This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kaiser, C.
Right arrow Articles by Kempkes, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kaiser, C.
Right arrow Articles by Kempkes, B.

 Previous Article  |  Next Article 

Journal of Virology, May 1999, p. 4481-4484, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Proto-Oncogene c-myc Is a Direct Target Gene of Epstein-Barr Virus Nuclear Antigen 2

Carmen Kaiser, Gerhard Laux, Dirk Eick, Nicola Jochner, Georg W. Bornkamm, and Bettina Kempkes*

Institut für Klinische Molekularbiologie und Tumorgenetik, GSF Forschungszentrum für Umwelt und Gesundheit, D-81377 Munich, Germany

Received 1 December 1998/Accepted 1 February 1999


    ABSTRACT
Top
Abstract
Text
References

Epstein-Barr virus (EBV) infects and transforms primary B lymphocytes in vitro. Viral infection initiates the cell cycle entry of the resting B lymphocytes. The maintenance of proliferation in the infected cells is strictly dependent on functional EBNA2. We have recently developed a conditional immortalization system for EBV by rendering the function of EBNA2, and thus proliferation of the immortalized cells, dependent on estrogen. This cellular system was used to identify early events preceding induction of proliferation. We show that LMP1 and c-myc are directly activated by EBNA2, indicating that all cellular factors essential for induction of these genes by EBNA2 are present in the resting cells. In contrast, induction of the cell cycle regulators cyclin D2 and cdk4 are secondary events, which require de novo protein synthesis.


    TEXT
Top
Abstract
Text
References

Transformation of primary B lymphocytes by Epstein-Barr virus (EBV) requires the concerted action of at least six viral gene products. The individual functions of these six genes cannot easily be analyzed during the infection and transformation process, since expression of these gene products is initiated consecutively over a period of 32 h, and the progression of the infected cells into the cell cycle is asynchronous (for reviews, see references 3 and 11).

EBV nuclear antigen 2 (EBNA2) is one of the first genes expressed postinfection and is absolutely required for viral transformation (2, 4). EBNA2 is a transactivator of viral genes (the latent membrane protein 1 [LMP1], LMP2A, and LMP2B genes), the viral C-promoter, and cellular genes (CD21, CD23, c-fgr, and BLR2) (for a review, see reference 11). EBNA2 carries a strong transactivation domain, which can interact with multiple constituents of the RNA polymerase II transcription complex, but does not bind to DNA directly (20-22). EBNA2 has to be recruited to the promoter of target genes by sequence-specific DNA binding proteins like recombination signal-binding protein Jkappa (RBP-J). RBP-J binds to the conserved core sequence CGTGGGAA. This sequence motif has been identified in the 5' untranslated regions of the viral Cp, LMP1 and LMP2, and the cellular CD21 and CD23 promoters (5, 12, 14, 24, 25). Binding of EBNA2 to these promoters via RBP-J is not sufficient to activate transcription and requires collaboration with factors like the Ets protein PU.1, POU domain proteins, activating transcription factor-c-Jun, or a component of the SNF-SWI complex, SNF5/Ini1 (7, 13, 18, 19, 23). In addition, EBNA2 can act as a repressor and efficiently suppress the expression of immunoglobulin M (IgM) (6).

In order to further define EBNA2 target genes, we have developed a model system to define EBNA2 target genes on the genetic background of an EBV-transformed cell line: a lymphoblastoid cell line conditional for EBNA2, designated ER/EB. This conditional EBNA2 was generated by fusing the open reading frame of EBNA2 to the gene fragment encoding the hormone-binding domain of the estrogen receptor (ER). The function of this ER-EBNA2 fusion protein is strictly dependent on estrogen (beta -estradiol), and cell lines transformed by virus expressing ER-EBNA2 can grow only in the presence of estrogen (8). We have recently shown that ER-EBNA2 does not bind to RBP-J in the absence of estrogen and that binding is restored by estrogen addition (9).

Estrogen-deprived cultures of lymphoblastoid cell lines expressing ER-EBNA2 cease proliferation and acquire the phenotype of resting B lymphocytes but can reenter the cell cycle upon estrogen stimulation. Reentry into the cell cycle is accompanied by the consecutive expression of G1-phase cell cycle regulators and thus is reminiscent of serum stimulation of fibroblast proliferation, or the stimulation of primary B cells by EBV infection or CD40 ligation in the presence of interleukin 4. We have shown previously that upregulation of LMP1 and MYC protein was followed by upregulation of cyclin D2 and cyclin-dependent kinase 4 (cdk4) protein, suggesting that this set of genes might represent good candidate EBNA2 target genes (8).

