Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways.
A hallmark of human papillomavirus (HPV) associated carcinogenesis is the integration of the viral DNA into the cellular genome, usually accompanied by the loss of expression of the viral E2 gene. E2 binds to and represses the viral promoter directing expression of the E6 and E7 oncogenes. The re-introduction and expression of exogenous E2 in HPV-positive cancer cells results in cellular growth arrest, while growth in the context of exogenous E2 can be restored through the expression of exogenous E6 and E7. Here we examine the individual contributions of the viral E6 and E7 genes to this phenotype. E6 alone displays moderate activity, whereas both E7 and adenovirus E1A display high activity in reversing E2-mediated cellular growth suppression. Using defined mutants of E7 and E1A, we show that an intact retinoblastoma interaction domain is required for this function. In addition, we show that the E2-mediated growth arrest of HPV-positive cells results in cellular senescence, and implicate the cyclin/cdk inhibitor p21(CIP) as a downstream E2 effector in this phenotype.
Wells
S I
SI
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Francis
D A
DA
Karpova
A Y
AY
Dowhanick
J J
JJ
Benson
J D
JD
Howley
P M
PM
D001483:Base Sequence; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D005260:Female; D005814:Genes, Viral; D006367:HeLa Cells; D006801:Humans; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D010641:Phenotype; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; C068651:E6 protein, Human papillomavirus type 16; D020319:Oligodeoxyribonucleotides, Antisense; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16