Adeno-associated virus type 2 increases proteosome-dependent degradation of p21WAF1 in a human papillomavirus type 31b-positive cervical carcinoma line.
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.
Alam
Samina
S
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Sen
Ellora
E
Brashear
Heidi
H
Meyers
Craig
C
D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D000229:Dependovirus / Q000145:classification / Q000502:physiology*; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D027383:Papillomaviridae / Q000302:isolation & purification* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000201:enzymology / Q000473:pathology / Q000821:virology*
C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051357:Cyclin-Dependent Kinase 2; D046988:Proteasome Endopeptidase Complex