1887

Abstract

Human cytomegalovirus infection of quiescent fibroblasts was found to induce a bi-phasic activation of mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MKK1/2) and two of their downstream targets, extracellular signal regulated kinase 1 and 2 (ERK1/2), as determined by Western blot analysis using phospho-specific antibodies. Treatment of infected fibroblasts with U0126, a potent and specific inhibitor of MKK1/2 kinase activity, completely blocked ERK1/2 activation following HCMV infection without affecting cell viability. Anti-viral studies demonstrate that in the presence of U0126, viral titres are reduced and viral DNA replication is inhibited. In addition, protein levels of two viral early genes that are required for viral DNA replication, UL44 and UL84, are significantly decreased in the presence of U0126. These results suggest that HCMV-mediated activation of MKK1/2 kinase activity enhances virus infectivity by ensuring timely initiation of viral DNA replication, possibly by regulating early gene expression.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-82-3-493
2001-03-01
2020-07-11
Loading full text...

Full text loading...

/deliver/fulltext/jgv/82/3/0820493a.html?itemId=/content/journal/jgv/10.1099/0022-1317-82-3-493&mimeType=html&fmt=ahah

References

  1. Boyle K. A., Pietropaolo R. L., Compton T.. 1999; Engagement of the cellular receptor for glycoprotein B of human cytomegalovirus activates the interferon-responsive pathway. Molecular and Cellular Biology19:3607–3613
    [Google Scholar]
  2. Bresnahan W. A., Boldogh I., Chi P., Thompson E. A., Albrecht T.. 1997a; Inhibition of cellular Cdk2 activity blocks human cytomegalovirus replication. Virology231:239–247
    [Google Scholar]
  3. Bresnahan W. A., Thompson E. A., Albrecht T.. 1997b; Human cytomegalovirus infection results in altered Cdk2 subcellular localization. Journal of General Virology78:1993–1997
    [Google Scholar]
  4. Britt W. J., Alford C. A.. 1996; Cytomegalovirus. In Fields Virology pp2493–2523 Edited by Fields B. N., Knipe D. M., Howley P. M.. Philadelphia: Lippincott–Raven;
    [Google Scholar]
  5. Chambers J., Angulo A., Amaratunga D., Guo H., Jiang Y., Wan J. S., Bittner A., Frueh K., Jackson M. R., Peterson P. A., Erlander M. G., Ghazal P.. 1999; DNA microarray of the complex human cytomegalovirus genome: profiling kinetics class with drug with drug sensitivity of viral gene expression. Journal of Virology73:5757–5766
    [Google Scholar]
  6. Chau N. H., Vanson C. D., Kerry J. A.. 1999; Transcriptional regulation of the human cytomegalovirus US11 early gene. Journal of Virology73:863–870
    [Google Scholar]
  7. Chee M. S., Bankier A. T., Beck S., Bohni R., Brown C. M., Cerny R., Horsnell T., Hutchison C. A.III., Kouzarides T., Martignetti J. A., Preddie E., Satchwell S. C., Tomlinson P., Weston K. M., Barrell B. G.. 1990; Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Current Topics in Microbiology and Immunology154:125–169
    [Google Scholar]
  8. Dhanasekaran N., Reddy E. P.. 1998; Signaling by dual specificity kinases. Oncogene17:1447–1455
    [Google Scholar]
  9. Favata M. F., Horiuchi K. Y., Manos E. J., Daulerio A. J., Stradley D. A., Feeser W. S., Van Dyk D. E., Pitts W. J., Earl R. A., Hobbs F., Copeland R. A., Magolda R. L., Scherle P. A., Trzaskos J. M.. 1998; Identification of a novel inhibitor of mitogen-activated protein kinase kinase. ournal of Biological Chemistry273:18623–18632
    [Google Scholar]
  10. Harel N. Y., Alwine J. C.. 1998; Phosphorylation of the human cytomegalovirus 86-kilodalton immediate-early protein IE2. Journal of Virology72:5481–5492
    [Google Scholar]
  11. He Y. S., Xu L., Huang E. S.. 1992; Characterization of human cytomegalovirus UL84 early gene and identification of its putative protein product. Journal of Virology66:1098–108
    [Google Scholar]
  12. Huang E.-S., Kowalik T. F.. 1993; The pathogenicity of human cytomegalovirus: an overview. In Molecular Aspects of Human Cytomegalovirus Diseases . pp1–45 Edited by Becker Y., Darai G., Huang E. S.. Berlin: Springer-Verlag;
  13. Johnson R. A., Huong S.-M., Huang E.-S.. 1999; Inhibitory effect of 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1 H-imidazole on HCMV DNA replication and permissive infection. Antiviral Research41:101–111
    [Google Scholar]
