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Journal of Virology, May 2006, p. 4927-4939, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4927-4939.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Adeno-Associated Virus Type 2 Increases Proteosome-Dependent Degradation of p21^WAF1 in a Human Papillomavirus Type 31b-Positive Cervical Carcinoma Line

Samina Alam, Ellora Sen, Heidi Brashear, and Craig Meyers^*

Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Received 12 September 2005/ Accepted 21 February 2006

Adeno-associated virus type 2 (AAV2) seropositivity is negatively correlated with the development of human papillomavirus (HPV)-associated cervical cancer. We have begun analysis of the molecular mechanisms underlying AAV2-mediated oncosuppression through cell cycle regulation in HPV-infected keratinocytes isolated from a low-grade cervical lesion. AAV2 superinfection of HPV type 31b (HPV31b)-positive cells at early times postinfection resulted in degradation of the cyclin-dependent kinase (CDK) inhibitor p21^WAF1 protein in a proteosome-dependent manner. Downstream consequences of lowering p21^WAF1 levels included a proportional loss of cyclin E/CDK2 complexes bound to p21^WAF1. The loss of stable p21^WAF1/cyclin E/CDK2 complexes coincided with an increase in CDK2-associated kinase activity and cyclin E levels. Both events have the potential to enhance the G₁/S transition point mediated by active cyclin E/CDK2 complexes. Concurrently, cyclin A and E2F levels were decreased, conditions reminiscent of delayed entrance into the S phase of the cell cycle. On the other hand, infection of primary human foreskin keratinocytes with AAV2 resulted in upregulation of p21^WAF1 protein levels, reminiscent of a block in G₁ phase progression. We propose that by downregulating p21^WAF1, AAV2 initiates cell cycle activities leading to enhanced G₁/S phase-like conditions which may be favorable for AAV2-specific functions and may lead to downstream interference with HPV-associated cervical cancer progression.

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* Corresponding author. Mailing address: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033. Phone: (717) 531-6240. Fax: (717) 531-4600. E-mail: cmm10{at}psu.edu.

Present address: National Brain Research Centre, Manesar 122 050, Haryana, India.

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Journal of Virology, May 2006, p. 4927-4939, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4927-4939.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Alam, S., Meyers, C. (2009). Adeno-Associated Virus Type 2 Induces Apoptosis in Human Papillomavirus-Infected Cell Lines but Not in Normal Keratinocytes. J. Virol. 83: 10286-10292 [Abstract] [Full Text]  
• Alam, S., Conway, M. J., Chen, H.-S., Meyers, C. (2008). The Cigarette Smoke Carcinogen Benzo[a]pyrene Enhances Human Papillomavirus Synthesis. J. Virol. 82: 1053-1058 [Abstract] [Full Text]