Degradation of p53, Not Telomerase Activation, by E6 Is Required for Bypass of Crisis and Immortalization by Human Papillomavirus Type 16 E6/E7
Open Access
- 1 June 2004
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 78 (11) , 5698-5706
- https://doi.org/10.1128/jvi.78.11.5698-5706.2004
Abstract
Bypass of two arrest points is essential in the process of cellular immortalization, one of the components of the transformation process. Expression of human papillomavirus type 16 E6 and E7 together can escape both senescence and crisis, processes which normally limit the proliferative capacity of primary human keratinocytes. Crisis is thought to be mediated by telomere shortening. Because E6 stimulates telomerase activity and exogenous expression of the TERT gene with E7 can immortalize keratinocytes, this function is thought to be important for E6 to cooperate with E7 to bypass crisis. However, it has also been reported that E6 dissociates increased telomerase activity from maintenance of telomere length and that a dominant-negative p53 molecule can substitute for E6 in cooperative immortalization of keratinocytes with E7. Thus, to determine which functions of E6 are required to allow bypass of crisis and immortalization of keratinocytes with E7, immortalization assays were performed using specific mutants of E6, in tandem with E7. In these experiments, every clone expressing an E6 mutant capable of degrading p53 was able to bypass crisis and immortalize, regardless of telomerase induction. All clones containing E6 mutants incapable of degrading p53 died at crisis. These results suggest that the ability of E6 to induce degradation of p53 compensates for continued telomere shortening in E6/E7 cells and demonstrate that degradation of p53 is required for immortalization by E6/E7, while increased telomerase activity is dispensable.Keywords
This publication has 136 references indexed in Scilit:
- Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cellsOncogene, 2003
- Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progressionGenes & Development, 2003
- Induction of a p95/Nbs1‐mediated S phase checkpoint by telomere 3′ overhang specific DNAThe FASEB Journal, 2002
- Activation of ATM and phosphorylation of p53 by heat shockOncogene, 2002
- ATM function and telomere stabilityOncogene, 2002
- Phosphorylation and Rapid Relocalization of 53BP1 to Nuclear Foci upon DNA DamageMolecular and Cellular Biology, 2001
- Ionizing radiation activates the ATM kinase throughout the cell cycleOncogene, 2000
- The Hallmarks of CancerCell, 2000
- Specific Association of Human Telomerase Activity with Immortal Cells and CancerScience, 1994
- Human papillomaviruses in the pathogenesis of anogenital cancerVirology, 1991