In the absence of ligand, the steroid receptors are associated with heat shock proteins, which keep the steroid receptor in an inactive conformation, and this inhibition is released by ligand binding (1, 15). It is generally assumed that the same inhibitory complex is formed by steroid receptor fusion proteins and renders the fusion partner nonfunctional in the absence of ligand. Thus, the mechanism by which the hormone-binding domain of steroid receptors can regulate the function of the fusion partners in chimeric proteins does not require de novo protein synthesis.

Since the objective of our study was to identify direct target genes of EBNA2, we reanalyzed induction of known EBNA2 target genes in the presence of the protein synthesis inhibitor anisomycin or cycloheximide. The abundance of LMP1 and c-myc RNA was increased upon estrogen stimulation in the absence of de novo protein synthesis (Fig. 1A and B, lanes 4 through 6).


View larger version (34K):
[in this window]
[in a new window]
  		FIG. 1.   (A and B) EBNA2 enhances c-myc and LMP1 RNA expression in the absence of de novo protein synthesis. ER/EB2-5 estrogen-deprived cell cultures were treated with 10 µM anisomycin (an) or 50 µg of cycloheximide (chx)/ml in the presence or absence of estrogen for 6 h. Protein synthesis inhibitors were added to the medium 1 h prior to estrogen stimulation in order to establish the translational block before activation of the cells. Total RNA (10 µg/lane) from each culture was isolated and analyzed for c-myc and LMP1 RNA expression. (C and D) Induction of high c-myc RNA levels occurs at the transcriptional level. (C) Nuclei were prepared from cells cultured in the presence (+) or absence (-) of estrogen for 6 h. Nuclear run-on RNAs were hybridized to c-myc and Ig-µ gene probes or vector DNA. (D) Hybridization signals were quantified with a Fuji BAS 100 scanner.

While anisomycin weakly stabilized c-myc transcripts independently of EBNA2 induction (Fig. 1B, lane 2), induction of both RNAs was strictly dependent on estrogen stimulation in the presence of cycloheximide (Fig. 1A and B, lanes 6). This EBNA2 requirement defined LMP1 and c-myc as direct EBNA2 target genes.

In order to further elucidate the mechanism by which EBNA2 induces c-myc RNA, we performed run-on assays of c-myc transcription. These transcription studies in isolated nuclei showed that transcription of the first exon of the c-myc gene was enhanced sevenfold in the presence of estrogen. We have recently reported that EBNA2 interferes with immunoglobulin (Ig) µ gene transcription in Burkitt's lymphoma cells (6). Here, we repeated our former experiments in order to show that the increase in c-myc transcription in ER/EB cells paralleled the decrease in Ig-µ gene transcription. Thus the increase was indeed specific for the c-myc gene (Fig. 1C and D). These data clearly demonstrate that transcription of the c-myc gene is activated by EBNA2. In the absence of functional EBNA2, transcription of the c-myc gene was not significantly increased compared to that of the vector control.

Blocking of protein synthesis was controlled by Western blot analysis of LMP1 protein, a well-characterized EBNA2 target gene. As expected, LMP1 protein was induced by EBNA2 (Fig. 2, lane 4), and both inhibitors (Fig. 2, lanes 5 and 6) efficiently abolished induction.


View larger version (41K):
[in this window]
[in a new window]
  		FIG. 2.   Protein synthesis is efficiently blocked by anisomycin and cycloheximide in estrogen-induced ER/EB2-5 cells. ER/EB2-5 cells were estrogen starved for 4 days and were then restimulated with estrogen (estr.) for 6 h in the presence or absence of 10 µM anisomycin (an) or 50 µg of cycloheximide (chx)/ml. Protein extracts (50 µg/lane) were subjected to Western blot analysis for ER-EBNA2 and LMP1 expression. Note that estrogen, in the absence of protein synthesis, induces a shift in the mobility of the ER-EBNA2 protein, which is due to phosphorylation (10).

The time course of LMP1 RNA expression was compared to the expression of the c-myc oncogene in the absence and presence of cycloheximide (Fig. 3). Transcripts of both genes could be detected within the first 2 h postinduction. This induction could also be observed in the presence of cycloheximide, confirming that EBNA2 can enhance expression of both genes in the absence of de novo protein synthesis.


View larger version (84K):
[in this window]
[in a new window]
  		FIG. 3.   c-myc and LMP1 are direct EBNA2 target genes. ER/EB2-5 estrogen-deprived cultures were stimulated with estrogen in the absence or presence of cycloheximide for the indicated times. RNA was extracted and subjected to Northern blot analysis for c-myc and LMP1 expression. The loading of the samples was controlled by ethidium bromide (EtBr) staining.