  14. Johnson R. A., Huong S.-M., Huang E.-S.. 2000; Activation of the mitogen activated protein kinase (MAPK) p38 by HCMV infection through two distinct pathways: a novel mechanism for activation of p38. Journal of Virology74:1158–1167
    [Google Scholar]
  15. Keay S., Baldwin B. R.. 1996; Evidence for the role of cell protein phosphorylation in human cytomegalovirus/host cell fusion. Journal of General Virology77:2597–2604
    [Google Scholar]
  16. Kerry J. A., Priddy M. A., Jervey T. Y., Kohler C. P., Stanley T. L., Vanson C. D., Jones T. R., Iskemderian A. C., Anders D. G., Stenberg R. M.. 1996; Multiple regulatory events influence human cytomegalovirus DNA polymerase (UL54) expression during viral infection. Journal of Virology70:373–382
    [Google Scholar]
  17. Kerry J. A., Vanson C. D., Staley T. L., Jones T. R., Stenberg R. M.. 1997; The role of ATF in regulating gene expression in human cytomegalovirus infected cells. 21st International Herpes Virus Meeting Abstract Poster #7
    [Google Scholar]
  18. Mar E.-C., Cheng Y.-C., Huang E.-S.. 1983; Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on human cytomegalovirus replication in vitro. Antimicrobial Agents and Chemotherapy24:518–521
    [Google Scholar]
  19. Marshall C. J.. 1995; Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell80:179–186
    [Google Scholar]
  20. Mocarski E.. S. Jr(1996; Cytomegaloviruses and their replication. In Fields Virology pp2447–2492 Edited by Fields B. N., Knipe D. M., Howley P. M.. Philadelphia: Lippincott–Raven;
    [Google Scholar]
  21. Pari G. S., Anders D. G.. 1993; Eleven loci encoding trans -acting factors are required for transient complementation of human cytomegalovirus ori Lyt-dependent DNA replication. Journal of Virology67:6979–6988
    [Google Scholar]
  22. Pari G. S., Kacica M. A., Anders D. G.. 1993; Open reading frames UL44, IRS1/TRS1, and UL36-38 are required for transient complementation of human cytomegalovirus oriLyt-dependent DNA synthesis. Journal of Virology67:2575–2582
    [Google Scholar]
  23. Ripalti A., Boccuni M. C., Campanini F., Landini M. P.. 1995; Cytomegalovirus-mediated induction of antisense mRNA expression to UL44 inhibits virus replication in an astrocytoma cell line: identification of an essential gene. Journal of Virology69:2047–2057
    [Google Scholar]
  24. Rodems S. M., Spector D. H.. 1998; Extracellular signal-regulated kinase activity is sustained early during human cytomegalovirus infection. Journal of Virology72:9173–9180
    [Google Scholar]
  25. Rodems S. M., Clark C. L., Spector D. H.. 1998; Separate DNA elements containing ATF/CREB and IE86 binding sites differentially regulate the human cytomegalovirus UL112-113 promoter at early and late times in the infection. Journal of Virology72:2697–2707
    [Google Scholar]
  26. Roizman B.. 1996; Herpesviridae. In Fields Virology pp2221–2230 Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia: Lippincott–Raven;
    [Google Scholar]
  27. Sarisky R. T., Hayward G. S.. 1996; Evidence that the UL84 gene product of human cytomegalovirus is essential for promoting ori Lyt-dependent DNA replication and formation of replication compartments in cotransfection assays. Journal of Virology70:7398–7413
    [Google Scholar]
  28. Seger R., Krebs E. G.. 1995; The MAPK signaling cascade. FASEB Journal9:726–734
    [Google Scholar]
  29. Tibbles L. A., Woodgett J. R.. 1999; The stress-activated protein kinase pathways. Cellular and Molecular Life Sciences55:1230–1254
    [Google Scholar]
  30. Wade E. J., Klucher K. M., Spector D. H.. 1992; An AP-1 binding site is the predominant cis -acting regulatory element in the 1·2-kilobase early RNA promoter of human cytomegalovirus. Journal of Virology66:2407–2417
    [Google Scholar]
  31. Widmann C., Gibson S., Jarpe B., Johnson G. L.. 1999; Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiological Reviews79:143–180
    [Google Scholar]
  32. Wing B. A., Lee G. C. Y., Huang E.-S.. 1996; The human cytomegalovirus UL94 open reading frame encodes a conserved herpesvirus capsid/tegument-associated virion protein that is expressed with true late kinetics. Journal of Virology70:3339–3345
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-82-3-493
Loading
/content/journal/jgv/10.1099/0022-1317-82-3-493
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error