Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase

Oncogene volume 18, pages 7676–7680 (1999)Cite this article

Abstract

Telomere shortening may be one of several factors that contribute to the onset of senescence in human cells. The p53 and pRb pathways are involved in the regulation of cell cycle progression from G1 into S phase and inactivation of these pathways leads to extension of life span. Short dysfunctional telomeres may be perceived as damaged DNA and may activate these pathways, leading to prolonged arrest in G1, typical of cells in senescence. Inactivation of the p53 and pRb pathways, however, does not lead to cell immortalization. Cells that overcome senescence and have an extended life span continue to lose telomeric DNA and subsequently enter a second phase of growth arrest termed `crisis'. Forced expression of telomerase in human cells leads to the elongation of telomeres and immortalization. The development of human cancer is frequently associated with the inactivation of the pRb and p53 pathways, attesting to the importance of senescence in restricting the tumor-forming ability of human cells. Cancer cells must also maintain telomere length and, in the majority of cases, this is associated with expression of telomerase activity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  • Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D and Barrett JC. . 1996 Proc. Natl. Acad. Sci. USA 93: 13742–13747.

  • Atadja P, Wong H, Garkavtsev I, Veillette C and Riabowol K. . 1995 Proc. Natl. Acad. Sci. USA 92: 8348–8352.

  • Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW and Harley CB. . 1992 Proc. Natl. Acad. Sci. USA 89: 10114–10118.

  • Almasan A, Linke SP, Paulson TG, Huang LC and Wahl GM. . 1995 Cancer Metastasis Rev. 14: 59–73.

  • Beattie TL, Zhou W, Robinson MO and Harrington L. . 1998 Curr. Biol. 8: 177–180.

  • Bischoff FZ, Yim SO, Pathak S, Grant G, Siciliano MJ, Giovanella BC, Strong LC and Tainsky MA. . 1990 Cancer Res. 50: 7979–7984.

  • Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA and Greider CW. . 1997 Cell 91: 25–34.

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu C, Morin GB, Harley CB, Shay JW, Lichtsteiner S and Wright WE. . 1998 Science 279: 349–352.

  • Bond JA, Wyllie FS and Wynford-Thomas D. . 1994 Oncogene 9: 1885–1889.

  • Brown JP, Wei W and Sedivy JM. . 1997 Science 277: 831–834.

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T and Hannon GJ. . 1995 Nature 377: 552–557.

  • Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA and Reddel RR. . 1997 Nature Med. 3: 1271–1274.

  • Bryan TM, Englezou A, Gupta J, Bacchetti S and Reddel RR. . 1995 EMBO J. 14: 4240–4248.

  • Chang E and Harley CB. . 1995 Proc. Natl. Acad. Sci. USA 92: 11190–11194.

  • Colgin LM and Reddel RR. . 1999 Curr. Opin. Genet. Dev. 9: 97–103.

  • Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S. . 1992 EMBO J. 11: 1921–1929.

  • Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM and Weinberg RA. . 1998 Proc. Natl. Acad. Sci. USA 95: 14723–14728.

  • Deng C, Zhang P, Harper JW, Elledge SJ and Leder P. . 1995 Cell 82: 675–684.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • Feng J, Funk WD, Wand S, Weinrich SL, Avilion AA, Chiu C, Adams RR, Chang E, Allsopp RC, Yu J, Siyuan L, West MD, Harley CB, Andrews WH, Greider CW and Villeponteau B. . 1995 Science 269: 1236–1241.

  • Foster SA and Galloway DA. . 1996 Oncogene 18: 1773–1779.

  • Foster SA, Wong DJ, Barrett MT and Galloway DA. . 1998 Mol. Cell. Biol. 18: 1793–1801.

  • Greider CW and Blackburn EH. . 1985 Cell 43: 405–413.

  • Halvorsen TL, Leibowitz G, Levine F. . 1999 Mol. Cell Biol. 19: 1864–1870.

  • Hara E, Smith R, Parry D, Tahara H, Stone S and Peters G. . 1996 Mol. Cell. Biol. 16: 859–867.

  • Harley CB, Futcher AB and Greider CW. . 1990 Nature 345: 458–460.

  • Harley CB, Vaziri H, Counter CM and Allsopp RC. . 1992 Exp. Gerontol. 27: 375–382.

  • Harrington EA, Bruce JL, Harlow E and Dyson N. . 1998 Proc. Natl. Acid. Sci. USA 95: 11945–11950.

  • Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, Arruda I and Robinson MO. . 1997a Science 275: 973–977.

  • Harrington L, Zhou W, McPhail T, Oulton R, Yeung DSK, Mar V, Bass MB and Robinson MO. . 1997b Genes Dev. 11: 3109–3115.

  • Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A and Donehower LA. . 1993 Oncogene 8: 2457–2467.

  • Hayflick L and Moorhead P. . 1961 Exp. Cell Res. 25: 585–621.

