Adeno-associated virus type 2 increases proteosome-dependent degradation of p21WAF1 in a human papillomavirus type 31b-positive cervical carcinoma line

Samina Alam, Ellora Sen, Heidi Brashear, Craig Meyers

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 p21WAF1 protein in a proteosome-dependent manner. Downstream consequences of lowering p21WAF1 levels included a proportional loss of cyclin E/CDK2 complexes bound to p21WAF1. 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 p21WAF1 protein levels, reminiscent of a block in G1 phase progression. We propose that by down-regulating p21WAF1, 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.

Original languageEnglish (US)
Pages (from-to)4927-4939
Number of pages13
JournalJournal of virology
Volume80
Issue number10
DOIs
StatePublished - May 1 2006

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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