LMP1 transcripts accumulated gradually within the first 6 h after estrogen stimulation in the absence and presence of cycloheximide, and comparison of both kinetics showed a weak delay only in the presence of cycloheximide. The transactivation of the LMP1 and other EBNA2-dependent promoters by EBNA2 requires multiple known and unknown DNA binding factors. Theoretically, the potentially low abundance of one or several of these factors in resting ER/EB cells could be limiting, and this could explain the delayed kinetics of LMP1 RNA induction. PU.1, Spi-B, and RBP-J, however, which have been shown to play a role in the regulation of expression of the LMP1 promoter, are abundantly expressed in primary B cells and in estrogen-deprived ER/EB cultures (13a) and are thus unlikely to be limiting. The limiting factors, potentially labile or not expressed, have yet to be identified.

There were, however, obvious differences when c-myc induction in the presence and absence of cycloheximide was compared. In the absence of cycloheximide, c-myc expression gradually increased over a period of 6 h, in a manner similar to the kinetics of LMP1 induction. In the presence of cycloheximide, c-myc RNA levels increased within the first 2 h postinduction. After this initial induction phase, c-myc was expressed at constant levels, which never equalled those reached in the presence of de novo protein synthesis. These results indicate that at least two independent mechanisms, characterized by their requirement for de novo protein synthesis, contribute to the induction of c-myc RNA expression by EBNA2. In order to define further these mechanisms of c-myc induction by EBNA2, we have tried to identify EBNA2-responsive cis elements within the upstream region of the c-myc promoter. So far, we have not been able to define such an element by transient transfection of c-myc promoter reporter constructs encompassing the 2.3 kb upstream of the P1 promoter (data not shown).

In ER/EB cells, LMP1 and c-myc expression is closely followed by cyclin D2 and cdk4 protein induction. Since EBNA2 in cooperation with EBNA-LP (leader protein) can induce cyclin D2 expression in resting B cells (17), we asked whether cyclin D2 is a direct target gene of EBNA2. Analysis of the RNA abundance of both genes after estrogen induction revealed, however, that although cyclin D2 and cdk4 RNAs are detectable after 3 to 6 h postinduction (Fig. 4), de novo protein synthesis is required for activation of cyclin D2 as well as cdk4 expression. EBNA-LP is unlikely to be a limiting factor, since it is expressed in estrogen-deprived ER/EB cultures and is not modulated upon estrogen addition (data not shown). We conclude that in contrast to LMP1 and c-myc, neither cyclin D2 nor cdk4 is a direct EBNA2 target.


View larger version (31K):
[in this window]
[in a new window]
  		FIG. 4.   Neither cyclin D2 nor cdk4 is a direct EBNA2 target gene. The Northern blots shown in Fig. 3 were stripped and reprobed for cyclin D2 and cdk4 expression.

Cyclin D2 and cdk4 are both elements of the basic cell cycle machinery and drive cell cycle progression in early G1. Since we and others have shown that cyclin D2 and cdk4 expression can be induced by various different B-cell activation protocols, we propose that induction of proliferation by EBNA2 is a secondary event potentially driven by the primary viral and cellular EBNA2 targets.

We show here for the first time that the proto-oncogene c-myc is a direct target gene of EBNA2. Our data clearly support the notion that activation of c-myc gene transcription is the primary cause for the observed elevated levels of c-myc RNA. However, our data do not formally exclude the possibility that secondary mechanisms such as stabilization of transcripts might cooperate with transcriptional induction. In addition, our data showing elevated levels of c-myc RNA in the absence of de novo protein synthesis do not exclude the possibility that EBNA2 acts in concert with other factors. Theoretically, EBNA2 could activate latent transcription factors which might cooperate with EBNA2 to activate transcription. Thus, the molecular mechanism by which EBNA2 activates transcription of the c-myc gene still has to be elucidated.

Ectopic expression of LMP1 in estrogen-deprived ER/EB cultures promotes cell survival but cannot substitute for functions provided by EBNA2 (26). In contrast, ectopic overexpression of c-myc, at very high levels, can drive proliferation in the absence of functional EBNA2 and LMP1 in estrogen-deprived ER/EB cells (16). This suggests that activation of c-myc by EBNA2 is an important step in the process of EBV-induced proliferation and immortalization.


    ACKNOWLEDGMENTS

This work was supported by Die Deutsche Forschungsgemeinschaft (SFB 217, SFB 455, and La948/2-2) and the Fonds der Chemischen Industrie. B.K. is a fellow of Das AIDS-Stipendienprogramm (Deutsches Krebsforschungszentrum).