  • Jiang X, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, Beeche M, Bodnar AG, Wahl GM, Tlsty TD and Chiu C. . 1999 Nat. Genet. 21: 111–114.

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ. . 1998 Cell 95: 8292–8297.

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ. . 1997 Cell 91: 649–659.

  • Kastan MB, Zhan Q, El-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B and Fornace Jr AJ. . 1992 Cell 71: 587–597.

  • Kilian A, Bowtell DL, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR and Jefferson RA. . 1997 Hum. Mol. Genet. 6: 2011–2019.

  • Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA and Klingelhutz AJ. . 1998 Nature 396: 84–88.

  • Kulju KS and Lehman JM. . 1995 Exp. Cell Res. 217: 336–345.

  • Klingelhutz AJ, Foster SA and McDougall JK. . 1996 Nature 380: 79–82.

  • Lee HW, Blasco MA, Gottlieb GJ, Horner JW, Greider CW and DePinho RA. . 1998 Nature 392: 569–574.

  • Levine AJ. . 1997 Cell 88: 323–331.

  • Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V and Cech TR. . 1997 Science 276: 561–567.

  • Livingstone LR, White A, Sprouse J, Livanos E, Jacks T and Tlsty TD. . 1992 Cell 70: 923–935.

  • Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA and Weinberg RA. . 1997 Cell 90: 785–795.

  • Milas M, Yu D, Sun D and Pollock RE. . 1998 Clin. Cancer Res. 4: 1573–1579.

  • Morales CP, Holt SE, Ouellette M, Kiran JK, Yan Y, Wilson KS, White MA, Wright WE and Shay JW. . 1999 Nat. Genet. 21: 115–118.

  • Morin GB. . 1989 Cell 59: 521–529.

  • Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB and Cech TR. . 1997 Science 277: 955–959.

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM and Smith JR. . 1994 Exp. Cell Res. 211: 90–98.

  • Nugent CI and Lundblad V. . 1998 Genes Dev. 1073–1085.

  • Olovnikov AM. . 1973 J. Theor. Biol. 41: 181–190.

  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C and DePinho RA. . 1998 Cell 92: 713–723.

  • Quelle DE, Zindy F, Ashmun RA and Sherr CJ. . 1995 Cell 83: 993–1000.

  • Rogan EM, Bryan TM, Hukku B, Maclean K, Chang AC, Moy EL, Englezou A, Warneford SG, Dalla-Pozza L and Reddel RR. . 1995 Mol. Cell. Biol. 15: 4745–4753.

  • Serrano M, Lee HW, Chin L, Cordon-Cardo C, Beach D and DePinho RA. . 1996 Cell 85: 27–37.

  • Shay JW, Pereira-Smith OM and Wright WE. . 1991 Exp. Cell Res. 196: 33–39.

  • Shay JW and Wright WE. . 1989 Exp. Cell Res. 184: 109–118.

  • Vaziri H, West MD, Allsopp RC, Davidson TS, Wu YS, Arrowsmith CH, Poirier GG and Benchimol S. . 1997 EMBO J. 16: 6018–6033.

  • Vaziri H and Benchimol S. . 1996 Exp. Gerontol. 31: 295–301.

  • Vaziri H and Benchimol S. . 1998 Curr. Biol. 8: 279–282.

  • Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D and Harley CB. . 1993 Am. J. Hum. Genetics 52: 661–667.

  • Vaziri H, Squire JA, Pandita TK, Bradley G, Kuba RM, Zhang H, Gulyas S, Hill RP, Nolan GP and Benchimol S. . 1999 Mol. Cell. Biol. 19: 2373–2379.

  • Wang J, Xie YL, Allan S, Beach D and Hannon GJ. . 1998 Genes Dev. 12: 1769–1774.

  • Watson JD. . 1972 Nature New Biol. 239: 197–201.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG, Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE, Shay JW, Harley CB and Morin GB. . 1997 Nat. Genet. 17: 498–502.

  • Wolman SR, Hirschhorn K and Todaro GJ. . 1964 Cytogenetics 3: 45–61.

  • Yin Y, Tainsky MA, Bischoff FZ, Strong L and Wahl GM. . 1992 Cell 70: 937–948.

  • Zhang Y, Xiong Y and Yarbrough WG. . 1998 Cell 92: 725–734.

Download references

Acknowledgements

This work was supported by grants from the Medical Research Council of Canada and the National Cancer Institute of Canada.

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology, Stanford University School of Medicine, Edward's Building, 300 Pasteur Drive Stanford, 94305-5332, California, CA, USA

    Homayoun Vaziri

  2. Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G-2M9, Canada

    Samuel Benchimol

  3. Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G-2M9, Canada

    Samuel Benchimol

Authors
  1. Homayoun Vaziri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel Benchimol
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaziri, H., Benchimol, S. Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase. Oncogene 18, 7676–7680 (1999). https://doi.org/10.1038/sj.onc.1203016

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203016

Keywords

This article is cited by

Search

Advanced search

Quick links