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Journal of Virology, April 2005, p. 3998-4011, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.3998-4011.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E1{wedge}E4-Induced G2 Arrest Is Associated with Cytoplasmic Retention of Active Cdk1/Cyclin B1 Complexes

Clare E. Davy,1 Deborah J. Jackson,1 Kenneth Raj,1 Woei Ling Peh,1 Shirley A. Southern,1 Papia Das,1 Rina Sorathia,1 Peter Laskey,1 Kate Middleton,1 Tomomi Nakahara,2 Qian Wang,1 Phillip J. Masterson,1 Paul F. Lambert,2 Scott Cuthill,3 Jonathan B. A. Millar,4 and John Doorbar1*

Division of Virology,1 Division of Yeast Genetics, National Institute for Medical Research, London,4 OSI Pharmaceuticals, Oxford, United Kingdom,3 McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine, Madison, Wisconsin2

Received 25 February 2004/ Accepted 2 November 2004

Human papillomavirus type 16 (HPV16) can cause cervical cancer. Expression of the viral E1{wedge}E4 protein is lost during malignant progression, but in premalignant lesions, E1{wedge}E4 is abundant in cells supporting viral DNA amplification. Expression of 16E1{wedge}E4 in cell culture causes G2 cell cycle arrest. Here we show that unlike many other G2 arrest mechanisms, 16E1{wedge}E4 does not inhibit the kinase activity of the Cdk1/cyclin B1 complex. Instead, 16E1{wedge}E4 uses a novel mechanism in which it sequesters Cdk1/cyclin B1 onto the cytokeratin network. This prevents the accumulation of active Cdk1/cyclin B1 complexes in the nucleus and hence prevents mitosis. A mutant 16E1{wedge}E4 (T22A, T23A) which does not bind cyclin B1 or alter its intracellular location fails to induce G2 arrest. The significance of these results is highlighted by the observation that in lesions induced by HPV16, there is evidence for Cdk1/cyclin B1 activity on the keratins of 16E1{wedge}E4-expressing cells. We hypothesize that E1{wedge}E4-induced G2 arrest may play a role in creating an environment optimal for viral DNA replication and that loss of E1{wedge}E4 expression may contribute to malignant progression.

* Corresponding author. Mailing address: Division of Virology, National Institute for Medical Research, London, NW7 1AA, United Kingdom. Phone: 44 (0) 20 8816 2623. Fax: 44 (0) 20 8906 4477. E-mail: jdoorba{at}nimr.mrc.ac.uk.

Journal of Virology, April 2005, p. 3998-4011, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.3998-4011.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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