    FOOTNOTES

* Corresponding author. Mailing address: Institut für Klinische Molekularbiologie und Tumorgenetik, GSF Forschungszentrum für Umwelt und Gesundheit, Marchioninistr. 25, D-81377 Munich, Germany. Phone: 49-89-7099-354. Fax: 49-89-7099-500. E-mail: kempkes{at}gsf.de.


    REFERENCES
Top
Abstract
Text
References

1. Beato, M., M. Truss, and S. Chavez. 1996. Control of transcription by steroid hormones. Ann. N.Y. Acad. Sci. 784:93-123[Medline].
2. Cohen, J. I., F. Wang, J. Mannick, and E. Kieff. 1989. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc. Natl. Acad. Sci. USA 86:9558-9562[Abstract/Free Full Text].
3. Farrell, P. J. 1995. Epstein-Barr virus immortalizing genes. Trends Microbiol. 3:105-109[Medline].
4. Hammerschmidt, W., and B. Sugden. 1989. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature 340:393-397[Medline].
5. Henkel, T., P. D. Ling, S. D. Hayward, and M. G. Peterson. 1994. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science 265:92-95[Abstract/Free Full Text].
6. Jochner, N., D. Eick, U. Zimber-Strobl, M. Pawlita, G. W. Bornkamm, and B. Kempkes. 1996. Epstein-Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin mu gene: implications for the expression of the translocated c-myc gene in Burkitt's lymphoma cells. EMBO J. 15:375-382[Medline].
7. Johannsen, E., E. Koh, G. Mosialos, X. Tong, E. Kieff, and S. R. Grossman. 1995. Epstein-Barr virus nuclear protein 2 transactivation of the latent membrane protein 1 promoter is mediated by Jkappa and PU.1. J. Virol. 69:253-262[Abstract].
8. Kempkes, B., M. Pawlita, U. Zimber-Strobl, G. Eissner, G. Laux, and G. W. Bornkamm. 1995. Epstein-Barr virus nuclear antigen 2-estrogen receptor fusion proteins transactivate viral and cellular genes and interact with RBP-J kappa in a conditional fashion. Virology 214:675-679[Medline].
9. Kempkes, B., D. Spitkovsky, P. Jansen-Durr, J. W. Ellwart, E. Kremmer, H. J. Delecluse, C. Rottenberger, G. W. Bornkamm, and W. Hammerschmidt. 1995. B-cell proliferation and induction of early G1-regulating proteins by Epstein-Barr virus mutants conditional for EBNA2. EMBO J. 14:88-96[Medline].
10. Kempkes, B., U. Zimber-Strobl, G. Eissner, M. Pawlita, M. Falk, W. Hammerschmidt, and G. W. Bornkamm. 1996. Epstein-Barr virus nuclear antigen 2 (EBNA2)-oestrogen receptor fusion proteins complement the EBNA2-deficient Epstein-Barr virus strain P3HR1 in transformation of primary B cells but suppress growth of human B cell lymphoma lines. J. Gen. Virol. 77:227-237[Abstract/Free Full Text].
11. Kieff, E. 1996. Epstein-Barr virus and its replication, p. 2343-2396. In B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, T. P. Monath, J. L. Melnick, B. Roizmann, and S. E. Straus (ed.), Virology. Lippincott-Raven Publishers, Philadelphia, Pa.
12. Laux, G., B. Adam, L. J. Strobl, and F. Moreau-Gachelin. 1994. The Spi-1/PU.1 and Spi-B ets family transcription factors and the recombination signal binding protein RBP-J kappa interact with an Epstein-Barr virus nuclear antigen 2 responsive cis-element. EMBO J. 13:5624-5632[Medline].
