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Journal of Virology, August 2006, p. 7416-7426, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00196-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role for Wee1 in Inhibition of G2-to-M Transition through the Cooperation of Distinct Human Papillomavirus Type 1 E4 Proteins

Gillian L. Knight, Andrew S. Turnell, and Sally Roberts*

Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, United Kingdom

Received 27 January 2006/ Accepted 12 May 2006

The infectious cycle of human papillomavirus type 1 (HPV1) is accompanied by abundant expression of the full-length E1^E4 protein (17-kDa) and smaller E4 polypeptides (16-, 11-, and 10-kDa) that arise by sequential loss of N-terminal E1^E4 sequences. HPV1 E4 inhibits G2-to-M transition of the cell cycle. Here, we show that HPV1 E4 proteins mediate inhibition of cell division by more than one mechanism. Cells arrested by coexpression of E1^E4 (E4-17K) and a truncated protein equivalent to the 16-kDa species (E4-16K) contain inactive cyclin B1-cdk1 complexes. Inactivation of cdk1 is through inhibitory Tyr15 phosphorylation, with cells containing elevated levels of Wee1, the kinase responsible for inhibitory cdk1 phosphorylation. Consistent with these findings, overexpression of Wee1 enhanced the extent to which E4-17K/16K-expressing cells arrest in G2, indicating that maintenance of Wee1 activity is necessary for inhibition of cell division induced by coexpression of the two E4 proteins. Moreover, we have determined that depletion of Wee1 by small interfering RNA (siRNA) alleviates the G2 block imposed by E4-17K/16K. In contrast however, maintenance of Wee1 activity is not necessary for G2-to-M inhibition mediated by E4-16K alone, as overexpression or depletion of Wee1 does not influence the G2 arrest function of E4-16K. Cells arrested by E4-16K expression contain low levels of active cyclin B1-cdk1 complexes. We hypothesize that differential expression of HPV1 E4 proteins during the viral life cycle determines the host cell cycle status. Different mechanisms of inhibition of G2-to-M transition reinforce the supposition that distinct E4 functions are important for HPV replication.

* Corresponding author. Mailing address: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-4147459. Fax: 44-121-4144486. E-mail: s.roberts{at}bham.ac.uk.

Journal of Virology, August 2006, p. 7416-7426, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00196-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Conway, M.J., Meyers, C. (2009). Replication and Assembly of Human Papillomaviruses. JDR 88: 307-317 [Abstract] [Full Text]  
  • Galloway, D. A. (2009). Human papillomaviruses: a growing field. Genes Dev. 23: 138-142 [Abstract] [Full Text]  
  • Roberts, S., Kingsbury, S. R., Stoeber, K., Knight, G. L., Gallimore, P. H., Williams, G. H. (2008). Identification of an Arginine-Rich Motif in Human Papillomavirus Type 1 E1^E4 Protein Necessary for E4-Mediated Inhibition of Cellular DNA Synthesis In Vitro and in Cells. J. Virol. 82: 9056-9064 [Abstract] [Full Text]  
  • Bell, I., Martin, A., Roberts, S. (2007). The E1^E4 Protein of Human Papillomavirus Interacts with the Serine-Arginine-Specific Protein Kinase SRPK1. J. Virol. 81: 5437-5448 [Abstract] [Full Text]  


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