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Journal of Virology, January 2003, p. 1-9, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.1-9.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ubiquitin-Dependent Proteolysis of Cyclin D1 Is Associated with Coxsackievirus-Induced Cell Growth Arrest

Honglin Luo,¹ Jingchun Zhang,¹ Frank Dastvan,² Bobby Yanagawa,¹ Michael A. Reidy,² Huifang M. Zhang,¹ Decheng Yang,¹ Janet E. Wilson,¹ and Bruce M. McManus^1*

McDonald Research Laboratories/The iCAPTUR⁴E Center, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada,¹ Department of Pathology, University of Washington, Seattle, Washington²

Received 25 July 2002/ Accepted 19 September 2002

Coxsackievirus group B3 (CVB3) replication is influenced by host cell cycle status. However, the effect of CVB3 infection on cell cycle regulation and the mechanisms involved are not precisely defined. In this study, we examined cell cycle progression and regulation when the infection was initiated in late G₁ phase of the cell cycle. Analysis of cellular DNA synthesis in infected cells by thymidine incorporation assays showed a significant reduction in [³H]thymidine uptake compared to that of sham-infected cells. To further clarify the effects of CVB3 on the host cell cycle, we examined the cell cycle regulatory proteins involved in G₁ progression and G₁/S transition. Infection resulted in dephosphorylation of retinoblastoma protein and reduced G₁ cyclin-dependent kinase activities, accompanied by decreased levels of G₁ cyclin protein expression (cyclin D1 and cyclin E). We further investigated the mechanisms by which CVB3 infection down-regulates cyclin D1 expression. Northern blotting showed that cyclin D1 mRNA levels were modestly increased following CVB3 infection, suggesting that cyclin D1 regulation occurs by a posttranscriptional mechanism. Viral infection resulted in only a 20 to 30% inhibition of cyclin D1 protein synthesis 3 h postinfection. However, the proteasome inhibitors MG132 and lactacystin prevent CVB3-induced cyclin D1 reduction, indicating that CVB3-induced down-regulation of cyclin D1 is facilitated by ubiquitin-proteasome proteolysis. Finally, using GSK3ß pathway inhibitors, we showed that the reduction of cyclin D1 is GSK3ß independent. Taken together, our results demonstrate that CVB3 infection disrupts host cell homeostasis by blocking the cell cycle at the G₁/S boundary and induces cell cycle arrest in part through an increase in ubiquitin-dependent proteolysis of cyclin D1.

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* Corresponding author. Mailing address: Cardiovascular Research Laboratory, University of British Columbia-St. Paul's Hospital, 1081 Burrard St., Vancouver, B.C., Canada V6Z 1Y6. Phone: (604) 806-8586. Fax: (604) 806-8351. E-mail: bmcmanus{at}mrl.ubc.ca.

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Journal of Virology, January 2003, p. 1-9, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.1-9.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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