13. Laux, G., F. Dugrillon, C. Eckert, B. Adam, U. Zimber-Strobl, and G. W. Bornkamm. 1994. Identification and characterization of an Epstein-Barr virus nuclear antigen 2-responsive cis element in the bidirectional promoter region of latent membrane protein and terminal protein 2 genes. J. Virol. 68:6947-6958[Abstract/Free Full Text].
13a. Laux, G. Unpublished data.
14. Ling, P. D., J. J. Hsieh, I. K. Ruf, D. R. Rawlins, and S. D. Hayward. 1994. EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J. Virol. 68:5375-5383[Abstract/Free Full Text].
15. Picard, D. 1994. Regulation of protein function through expression of chimaeric proteins. Curr. Opin. Biotechnol. 5:511-515[Medline].
16. Polack, A., K. Hortnagel, A. Pajic, B. Christoph, B. Baier, M. Falk, J. Mautner, C. Geltinger, G. W. Bornkamm, and B. Kempkes. 1996. c-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc. Natl. Acad. Sci. USA 93:10411-10416[Abstract/Free Full Text].
17. Sinclair, A. J., I. Palmero, G. Peters, and P. J. Farrell. 1994. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO J. 13:3321-3328[Medline].
18. Sjöblom, A., A. Jansson, W. Yang, S. Lain, T. Nilsson, and L. Rymo. 1995. PU box-binding transcription factors and a POU domain protein cooperate in the Epstein-Barr virus (EBV) nuclear antigen 2-induced transactivation of the EBV latent membrane protein 1 promoter. J. Gen. Virol. 76:2679-2692[Abstract/Free Full Text].
19. Sjöblom, A., W. Yang, L. Palmqvist, A. Jansson, and L. Rymo. 1998. An ATF/CRE element mediates both EBNA2-dependent and EBNA2-independent activation of the Epstein-Barr virus LMP1 gene promoter. J. Virol. 72:1365-1376[Abstract/Free Full Text].
20. Tong, X., R. Drapkin, D. Reinberg, and E. Kieff. 1995. The 62- and 80-kDa subunits of transcription factor IIH mediate the interaction with Epstein-Barr virus nuclear protein 2. Proc. Natl. Acad. Sci. USA 92:3259-3263[Abstract/Free Full Text].
21. Tong, X., R. Drapkin, R. Yalamanchili, G. Mosialos, and E. Kieff. 1995. The Epstein-Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE. Mol. Cell. Biol. 15:4735-4744[Abstract].
22. Tong, X., F. Wang, C. J. Thut, and E. Kieff. 1995. The Epstein-Barr virus nuclear protein 2 acidic domain can interact with TFIIB, TAF40, and RPA70 but not with TATA-binding protein. J. Virol. 69:585-588[Abstract].
23. Wu, D. Y., G. V. Kalpana, S. P. Goff, and W. H. Schubach. 1996. Epstein-Barr virus nuclear protein 2 (EBNA2) binds to a component of the human SNF-SWI complex, hSNF5/Ini1. J. Virol. 70:6020-6028[Abstract].
24. Zimber-Strobl, U., E. Kremmer, F. Grasser, G. Marschall, G. Laux, and G. W. Bornkamm. 1993. The Epstein-Barr virus nuclear antigen 2 interacts with an EBNA2 responsive cis-element of the terminal protein 1 gene promoter. EMBO J. 12:167-175[Medline].
25. Zimber-Strobl, U., L. J. Strobl, C. Meitinger, R. Hinrichs, T. Sakai, T. Furukawa, T. Honjo, and G. W. Bornkamm. 1994. Epstein-Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-J kappa, the homologue of Drosophila Suppressor of Hairless. EMBO J. 13:4973-4982[Medline].
26. Zimber-Strobl, U., B. Kempkes, G. Marschall, R. Zeidler, C. Van Kooten, J. Banchereau, G. W. Bornkamm, and W. Hammerschmidt. 1996. Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J. 15:7070-7078[Medline].

