This Article
Right arrow Full Text
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 Rodriguez, A.
Right arrow Articles by Flemington, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rodriguez, A.
Right arrow Articles by Flemington, E.

 Previous Article  |  Next Article 

Journal of Virology, November 1999, p. 9029-9038, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Genetic Dissection of Cell Growth Arrest Functions Mediated by the Epstein-Barr Virus Lytic Gene Product, Zta

Antonio Rodriguez, Monica Armstrong, Daniel Dwyer, and Erik Flemington*

Harvard University and Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Received 12 May 1999/Accepted 3 August 1999

Expression of the Epstein-Barr virus (EBV) latency-associated genes activates cell cycle progression and drives immortalization of the infected cell. In contrast, progression of the EBV replication program occurs most efficiently in growth-arrested cells. Previous studies showed that the EBV-encoded immediate-early transcription factor, Zta, can induce expression of the cyclin-dependent kinase inhibitors, p21 and p27, the tumor suppressor, p53, and cell growth arrest. Moreover, Zta-mediated induction of growth arrest occurs independently of its transcriptional transactivation function. Here we show that substitution of Zta's basic DNA binding domain with the analogous region of the Zta homologue, c-Fos, abrogates Zta's ability to induce growth arrest and to induce p21, p27, or p53 expression, suggesting that protein-protein interactions between this region of Zta and key cell cycle control proteins are involved in signaling cell cycle arrest. We also show that despite the crucial role for Zta's basic domain in eliciting cell growth arrest, its amino terminus is required for efficient induction of p27 and it modulates the level of p53 induction. Last, we provide evidence that Zta-mediated inductions of p21, p27, and p53 occur, at least in part, through distinct pathways. Therefore, Zta interacts with multiple growth arrest pathways, a property which may have evolved partly as a means to ensure that lytic replication occurs in a growth-arrested setting in multiple different tissues in various states of differentiation.

* Corresponding author. Mailing address: Department of CIA, Rm. D1420B, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02446. Phone: (617) 632-3852. Fax: (617) 632-2662. E-mail: erik_flemington{at}dfci.harvard.edu.

