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Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage

Oncogene volume 24, pages 1501–1509 (2005)Cite this article

Abstract

Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC−/−) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis. Specific changes in gene expression were associated with telomere shortening and chronic liver damage and these gene expression changes were partially reversed by adenovirus mediated telomerase gene delivery. This study gives experimental evidence that the negative impact of telomere shortening on organ homeostasis and organismal survival can surpass the beneficial effects of telomere shortening on suppression of tumor growth in the setting of chronic organ damage.

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References

  • Albrecht JH, Meyer AH and Hu MY . (1997). Hepatology, 25, 557–563.

  • 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.

  • Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L and DePinho RA . (2000). Nature, 406, 641–645.

  • Blasco MA, Lee HW, Rizen M, Hanahan D, DePinho R and Greider CW . (1997). Ciba Found. Symp., 211, 160–170 discussion 170–176.

  • Briscioli V, Manoukian S, Selicorni A, Livini E and Lalatta F . (1995). Am. J. Med. Genet., 58, 21–23.

  • Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW and DePinho RA . (1999). Cell, 97, 527–538.

  • Chisari FV, Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD and Brinster RL . (1987). Proc. Natl. Acad. Sci. USA, 84, 6909–6913.

  • Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL and Palmiter RD . (1989). Cell, 59, 1145–1156.

  • Delhaye M, Louis H, Degraef C, Le Moine O, Deviere J, Gulbis B, Jacobovitz D, Adler M and Galand P . (1996). Hepatology, 23, 1003–1011.

  • Delhaye M, Louis H, Degraef C, Le Moine O, Deviere J, Peny MO, Adler M and Galand P . (1999). J. Hepatol., 30, 461–471.

  • Djojosubroto MW, Choi YS, Lee HW and Rudolph KL . (2003). Mol. Cells, 15, 164–175.

  • Edwards J and Dalton A . (1942). J. Natl. Cancer Inst., 3, 19–41.

  • Eschenbrenner A and Miller E . (1946). J. Natl. Cancer Inst., 6, 325–341.

  • Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL and DePinho RA . (2003). Cancer Res., 63, 5021–5027.

  • Gonzalez-Suarez E, Samper E, Flores JM and Blasco MA . (2000). Nat. Genet., 26, 114–117.

  • Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH, Greider CW and DePinho RA . (1999). Cell, 97, 515–525.

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

  • Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW and Blasco MA . (1999). EMBO J., 18, 2950–2960.

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

  • Ly DH, Lockhart DJ, Lerner RA and Schultz PG . (2000). Science, 287, 2486–2492.

  • Minamishima YA and Nakayama K . (2002). Cancer Res., 62, 995–999.

  • Plentz RR, Caselitz M, Bleck JS, Gebel M, Flemming P, Kubicka S, MP M and Rudolph KL . (2004). Hepatology, 40, 80–86.

  • Plentz RR, Wiemann SU, Flemming P, Meier PN, Kubicka S, Kreipe H, Manns MP and Rudolph KL . (2003). Gut, 52, 1304–1307.

  • Ramirez R, Carracedo J, Jimenez R, Canela A, Herrera E, Aljama P and Blasco MA . (2003). J. Biol. Chem., 278, 836–842.

  • Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C and DePinho RA . (1999). Cell, 96, 701–712.

  • Rudolph KL, Chang S, Millard M, Schreiber-Agus N and DePinho RA . (2000). Science, 287, 1253–1258.

  • Rudolph KL, Millard M, Bosenberg MW and DePinho RA . (2001). Nat. Genet., 28, 155–159.

  • Satyanarayana A, Manns M and Rudolph K . (2004). Hepatology, 40, 276–283.

  • Satyanarayana A, Wiemann SU, Buer J, Lauber J, Dittmar KE, Wustefeld T, Blasco MA, Manns MP and Rudolph KL . (2003). EMBO J., 22, 4003–4013.

  • Stewart SA and Weinberg RA . (2000). Semin. Cancer Biol., 10, 399–406.

  • Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP and Rudolph KL . (2002). FASEB J., 16, 935–942.

  • Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C, Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW and DePinho RA . (2000). Nat. Genet., 26, 85–88.

  • Wright WE, Piatyszek MA, Rainey WE, Byrd W and Shay JW . (1996). Dev. Genet., 18, 173–179.

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Acknowledgements

KLR is supported by the Deutsche Forschungsgemeinschaft (Emmy-Noether-Programm: Ru 745/2-2 and KFO119) and a grant of the Deutsche Krebshilfe e.V. (10-1809-Ru1).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Carl-Neuberg-Str. 1, Germany

    Stefanie U Wiemann, Ande Satyanarayana, Michael P Manns & Karl Lenhard Rudolph

  2. Institute of Medical Microbiology, Medical School of Hannover, Carl-Neuberg-Str. 1, Germany

    Jan Buer

  3. Institute of Cell and Molecular Pathology, Medical School of Hannover, Carl-Neuberg-Str. 1, Germany

    Kenji Kamino

Authors
  1. Stefanie U Wiemann
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  2. Ande Satyanarayana
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  3. Jan Buer
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  4. Kenji Kamino
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  5. Michael P Manns
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  6. Karl Lenhard Rudolph
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Correspondence to Karl Lenhard Rudolph.

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Wiemann, S., Satyanarayana, A., Buer, J. et al. Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage. Oncogene 24, 1501–1509 (2005). https://doi.org/10.1038/sj.onc.1208308

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