Journal of Virology, May 1999, p. 4481-4484, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Lee, S., Sakakibara, S., Maruo, S., Zhao, B., Calderwood, M. A., Holthaus, A. M., Lai, C.-Y., Takada, K., Kieff, E., Johannsen, E. (2009). Epstein-Barr Virus Nuclear Protein 3C Domains Necessary for Lymphoblastoid Cell Growth: Interaction with RBP-J{kappa} Regulates TCL1. J. Virol. 83: 12368-12377 [Abstract] [Full Text]  
  • Kohlhof, H., Hampel, F., Hoffmann, R., Burtscher, H., Weidle, U. H., Holzel, M., Eick, D., Zimber-Strobl, U., Strobl, L. J. (2009). Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus-infected B cells. Blood 113: 5506-5515 [Abstract] [Full Text]  
  • Faumont, N., Durand-Panteix, S., Schlee, M., Gromminger, S., Schuhmacher, M., Holzel, M., Laux, G., Mailhammer, R., Rosenwald, A., Staudt, L. M., Bornkamm, G. W., Feuillard, J. (2009). c-Myc and Rel/NF-{kappa}B Are the Two Master Transcriptional Systems Activated in the Latency III Program of Epstein-Barr Virus-Immortalized B Cells. J. Virol. 83: 5014-5027 [Abstract] [Full Text]  
  • Pan, S.-H., Tai, C.-C., Lin, C.-S., Hsu, W.-B., Chou, S.-F., Lai, C.-C., Chen, J.-Y., Tien, H.-F., Lee, F.-Y., Wang, W.-B. (2009). Epstein-Barr virus nuclear antigen 2 disrupts mitotic checkpoint and causes chromosomal instability. Carcinogenesis 30: 366-375 [Abstract] [Full Text]  
  • Lubyova, B., Kellum, M. J., Frisancho, J. A., Pitha, P. M. (2007). Stimulation of c-Myc Transcriptional Activity by vIRF-3 of Kaposi Sarcoma-associated Herpesvirus. J. Biol. Chem. 282: 31944-31953 [Abstract] [Full Text]  
  • Xing, L., Kieff, E. (2007). Epstein-Barr Virus BHRF1 Micro- and Stable RNAs during Latency III and after Induction of Replication. J. Virol. 81: 9967-9975 [Abstract] [Full Text]  
  • Maruo, S., Wu, Y., Ishikawa, S., Kanda, T., Iwakiri, D., Takada, K. (2006). Epstein-Barr virus nuclear protein EBNA3C is required for cell cycle progression and growth maintenance of lymphoblastoid cells. Proc. Natl. Acad. Sci. USA 103: 19500-19505 [Abstract] [Full Text]  
  • Maier, S., Staffler, G., Hartmann, A., Hock, J., Henning, K., Grabusic, K., Mailhammer, R., Hoffmann, R., Wilmanns, M., Lang, R., Mages, J., Kempkes, B. (2006). Cellular Target Genes of Epstein-Barr Virus Nuclear Antigen 2. J. Virol. 80: 9761-9771 [Abstract] [Full Text]  
  • Spender, L. C., Lucchesi, W., Bodelon, G., Bilancio, A., Karstegl, C. E., Asano, T., Dittrich-Breiholz, O., Kracht, M., Vanhaesebroeck, B., Farrell, P. J. (2006). Cell target genes of Epstein-Barr virus transcription factor EBNA-2: induction of the p55{alpha} regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells.. J. Gen. Virol. 87: 2859-2867 [Abstract] [Full Text]  
  • Mohan, J., Dement-Brown, J., Maier, S., Ise, T., Kempkes, B., Tolnay, M. (2006). Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1. Blood 107: 4433-4439 [Abstract] [Full Text]  
  • Le Clorennec, C., Youlyouz-Marfak, I., Adriaenssens, E., Coll, J., Bornkamm, G. W., Feuillard, J. (2006). EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1: role of NF-{kappa}B, STAT1, and p53. Blood 107: 2070-2078 [Abstract] [Full Text]  
  • Zhao, B., Maruo, S., Cooper, A., R. Chase, M., Johannsen, E., Kieff, E., Cahir-McFarland, E. (2006). RNAs induced by Epstein-Barr virus nuclear antigen 2 in lymphoblastoid cell lines. Proc. Natl. Acad. Sci. USA 103: 1900-1905 [Abstract] [Full Text]  
  • Maruo, S., Johannsen, E., Illanes, D., Cooper, A., Zhao, B., Kieff, E. (2005). Epstein-Barr Virus Nuclear Protein 3A Domains Essential for Growth of Lymphoblasts: Transcriptional Regulation through RBP-J{kappa}/CBF1 Is Critical. J. Virol. 79: 10171-10179 [Abstract] [Full Text]  
  • Maier, S., Santak, M., Mantik, A., Grabusic, K., Kremmer, E., Hammerschmidt, W., Kempkes, B. (2005). A Somatic Knockout of CBF1 in a Human B-Cell Line Reveals that Induction of CD21 and CCR7 by EBNA-2 Is Strictly CBF1 Dependent and that Downregulation of Immunoglobulin M Is Partially CBF1 Independent. J. Virol. 79: 8784-8792 [Abstract] [Full Text]  
