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Mice without telomerase: what can they teach us about human cancer?

Nature Medicine volume 6, pages 852–855 (2000)Cite this article

Abstract

Unicellular organisms, human cells and mice have provided insights into the processes of senescence, crisis, genomic instability and cancer in humans. Here, Artandi and DePinho discuss how studies in mice have uncovered a complex interplay between the ARF-p53 pathway, genomic instability due to telomere dysfunction, and the suppression or promotion of cancer.

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Figure 1: a, The impact of crisis depends on genetic context.

References

  1. Hayflick, L. & Moorhead, P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  PubMed  Google Scholar 

  2. Bodnar, A.G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349– 352 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279– 282 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Hara, E., Tsurui, H., Shinozaki, A., Nakada, S. & Oda, K. Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem. Biophys. Res. Comm. 179, 528–534 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Shay, J.W., Pereira-Smith, O.M. & Wright, W.E. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).

    Article  CAS  PubMed  Google Scholar 

  6. Counter, C.M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 ( 1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Counter, C.M. et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl. Acad. Sci. USA 95, 14723–14728 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhu, J., Wang, H., Bishop, J.M. & Blackburn, E.H. Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening. Proc. Natl. Acad. Sci. USA 96, 3723–3728 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Muller, H.J. The remaking of chromosomes. Collecting Net 8, 182–195 (1938).

    Google Scholar 

  10. McClintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 ( 1941).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Olovnikov, A.M. Principle of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk. SSSR 201, 1496–1499 (1971).

    CAS  PubMed  Google Scholar 

  12. Watson, J.D. Origin of concatemeric T7 DNA. Nat. New Biol. 239, 197–201 (1972).

    Article  CAS  PubMed  Google Scholar 

  13. Wright, W.E. & Shay, J.W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality . Cell 85, 27–37 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. de Lange, T. & DePinho, R.A. Unlimited mileage from telomerase? Science 283, 947–949 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Kiyono, T. et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396, 84–88 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Blasco, M.A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25– 34 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Lee, H.W. et al. Essential role of mouse telomerase in highly proliferative organs . Nature 392, 569–574 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Niida, H. et al. Severe growth defect in mouse cells lacking the telomerase RNA component. Nature Genet. 19, 203– 206 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Rudolph, K.L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321– 1325 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  24. Kirk, K.E., Harmon, B.P., Reichardt, I.K., Sedat, J.W. & Blackburn, E.H. Block in anaphase chromosome separation caused by a telomerase template mutation. Science 275, 1478–1481 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Nakamura, T.M., Cooper, J.P. & Cech, T.R. Two modes of survival of fission yeast without telomerase . Science 282, 493–496 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Lundblad, V. & Szostak, J.W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Yu, G.L., Bradley, J.D., Attardi, L.D. & Blackburn, E.H. In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature 344, 126–132 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Sandell, L.L. & Zakian, V.A. Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell 19, 729–739 (1993).

    Article  Google Scholar 

  29. Greenberg, R.A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97, 515–525 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Hahn, W.C. et al. Creation of human tumour cells with defined genetic elements . Nature 400, 464–468 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Lundblad, V. & Blackburn, E.H. An alternative pathway for yeast telomere maintenance rescues est1-senescence. Cell 73, 347–360 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Bryan, T.M., Englezou, A., Gupta, J., Bacchetti, S. & Reddel, R.R. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 14, 4240–4248 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chadeneau, C., Hay, K., Hirte, H.W., Gallinger, S. & Bacchetti, S. Telomerase activity associated with acquisition of malignancy in human colorectal cancer. Cancer Res. 55, 2533–2536 (1995).

    CAS  PubMed  Google Scholar 

  34. Kolquist, K.A. et al. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nature Genet. 19, 182–186 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Hastie, N.D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866– 868 (1990).

    Article  CAS  PubMed  Google Scholar 

  36. Nishizaki, T. et al. Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization. Genes Chromosom. Cancer 19, 267–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Buerger, H. et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways. J. Pathol. 187, 396–402 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Al-Mulla, F., Keith, W.N., Pickford, I.R., Going, J.J. & Birnie, G.D. Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases . Genes Chromosom. Cancer 24, 306– 314 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Shay, J.W. & Wright, W.E. Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen . Exp. Cell Res. 184, 109– 118 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Shay, J.W., Van Der Haegen, B.A., Ying, Y. & Wright, W.E. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp. Cell Res. 209, 45–52 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Bardeesy, S. Chang, M. Meyerson, T. Raveh, N. Sharpless and K.-K. Wong for reviewing the manuscript.

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Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts

    Steven E. Artandi

  2. Departments of Genetics and Medicine, Harvard Medical School, Boston, 02115, Massachusetts

    Ronald A. DePinho

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  1. Steven E. Artandi
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  2. Ronald A. DePinho
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Artandi, S., DePinho, R. Mice without telomerase: what can they teach us about human cancer?. Nat Med 6, 852–855 (2000). https://doi.org/10.1038/78595

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