Journal of Virology, November 1999, p. 9029-9038, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Bailey, S. G., Verrall, E., Schelcher, C., Rhie, A., Doherty, A. J., Sinclair, A. J. (2009). Functional Interaction between Epstein-Barr Virus Replication Protein Zta and Host DNA Damage Response Protein 53BP1. J. Virol. 83: 11116-11122 [Abstract] [Full Text]  
  • Katsumura, K. R., Maruo, S., Wu, Y., Kanda, T., Takada, K. (2009). Quantitative evaluation of the role of Epstein-Barr virus immediate-early protein BZLF1 in B-cell transformation. J. Gen. Virol. 90: 2331-2341 [Abstract] [Full Text]  
  • Huang, J., Liao, G., Chen, H., Wu, F. Y., Hutt-Fletcher, L., Hayward, G. S., Hayward, S. D. (2006). Contribution of C/EBP Proteins to Epstein-Barr Virus Lytic Gene Expression and Replication in Epithelial Cells. J. Virol. 80: 1098-1109 [Abstract] [Full Text]  
  • Schelcher, C., Valencia, S., Delecluse, H.-J., Hicks, M., Sinclair, A. J. (2005). Mutation of a Single Amino Acid Residue in the Basic Region of the Epstein-Barr Virus (EBV) Lytic Cycle Switch Protein Zta (BZLF1) Prevents Reactivation of EBV from Latency. J. Virol. 79: 13822-13828 [Abstract] [Full Text]  
  • Lin, Z., Yin, Q., Flemington, E. (2004). Identification of a Negative Regulatory Element in the Epstein-Barr Virus Zta Transactivation Domain That Is Regulated by the Cell Cycle Control Factors c-Myc and E2F1. J. Virol. 78: 11962-11971 [Abstract] [Full Text]  
  • Huang, J., Chen, H., Hutt-Fletcher, L., Ambinder, R. F., Hayward, S. D. (2003). Lytic Viral Replication as a Contributor to the Detection of Epstein-Barr Virus in Breast Cancer. J. Virol. 77: 13267-13274 [Abstract] [Full Text]  
  • Izumiya, Y., Lin, S.-F., Ellison, T. J., Levy, A. M., Mayeur, G. L., Izumiya, C., Kung, H.-J. (2003). Cell Cycle Regulation by Kaposi's Sarcoma-Associated Herpesvirus K-bZIP: Direct Interaction with Cyclin-CDK2 and Induction of G1 Growth Arrest. J. Virol. 77: 9652-9661 [Abstract] [Full Text]  
  • Sinclair, A. J. (2003). bZIP proteins of human gammaherpesviruses. J. Gen. Virol. 84: 1941-1949 [Abstract] [Full Text]  
  • Wiebusch, L., Asmar, J., Uecker, R., Hagemeier, C. (2003). Human cytomegalovirus immediate-early over protein 2 (IE2)-mediated activation of cyclin E is cell-cycle-independent and forces S-phase entry in IE2-arrested cells. J. Gen. Virol. 84: 51-60 [Abstract] [Full Text]  
  • Kudoh, A., Fujita, M., Kiyono, T., Kuzushima, K., Sugaya, Y., Izuta, S., Nishiyama, Y., Tsurumi, T. (2002). Reactivation of Lytic Replication from B Cells Latently Infected with Epstein-Barr Virus Occurs with High S-Phase Cyclin-Dependent Kinase Activity while Inhibiting Cellular DNA Replication. J. Virol. 77: 851-861 [Abstract] [Full Text]  
  • Wu, F. Y., Chen, H., Wang, S. E., apRhys, C. M. J., Liao, G., Fujimuro, M., Farrell, C. J., Huang, J., Hayward, S. D., Hayward, G. S. (2002). CCAAT/Enhancer Binding Protein {alpha} Interacts with ZTA and Mediates ZTA-Induced p21CIP-1 Accumulation and G1 Cell Cycle Arrest during the Epstein-Barr Virus Lytic Cycle. J. Virol. 77: 1481-1500 [Abstract] [Full Text]  
  • Mauser, A., Saito, S.'i., Appella, E., Anderson, C. W., Seaman, W. T., Kenney, S. (2002). The Epstein-Barr Virus Immediate-Early Protein BZLF1 Regulates p53 Function through Multiple Mechanisms. J. Virol. 76: 12503-12512 [Abstract] [Full Text]  
  • Mauser, A., Holley-Guthrie, E., Zanation, A., Yarborough, W., Kaufmann, W., Klingelhutz, A., Seaman, W. T., Kenney, S. (2002). The Epstein-Barr Virus Immediate-Early Protein BZLF1 Induces Expression of E2F-1 and Other Proteins Involved in Cell Cycle Progression in Primary Keratinocytes and Gastric Carcinoma Cells. J. Virol. 76: 12543-12552 [Abstract] [Full Text]  
  • Wu, F. Y., Tang, Q.-Q., Chen, H., ApRhys, C., Farrell, C., Chen, J., Fujimuro, M., Lane, M. D., Hayward, G. S. (2002). Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21CIP-1-mediated G1 cell cycle arrest through CCAAT/enhancer-binding protein-alpha. Proc. Natl. Acad. Sci. USA 99: 10683-10688 [Abstract] [Full Text]  
  • Liao, G., Wu, F. Y., Hayward, S. D. (2001). Interaction with the Epstein-Barr Virus Helicase Targets Zta to DNA Replication Compartments. J. Virol. 75: 8792-8802 [Abstract] [Full Text]  
  • Flemington, E. K. (2001). Herpesvirus Lytic Replication and the Cell Cycle: Arresting New Developments. J. Virol. 75: 4475-4481 [Full Text]  
  • Rodriguez, A., Jung, E. J., Flemington, E. K. (2001). Cell Cycle Analysis of Epstein-Barr Virus-Infected Cells following Treatment with Lytic Cycle-Inducing Agents. J. Virol. 75: 4482-4489 [Abstract] [Full Text]  
  • Polson, A. G., Huang, L., Lukac, D. M., Blethrow, J. D., Morgan, D. O., Burlingame, A. L., Ganem, D. (2001). Kaposi's Sarcoma-Associated Herpesvirus K-bZIP Protein Is Phosphorylated by Cyclin-Dependent Kinases. J. Virol. 75: 3175-3184 [Abstract] [Full Text]  
  • Inman, G. J., Binné, U. K., Parker, G. A., Farrell, P. J., Allday, M. J. (2001). Activators of the Epstein-Barr Virus Lytic Program Concomitantly Induce Apoptosis, but Lytic Gene Expression Protects from Cell Death. J. Virol. 75: 2400-2410 [Abstract] [Full Text]  
  • Park, J., Seo, T., Hwang, S., Lee, D., Gwack, Y., Choe, J. (2000). The K-bZIP Protein from Kaposi's Sarcoma-Associated Herpesvirus Interacts with p53 and Represses Its Transcriptional Activity. J. Virol. 74: 11977-11982 [Abstract] [Full Text]  
  • Feng, P., Ren, E. C., Liu, D., Chan, S. H., Hu, H. (2000). Expression of Epstein-Barr virus lytic gene BRLF1 in nasopharyngeal carcinoma: potential use in diagnosis. J. Gen. Virol. 81: 2417-2423 [Abstract] [Full Text]  
  • Aho, S., Buisson, M., Pajunen, T., Ryoo, Y. W., Giot, J.-F., Gruffat, H., Sergeant, A., Uitto, J. (2000). Ubinuclein, a Novel Nuclear Protein Interacting with Cellular and Viral Transcription Factors. JCB 148: 1165-1176 [Abstract] [Full Text]  


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