This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
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 van Dyk, L. F.
Right arrow Articles by Virgin, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Dyk, L. F.
Right arrow Articles by Virgin, H. W., IV

 Previous Article  |  Next Article 

Journal of Virology, June 1999, p. 5110-5122, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes

Linda F. van Dyk,1 Jay L. Hess,2 Jonathan D. Katz,1 Meagan Jacoby,1 Samuel H. Speck,1,* and Herbert W. Virgin IV1,*

Center for Immunology, Departments of Pathology and Molecular Microbiology,1 and Lauren V. Ackerman Laboratory of Surgical Pathology,2 Washington University School of Medicine, St. Louis, Missouri

Received 10 November 1998/Accepted 4 March 1999

Several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (gamma HV68) viral cyclin (v-cyclin). The gamma HV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the gamma HV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the gamma HV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lck proximal promoter to express the gamma HV68 v-cyclin in early T cells. Expression of the gamma HV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse-labeling. Expression of the gamma HV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+ CD8+ double-positive thymocytes and decreased numbers of CD4+ or CD8+ single-positive and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, gamma HV68-v-cyclin-transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 gamma HV68-v-cyclin-transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the gamma HV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the gamma HV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the gamma HV68 v-cyclin gene is an oncogene.

* Corresponding author. Mailing address: Center for Immunology, Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, Box B118, 660 S. Euclid Ave., St. Louis, MO 63110-1093. Phone for Samuel H. Speck: (314) 362-0367. Fax: (314) 362-4096. E-mail: speck{at}pathbox.wustl.edu. Phone for Herbert W. Virgin IV: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu.

