Adeno-associated Virus Type 2 Increases Proteosome-Dependent Degradation of p21WAF1 in a Human Papillomavirus Type 31b-positive Cervical Carcinoma Line

J Virol. 2006 May;80(10):4927-39. doi: 10.1128/JVI.80.10.4927-4939.2006.

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 onco-suppression 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 G(1)/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 G(1) phase progression. We propose that by down regulating p21(WAF1), AAV2 initiates cell cycle activities leading to enhanced G(1)/S phase-like conditions which may be favorable for AAV2-specific functions and may lead to downstream interference with HPV-associated cervical cancer progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / physiology
  • Cell Line
  • Cervical Intraepithelial Neoplasia / enzymology
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology*
  • Cyclin E / biosynthesis
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Dependovirus / classification
  • Dependovirus / physiology*
  • Female
  • Humans
  • Keratinocytes / enzymology
  • Keratinocytes / metabolism
  • Keratinocytes / virology
  • Papillomaviridae / isolation & purification*
  • Papillomaviridae / physiology
  • Proteasome Endopeptidase Complex / physiology*
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • Up-Regulation / physiology
  • Uterine Cervical Neoplasms / enzymology
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*

Substances

  • CDKN1A protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53
  • Cyclin-Dependent Kinase 2
  • Proteasome Endopeptidase Complex