Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells.
The human papillomavirus (HPV) E2 protein is an important regulator of viral E6 and E7 gene expression. E2 can repress the viral promoter for E6 and E7 expression as well as block progression of the cell cycle in cancer cells harboring the DNA of "high-risk" HPV types. Although the phenomenon of E2-mediated growth arrest of HeLa cells and other HPV-positive cancer cells has been well documented, the specific mechanism by which E2 affects cellular proliferation has not yet been elucidated. Here, we show that bovine papillomavirus (BPV) E2-induced growth arrest of HeLa cells requires the repression of the E6 and E7 promoter. This repression is specific for E2TA and not E2TR, a BPV E2 variant that lacks the N-terminal transactivation domain. We demonstrate that expression of HPV16 E6 and E7 from a heterologous promoter that is not regulated by E2 rescues HeLa cells from E2-mediated growth arrest. Our data indicate that the pathway of E2-mediated growth arrest of HeLa cells requires repression of E6 and E7 expression through an activity specified by the transactivation domain of E2TA.
Francis
D A
DA
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Schmid
S I
SI
Howley
P M
PM
D000818:Animals; D002417:Cattle; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015967:Gene Expression Regulation, Viral; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics; D016662:Virus Integration
D004268:DNA-Binding Proteins; C051550:E2 protein, Bovine papillomavirus; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16