  • Yue, W., Gershburg, E., Pagano, J. S. (2005). Hyperphosphorylation of EBNA2 by Epstein-Barr Virus Protein Kinase Suppresses Transactivation of the LMP1 Promoter. J. Virol. 79: 5880-5885 [Abstract] [Full Text]  
  • Peng, R., Moses, S. C., Tan, J., Kremmer, E., Ling, P. D. (2005). The Epstein-Barr Virus EBNA-LP Protein Preferentially Coactivates EBNA2-Mediated Stimulation of Latent Membrane Proteins Expressed from the Viral Divergent Promoter. J. Virol. 79: 4492-4505 [Abstract] [Full Text]  
  • Pages, F., Galon, J., Karaschuk, G., Dudziak, D., Camus, M., Lazar, V., Camilleri-Broet, S., Lagorce-Pages, C., Lebel-Binay, S., Laux, G., Fridman, W.-H., Henglein, B. (2005). Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells. Blood 105: 1632-1639 [Abstract] [Full Text]  
  • Lee, J. M., Lee, K.-H., Farrell, C. J., Ling, P. D., Kempkes, B., Park, J. H., Hayward, S. D. (2004). EBNA2 Is Required for Protection of Latently Epstein-Barr Virus-Infected B Cells against Specific Apoptotic Stimuli. J. Virol. 78: 12694-12697 [Abstract] [Full Text]  
  • Gao, X., Wang, H., Sairenji, T. (2004). Inhibition of Epstein-Barr Virus (EBV) Reactivation by Short Interfering RNAs Targeting p38 Mitogen-Activated Protein Kinase or c-myc in EBV-Positive Epithelial Cells. J. Virol. 78: 11798-11806 [Abstract] [Full Text]  
  • Kwiatkowski, B., Chen, S. Y. J., Schubach, W. H. (2004). CKII Site in Epstein-Barr Virus Nuclear Protein 2 Controls Binding to hSNF5/Ini1 and Is Important for Growth Transformation. J. Virol. 78: 6067-6072 [Abstract] [Full Text]  
  • Gordadze, A. V., Onunwor, C. W., Peng, R., Poston, D., Kremmer, E., Ling, P. D. (2004). EBNA2 Amino Acids 3 to 30 Are Required for Induction of LMP-1 and Immortalization Maintenance. J. Virol. 78: 3919-3929 [Abstract] [Full Text]  
  • Schlee, M., Krug, T., Gires, O., Zeidler, R., Hammerschmidt, W., Mailhammer, R., Laux, G., Sauer, G., Lovric, J., Bornkamm, G. W. (2004). Identification of Epstein-Barr Virus (EBV) Nuclear Antigen 2 (EBNA2) Target Proteins by Proteome Analysis: Activation of EBNA2 in Conditionally Immortalized B Cells Reflects Early Events after Infection of Primary B Cells by EBV. J. Virol. 78: 3941-3952 [Abstract] [Full Text]  
  • Cahir-McFarland, E. D., Carter, K., Rosenwald, A., Giltnane, J. M., Henrickson, S. E., Staudt, L. M., Kieff, E. (2004). Role of NF-{kappa}B in Cell Survival and Transcription of Latent Membrane Protein 1-Expressing or Epstein-Barr Virus Latency III-Infected Cells. J. Virol. 78: 4108-4119 [Abstract] [Full Text]  
  • Thompson, M. P., Kurzrock, R. (2004). Epstein-Barr Virus and Cancer. Clin. Cancer Res. 10: 803-821 [Abstract] [Full Text]  
  • Shackelford, J., Maier, C., Pagano, J. S. (2003). Epstein-Barr virus activates {beta}-catenin in type III latently infected B lymphocyte lines: Association with deubiquitinating enzymes. Proc. Natl. Acad. Sci. USA 100: 15572-15576 [Abstract] [Full Text]  
  • Maruo, S., Johannsen, E., Illanes, D., Cooper, A., Kieff, E. (2003). Epstein-Barr Virus Nuclear Protein EBNA3A Is Critical for Maintaining Lymphoblastoid Cell Line Growth. J. Virol. 77: 10437-10447 [Abstract] [Full Text]  
  • Rao, P., Kadesch, T. (2003). The Intracellular Form of Notch Blocks Transforming Growth Factor {beta}-Mediated Growth Arrest in Mv1Lu Epithelial Cells. Mol. Cell. Biol. 23: 6694-6701 [Abstract] [Full Text]  
  • Dudziak, D., Kieser, A., Dirmeier, U., Nimmerjahn, F., Berchtold, S., Steinkasserer, A., Marschall, G., Hammerschmidt, W., Laux, G., Bornkamm, G. W. (2003). Latent Membrane Protein 1 of Epstein-Barr Virus Induces CD83 by the NF-{kappa}B Signaling Pathway. J. Virol. 77: 8290-8298 [Abstract] [Full Text]  
  • Johansen, L. M., Deppmann, C. D., Erickson, K. D., Coffin, W. F. III, Thornton, T. M., Humphrey, S. E., Martin, J. M., Taparowsky, E. J. (2003). EBNA2 and Activated Notch Induce Expression of BATF. J. Virol. 77: 6029-6040 [Abstract] [Full Text]  
