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Journal of Virology, October 2003, p. 10566-10574, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10566-10574.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Direct Activation of Cyclin-Dependent Kinase 2 by Human Papillomavirus E7

Wanxia He,1 Doug Staples,2 Clark Smith,2 and Chris Fisher1*

Genomics-ID,1 Research Operations, Pharmacia Corp., Kalamazoo, Michigan 490062

Received 23 May 2003/ Accepted 10 July 2003

Addition of human papillomavirus (HPV) E7 CDK2/cyclin A or CDK2/cyclin E, purified from either insect cells or bacteria, dramatically upregulates histone H1 kinase activity. Activation is substrate specific, with a smaller effect noted for retinoblastoma protein (Rb). The CDK2 stimulatory activity is equivalent in high-risk (HPV type 16 [HPV16] and HPV31) and low-risk (HPV6b) E7. Mutational analyses of HPV16 E7 indicate that the major activity resides in amino acids 9 to 38, spanning CR1 and CR2, and does not require casein kinase II or Rb-binding domain functions. Synthetic peptides spanning HPV16 amino acid residues 9 to 38 also activate CDK2. Peptides containing this sequence that carry biotin on the carboxy terminus, as well as a photoactivated cross-linking group (benzophenone), also activate the complex and covalently associate with the CDK2/cyclin A complex in a specific manner requiring UV. Cross-linking studies that use protein monomers detect association of the E7 peptides with cyclin A but not CDK2. Together, our results indicate a novel mechanism whereby E7 promotes HPV replication by directly altering CDK2 activity and substrate specificity.

* Corresponding author. Present address: 4717 Campus Dr., Kalamazoo, MI 49008. Phone: (269) 345-3273. Fax: (269) 372-3397. E-mail: cfisher1{at}chartermi.net.

Journal of Virology, October 2003, p. 10566-10574, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10566-10574.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Shin, M.-K., Balsitis, S., Brake, T., Lambert, P. F. (2009). Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis. Cancer Res. 69: 5656-5663 [Abstract] [Full Text]  
  • Nguyen, C. L., Eichwald, C., Nibert, M. L., Munger, K. (2007). Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Centrosomal Component {gamma}-Tubulin. J. Virol. 81: 13533-13543 [Abstract] [Full Text]  
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