Journal of Virology, June 1999, p. 5110-5122, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Jia, Q., Freeman, M. L., Yager, E. J., McHardy, I., Tong, L., Martinez-Guzman, D., Rickabaugh, T., Hwang, S., Blackman, M. A., Sun, R., Wu, T.-T. (2010). Induction of Protective Immunity against Murine Gammaherpesvirus 68 Infection in the Absence of Viral Latency. J. Virol. 84: 2453-2465 [Abstract] [Full Text]  
  • Forrest, J. C., Speck, S. H. (2008). Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade. J. Virol. 82: 7688-7699 [Abstract] [Full Text]  
  • Tarakanova, V. L., Kreisel, F., White, D. W., Virgin, H. W. IV (2008). Murine Gammaherpesvirus 68 Genes both Induce and Suppress Lymphoproliferative Disease. J. Virol. 82: 1034-1039 [Abstract] [Full Text]  
  • Forrest, J. C., Paden, C. R., Allen, R. D. III, Collins, J., Speck, S. H. (2007). ORF73-Null Murine Gammaherpesvirus 68 Reveals Roles for mLANA and p53 in Virus Replication. J. Virol. 81: 11957-11971 [Abstract] [Full Text]  
  • Mora, A. L., Torres-Gonzalez, E., Rojas, M., Xu, J., Ritzenthaler, J., Speck, S. H., Roman, J., Brigham, K., Stecenko, A. (2007). Control of Virus Reactivation Arrests Pulmonary Herpesvirus-induced Fibrosis in IFN-{gamma} Receptor-deficient Mice. Am. J. Respir. Crit. Care Med. 175: 1139-1150 [Abstract] [Full Text]  
  • Upton, J. W., Speck, S. H. (2006). Evidence for CDK-Dependent and CDK-Independent Functions of the Murine Gammaherpesvirus 68 v-Cyclin. J. Virol. 80: 11946-11959 [Abstract] [Full Text]  
  • Moser, J. M., Upton, J. W., Gray, K. S., Speck, S. H. (2005). Ex Vivo Stimulation of B Cells Latently Infected with Gammaherpesvirus 68 Triggers Reactivation from Latency. J. Virol. 79: 5227-5231 [Abstract] [Full Text]  
  • An, F.-Q., Compitello, N., Horwitz, E., Sramkoski, M., Knudsen, E. S., Renne, R. (2005). The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Modulates Cellular Gene Expression and Protects Lymphoid Cells from p16 INK4A-induced Cell Cycle Arrest. J. Biol. Chem. 280: 3862-3874 [Abstract] [Full Text]  
  • Sparks-Thissen, R. L., Braaten, D. C., Kreher, S., Speck, S. H., Virgin, H. W. IV (2004). An Optimized CD4 T-Cell Response Can Control Productive and Latent Gammaherpesvirus Infection. J. Virol. 78: 6827-6835 [Abstract] [Full Text]  
  • Verschuren, E. W., Hodgson, J. G., Gray, J. W., Kogan, S., Jones, N., Evan, G. I. (2004). The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis. Cancer Res. 64: 581-589 [Abstract] [Full Text]  
  • Holzschu, D., Lapierre, L. A., Lairmore, M. D. (2003). Comparative Pathogenesis of Epsilonretroviruses. J. Virol. 77: 12385-12391 [Full Text]  
  • van Dyk, L. F., Virgin, H. W. IV, Speck, S. H. (2003). Maintenance of Gammaherpesvirus Latency Requires Viral Cyclin in the Absence of B Lymphocytes. J. Virol. 77: 5118-5126 [Abstract] [Full Text]  
  • Kalejta, R. F., Shenk, T. (2003). The Human Cytomegalovirus UL82 Gene Product (pp71) Accelerates Progression through the G1 Phase of the Cell Cycle. J. Virol. 77: 3451-3459 [Abstract] [Full Text]  
  • Ebrahimi, B., Dutia, B. M., Roberts, K. L., Garcia-Ramirez, J. J., Dickinson, P., Stewart, J. P., Ghazal, P., Roy, D. J., Nash, A. A. (2003). Transcriptome profile of murine gammaherpesvirus-68 lytic infection. J. Gen. Virol. 84: 99-109 [Abstract] [Full Text]  
  • Flano, E., Kim, I.-J., Woodland, D. L., Blackman, M. A. (2002). {gamma}-Herpesvirus Latency Is Preferentially Maintained in Splenic Germinal Center and Memory B Cells. JEM 196: 1363-1372 [Abstract] [Full Text]  
  • Gangappa, S., Kapadia, S. B., Speck, S. H., Virgin, H. W. IV (2002). Antibody to a Lytic Cycle Viral Protein Decreases Gammaherpesvirus Latency in B-Cell-Deficient Mice. J. Virol. 76: 11460-11468 [Abstract] [Full Text]  
  • Cuconati, A., White, E. (2002). Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev. 16: 2465-2478 [Full Text]  
  • Wakeling, M. N., Roy, D. J., Nash, A. A., Stewart, J. P. (2001). Characterization of the murine gammaherpesvirus 68 ORF74 product: a novel oncogenic G protein-coupled receptor. J. Gen. Virol. 82: 1187-1197 [Abstract] [Full Text]  
  • Ensser, A., Glykofrydes, D., Niphuis, H., Kuhn, E. M., Rosenwirth, B., Heeney, J. L., Niedobitek, G., Muller-Fleckenstein, I., Fleckenstein, B. (2001). Independence of Herpesvirus-Induced T Cell Lymphoma from Viral Cyclin D Homologue. JEM 193: 637-642 [Abstract] [Full Text]  
  • Presti, R. M., Popkin, D. L., Connick, M., Paetzold, S., Virgin, H. W. IV (2001). Novel Cell Type-Specific Antiviral Mechanism of Interferon {gamma} Action in Macrophages. JEM 193: 483-496 [Abstract] [Full Text]  
  • van Dyk, L. F., Virgin, H. W. IV, Speck, S. H. (2000). The Murine Gammaherpesvirus 68 v-Cyclin Is a Critical Regulator of Reactivation from Latency. J. Virol. 74: 7451-7461 [Abstract] [Full Text]  
  • van Berkel, V., Barrett, J., Tiffany, H. L., Fremont, D. H., Murphy, P. M., McFadden, G., Speck, S. H., Virgin, H. W. IV (2000). Identification of a Gammaherpesvirus Selective Chemokine Binding Protein That Inhibits Chemokine Action. J. Virol. 74: 6741-6747 [Abstract] [Full Text]  
  • Hoge, A. T., Hendrickson, S. B., Burns, W. H. (2000). Murine Gammaherpesvirus 68 Cyclin D Homologue Is Required for Efficient Reactivation from Latency. J. Virol. 74: 7016-7023 [Abstract] [Full Text]  
  • Kapadia, S. B., Molina, H., van Berkel, V., Speck, S. H., Virgin, H. W. IV (1999). Murine Gammaherpesvirus 68 Encodes a Functional Regulator of Complement Activation. J. Virol. 73: 7658-7670 [Abstract] [Full Text]  
  • Gangappa, S., van Dyk, L. F., Jewett, T. J., Speck, S. H., Virgin, H. W. IV (2002). Identification of the In Vivo Role of a Viral bcl-2. JEM 195: 931-940 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»