This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goodwin, E. C. Articles by DiMaio, D. Search for Related Content PubMed PubMed Citation Articles by Goodwin, E. C. Articles by DiMaio, D.

Induced Senescence in HeLa Cervical Carcinoma Cells Containing Elevated Telomerase Activity and Extended Telomeres¹

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510

Proliferation of normal somatic human cells in culture is limited by replicative senescence, a growth-arrested state that appears to be triggered by the erosion of telomeres. Tumor cells such as HeLa cervical carcinoma cells, which contain short telomeres, can be induced to undergo senescence by various manipulations including oncogene withdrawal. Repression of the human papillomavirus (HPV) type 18 E6/E7 genes in HeLa cells by the bovine papillomavirus E2 transcriptional regulatory protein results in reactivation of the dormant p53 and p105^Rb tumor suppressor pathways in these cells, repression of telomerase, and profound growth arrest. Strikingly, the growth-arrested cells rapidly and synchronously acquired numerous characteristics of primary cells undergoing replicative senescence. To explore the role of telomerase and telomere length in induced senescence, we expressed an exogenous hTERT gene, which encodes the catalytic subunit of telomerase, to generate stable HeLa cell clones with elevated telomerase activity and extended telomeres. Expression of the E2 protein in these cells repressed HPV E6/E7 expression, activated tumor suppressor pathways, and induced senescence as assessed by growth arrest, morphological changes, senescence-associated ß-galactosidase expression, and increased autofluorescence. Cells carrying the hTERT gene and control cells displayed identical responses to E2 expression. Therefore, HeLa cell senescence induced by HPV repression is not triggered by short telomeres or low levels of telomerase activity.

This article has been cited by other articles:

				Y.-W. Cheng, T.-C. Wu, C.-Y. Chen, M.-C. Chou, J.-L. Ko, and H. Lee Human Telomerase Reverse Transcriptase Activated by E6 Oncoprotein Is Required for Human Papillomavirus-16/18-Infected Lung Tumorigenesis Clin. Cancer Res., November 15, 2008; 14(22): 7173 - 7179. [Abstract] [Full Text] [PDF]

				M. L. Nguyen, R. M. Kraft, M. Aubert, E. Goodwin, D. DiMaio, and J. A. Blaho p53 and hTERT Determine Sensitivity to Viral Apoptosis J. Virol., December 1, 2007; 81(23): 12985 - 12995. [Abstract] [Full Text] [PDF]

				K. Johung, E. C. Goodwin, and D. DiMaio Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence J. Virol., March 1, 2007; 81(5): 2102 - 2116. [Abstract] [Full Text] [PDF]

				S.-Y. Wu, A-Y. Lee, S. Y. Hou, J. K. Kemper, H. Erdjument-Bromage, P. Tempst, and C.-M. Chiang Brd4 links chromatin targeting to HPV transcriptional silencing Genes & Dev., September 1, 2006; 20(17): 2383 - 2396. [Abstract] [Full Text] [PDF]

				O. Binda, J.-S. Roy, and P. E. Branton RBP1 Family Proteins Exhibit SUMOylation-Dependent Transcriptional Repression and Induce Cell Growth Inhibition Reminiscent of Senescence Mol. Cell. Biol., March 1, 2006; 26(5): 1917 - 1931. [Abstract] [Full Text] [PDF]

				T. M. Wise-Draper, H. V. Allen, M. N. Thobe, E. E. Jones, K. B. Habash, K. Munger, and S. I. Wells The Human DEK Proto-Oncogene Is a Senescence Inhibitor and an Upregulated Target of High-Risk Human Papillomavirus E7 J. Virol., November 15, 2005; 79(22): 14309 - 14317. [Abstract] [Full Text] [PDF]

				H. M. Chan, M. Narita, S. W. Lowe, and D. M. Livingston The p400 E1A-associated protein is a novel component of the p53 -> p21 senescence pathway Genes & Dev., January 15, 2005; 19(2): 196 - 201. [Abstract] [Full Text] [PDF]

				P. Fotiadou, O. Henegariu, and J. B. Sweasy DNA Polymerase {beta} Interacts with TRF2 and Induces Telomere Dysfunction in a Murine Mammary Cell Line Cancer Res., June 1, 2004; 64(11): 3830 - 3837. [Abstract] [Full Text] [PDF]

				S. M. Horner, R. A. DeFilippis, L. Manuelidis, and D. DiMaio Repression of the Human Papillomavirus E6 Gene Initiates p53-Dependent, Telomerase-Independent Senescence and Apoptosis in HeLa Cervical Carcinoma Cells J. Virol., April 15, 2004; 78(8): 4063 - 4073. [Abstract] [Full Text] [PDF]

				G. Kennedy, J. Komano, and B. Sugden Epstein-Barr virus provides a survival factor to Burkitt's lymphomas PNAS, November 25, 2003; 100(24): 14269 - 14274. [Abstract] [Full Text] [PDF]

				S. I. Wells, B. J. Aronow, T. M. Wise, S. S. Williams, J. A. Couget, and P. M. Howley Transcriptome signature of irreversible senescence in human papillomavirus-positive cervical cancer cells PNAS, June 10, 2003; 100(12): 7093 - 7098. [Abstract] [Full Text] [PDF]

				I. B. Roninson Tumor Cell Senescence in Cancer Treatment Cancer Res., June 1, 2003; 63(11): 2705 - 2715. [Abstract] [Full Text] [PDF]

				R. A. DeFilippis, E. C. Goodwin, L. Wu, and D. DiMaio Endogenous Human Papillomavirus E6 and E7 Proteins Differentially Regulate Proliferation, Senescence, and Apoptosis in HeLa Cervical Carcinoma Cells J. Virol., January 15, 2003; 77(2): 1551 - 1563. [Abstract] [Full Text] [PDF]

				R. Marcotte and E. Wang Replicative Senescence Revisited J Gerontol A Biol Sci Med Sci, July 1, 2002; 57(7): B257 - B269. [Abstract] [Full Text] [PDF]

				W. Boner, E. R. Taylor, E. Tsirimonaki, K. Yamane, M. S. Campo, and I. M. Morgan A Functional Interaction between the Human Papillomavirus 16 Transcription/Replication Factor E2 and the DNA Damage Response Protein TopBP1 J. Biol. Chem., June 14, 2002; 277(25): 22297 - 22303. [Abstract] [Full Text] [PDF]