Induction of senescence-like state and suppression of telomerase activity through inhibition of HPV E6/E7 gene expression in cells immortalized by HPV16 DNA.
The E6 and E7 oncoproteins of human papillomavirus (HPV) play a major role in the development of cervical carcinoma. In this study, a recombinant adenovirus that expresses the bovine papillomavirus (BPV) E2, which has been shown to inhibit HPV early gene expression, was delivered to two HPV-immortalized cell lines as well as CaSki, a cervical carcinoma cell line. We tested whether the carcinoma and the immortal cells were equally affected by the expression of BPV E2. In all cell lines, BPV E2-mediated inhibition of HPV E6/E7 expression caused a dramatic suppression of cell growth, being preceded by the activation of the p53-Rb growth-inhibitory pathway, and a decrease in hTERT mRNA expression and telomerase activity. This suggests that the HPV E6 and E7 proteins are required not only for induction of the proliferative phenotype and telomerase activity, but also for their maintenance. In both the carcinoma and the immortal lines, the number of cells with enlarged cytoplasm and senescence-associated beta-galactosidase activity, which are markers for cellular senescence, was significantly increased. These results suggest that a senescence program exists in cells immortalized by HPV DNA as well as in cervical carcinoma cells.
Lee
Chan Jae
CJ
Department of Life Science, University of Seoul, 90 Jeonnongdong, Dongdaemungu, Korea.
Suh
Eun Jung
EJ
Kang
Hyun Tae
HT
Im
Jun Sub
JS
Um
Soo Jong
SJ
Park
Jong Sup
JS
Hwang
Eun Seong
ES
D000818:Animals; D015415:Biomarkers; D002417:Cattle; D018797:Cell Cycle Proteins; D002455:Cell Division; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004279:DNA, Viral / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050684:E2F Transcription Factors; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C051550:E2 protein, Bovine papillomavirus; D050684:E2F Transcription Factors; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D019098:Telomerase