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Journal of Virology, April 2008, p. 3415-3427, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01708-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Adenovirus E1B55K Region Is Required To Enhance Cyclin E Expression for Efficient Viral DNA Replication{triangledown}

Xinyu Zheng,1,4,{dagger} Xiao-Mei Rao,1,{dagger} Jorge G. Gomez-Gutierrez,2 Hongying Hao,2 Kelly M. McMasters,1,2 and H. Sam Zhou1,2,3*

James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky,1 Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky,2 Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky,3 Department of Surgery, First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China4

Received 6 August 2007/ Accepted 9 January 2008

Adenoviruses (Ads) with E1B55K mutations can selectively replicate in and destroy cancer cells. However, the mechanism of Ad-selective replication in tumor cells is not well characterized. We have shown previously that expression of several cell cycle-regulating genes is markedly affected by the Ad E1b gene in WI-38 human lung fibroblast cells (X. Rao, et al., Virology 350:418-428, 2006). In the current study, we show that the Ad E1B55K region is required to enhance cyclin E expression and that the failure to induce cyclin E overexpression due to E1B55K mutations prevents viral DNA from undergoing efficient replication in WI-38 cells, especially when the cells are arrested in the G0 phase of the cell cycle by serum starvation. In contrast, cyclin E induction is less dependent on the function encoded in the E1B55K region in A549 and other cancer cells that are permissive for replication of E1B55K-mutated viruses, whether the cells are in the S phase or G0 phase. The small interfering RNA that specifically inhibits cyclin E expression partially decreased viral replication. Our study provides evidence suggesting that E1B55K may be involved in cell cycle regulation that is important for efficient viral DNA replication and that cyclin E overexpression in cancer cells may be associated with the oncolytic replication of E1B55K-mutated viruses.

* Corresponding author. Mailing address: University of Louisville School of Medicine, Baxter II, Room 321, 580 S. Preston St., Louisville, KY 40202. Phone: (502) 852-5745. Fax: (502) 852-2356. E-mail: hsamzhou{at}yahoo.com

{triangledown} Published ahead of print on 30 January 2008.

{dagger} These authors contributed equally to this work.

Journal of Virology, April 2008, p. 3415-3427, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01708-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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