  • Cooper, A., Johannsen, E., Maruo, S., Cahir-McFarland, E., Illanes, D., Davidson, D., Kieff, E. (2002). EBNA3A Association with RBP-J{kappa} Down-Regulates c-myc and Epstein-Barr Virus-Transformed Lymphoblast Growth. J. Virol. 77: 999-1010 [Abstract] [Full Text]  
  • Carter, K. L., Cahir-McFarland, E., Kieff, E. (2002). Epstein-Barr Virus-Induced Changes in B-Lymphocyte Gene Expression. J. Virol. 76: 10427-10436 [Abstract] [Full Text]  
  • Gordadze, A. V., Poston, D., Ling, P. D. (2002). The EBNA2 Polyproline Region Is Dispensable for Epstein-Barr Virus-Mediated Immortalization Maintenance. J. Virol. 76: 7349-7355 [Abstract] [Full Text]  
  • Dufva, M., Flodin, J., Nerstedt, A., Ruetschi, U., Rymo, L. (2002). Epstein-Barr virus nuclear antigen 5 inhibits pre-mRNA cleavage and polyadenylation. Nucleic Acids Res 30: 2131-2143 [Abstract] [Full Text]  
  • Spender, L. C., Cornish, G. H., Sullivan, A., Farrell, P. J. (2002). Expression of Transcription Factor AML-2 (RUNX3, CBF{alpha}-3) Is Induced by Epstein-Barr Virus EBNA-2 and Correlates with the B-Cell Activation Phenotype. J. Virol. 76: 4919-4927 [Abstract] [Full Text]  
  • Lin, J., Johannsen, E., Robertson, E., Kieff, E. (2002). Epstein-Barr Virus Nuclear Antigen 3C Putative Repression Domain Mediates Coactivation of the LMP1 Promoter with EBNA-2. J. Virol. 76: 232-242 [Abstract] [Full Text]  
  • McCann, E. M., Kelly, G. L., Rickinson, A. B., Bell, A. I. (2001). Genetic analysis of the Epstein-Barr virus-coded leader protein EBNA-LP as a co-activator of EBNA2 function. J. Gen. Virol. 82: 3067-3079 [Abstract] [Full Text]  
  • Gordadze, A. V., Peng, R., Tan, J., Liu, G., Sutton, R., Kempkes, B., Bornkamm, G. W., Ling, P. D. (2001). Notch1IC Partially Replaces EBNA2 Function in B Cells Immortalized by Epstein-Barr Virus. J. Virol. 75: 5899-5912 [Abstract] [Full Text]  
  • Spender, L. C., Cornish, G. H., Rowland, B., Kempkes, B., Farrell, P. J. (2001). Direct and Indirect Regulation of Cytokine and Cell Cycle Proteins by EBNA-2 during Epstein-Barr Virus Infection. J. Virol. 75: 3537-3546 [Abstract] [Full Text]  
  • Höfelmayr, H., Strobl, L. J., Marschall, G., Bornkamm, G. W., Zimber-Strobl, U. (2001). Activated Notch1 Can Transiently Substitute for EBNA2 in the Maintenance of Proliferation of LMP1-Expressing Immortalized B Cells. J. Virol. 75: 2033-2040 [Abstract] [Full Text]  
  • Han, I., Harada, S., Weaver, D., Xue, Y., Lane, W., Orstavik, S., Skalhegg, B., Kieff, E. (2001). EBNA-LP Associates with Cellular Proteins Including DNA-PK and HA95. J. Virol. 75: 2475-2481 [Abstract] [Full Text]  
  • Harada, S., Yalamanchili, R., Kieff, E. (2001). Epstein-Barr Virus Nuclear Protein 2 Has at Least Two N-Terminal Domains That Mediate Self-Association. J. Virol. 75: 2482-2487 [Abstract] [Full Text]  
  • Young, L S, Dawson, C W, Eliopoulos, A G (2000). The expression and function of Epstein-Barr virus encoded latent genes. Mol. Pathol. 53: 238-247 [Abstract] [Full Text]  
  • Fuentes-Pananá, E. M., Peng, R., Brewer, G., Tan, J., Ling, P. D. (2000). Regulation of the Epstein-Barr Virus C Promoter by AUF1 and the Cyclic AMP/Protein Kinase A Signaling Pathway. J. Virol. 74: 8166-8175 [Abstract] [Full Text]  
  • Wang, L., Grossman, S. R., Kieff, E. (2000). Epstein-Barr virus nuclear protein 2 interacts with p300, CBP, and PCAF histone acetyltransferases in activation of the LMP1 promoter. Proc. Natl. Acad. Sci. USA 97: 430-435 [Abstract] [Full Text]  
  • Jayachandra, S., Low, K. G., Thlick, A.-E., Yu, J., Ling, P. D., Chang, Y., Moore, P. S. (1999). Three unrelated viral transforming proteins (vIRF, EBNA2, and E1A) induce the MYC oncogene through the interferon-responsive PRF element by using different transcription coadaptors. Proc. Natl. Acad. Sci. USA 96: 11566-11571 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kaiser, C.
Right arrow Articles by Kempkes, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kaiser, C.
Right arrow Articles by Kempkes, B.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»