself as a latent episome in a proliferative cell and converts to a lytic replicating genome when the host exits from the last cell cycle (Feederle et al., 2007;Sun & Thorley-Lawson, 2007;Tao et al., 1995). The reactivation of EBV from latency can be induced by various chemicals (Takada, 1984;zur Hausen et al., 1978) or by ectopic expression of the immediate-early transcription activators Zta (aka BZLF1, ZEBRA and IE1) or Rta (aka BRLF1 and IE2) (Countryman & Miller, 1985;Ragoczy et al., 1998;Zalani et al., 1996). Furthermore, Zta and Rta activate each other and function synergistically to complete a full productive replication cycle (Feederle et al., 2000). Expression of Rta in nasopharyngeal carcinoma (NPC) cells is potentially useful in early diagnosis (Feng et al., 2000).The cell cycle is an ordered, tightly regulated process involving multiple checkpoints that ensure a faithful round of cell duplication. However, these fine-tuned processes are often perturbed by an invading virus once a lytic replication cycle is initiated (Flemington, 2001 limited viral gene products and trigger an S phase cell cycle so that a copious environment for viral replication is guaranteed (Hiscott & Defendi, 1979). On the other hand, large DNA viruses, such as herpesviruses, usually encode their own e...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epstein–Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity

Huang

Hsieh

Chen

et al. 2012

Journal of General Virology

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“…3 ). Rta can induce the expression of E2F, which would favor cell cycle progression [ 219 ]. Thus, despite the ability of EBV to cause cell cycle arrest during a lytic infection, it has also been shown to stimulate certain cell cycle activation pathways [ 7 ].…”

Section: Epstein-barr Virusmentioning

confidence: 99%

Cell Cycle Regulation During Viral Infection

Bagga

Bouchard

2014

Methods in Molecular Biology

138

114

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To replicate their genomes in cells and generate new progeny, viruses typically require factors provided by the cells that they have infected. Subversion of the cellular machinery that controls replication of the infected host cell is a common activity of many viruses. Viruses employ different strategies to deregulate cell cycle checkpoint controls and modulate cell proliferation pathways. A number of DNA and RNA viruses encode proteins that target critical cell cycle regulators to achieve cellular conditions that are beneficial for viral replication. Many DNA viruses induce quiescent cells to enter the cell cycle; this is thought to increase pools of deoxynucleotides and thus, facilitate viral replication. In contrast, some viruses can arrest cells in a particular phase of the cell cycle that is favorable for replication of the specific virus. Cell cycle arrest may inhibit early cell death of infected cells, allow the cells to evade immune defenses, or help promote virus assembly. Although beneficial for the viral life cycle, virus-mediated alterations in normal cell cycle control mechanisms could have detrimental effects on cellular physiology and may ultimately contribute to pathologies associated with the viral infection, including cell transformation and cancer progression and maintenance. In this chapter, we summarize various strategies employed by DNA and RNA viruses to modulate the replication cycle of the virus-infected cell. When known, we describe how these virus-associated effects influence replication of the virus and contribute to diseases associated with infection by that specific virus.

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“…Activation of EBV lytic replication is concomitant with the induction of apoptosis, probably due to the apoptotic effect of RTA or activation of the DNA damage response [32,33]. However, full activation of caspase cascade and subsequent cell death will be inhibited by two viral Bcl-2 homologs, BHRF1 and BALF1 [34,35], and other indispensable late lytic cycle proteins of EBV [36].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of nasopharyngeal carcinoma growth by RTA‐expressing baculovirus vectors containing oriP

Wang

Shan

et al. 2008

The Journal of Gene Medicine

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The Epstein-Barr Virus Protein BRLF1 Activates S Phase Entry through E2F1 Induction

Cited by 56 publications

References 68 publications

Epstein–Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity

Epstein–Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity

Cell Cycle Regulation During Viral Infection

Inhibition of nasopharyngeal carcinoma growth by RTA‐expressing baculovirus vectors containing oriP

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