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:

Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression

Oncogene volume 20, pages 278–288 (2001)Cite this article

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar degeneration, immunodeficiencies, genomic instability and gonadal atrophy. A-T patients are hypersensitive to ionizing radiation and have an elevated cancer risk. Cells derived from A-T patients require higher levels of serum factors, exhibit cytoskeletal defects and undergo premature senescence in culture. We show here that expression of the catalytic subunit of telomerase (hTERT) in primary A-T patient fibroblasts can rescue the premature senescence phenotype. Ectopic expression of hTERT does not rescue the radiosensitivity or the telomere fusions in A-T fibroblasts. The hTERT+AT cells also retain the characteristic defects in cell-cycle checkpoints, and show increased chromosome damage before and after ionizing radiation. Although A-T patients have an increased susceptibility to cancer, the expression of hTERT in A-T fibroblasts does not stimulate malignant transformation. These immortalized A-T cells provide a more stable cell system to investigate the molecular mechanisms underlying the cellular phenotypes of Ataxia-telangiectasia.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Ashburner BP, Shackelford RE, Baldwin Jr AS and Paules RS. . 1999 Cancer Res. 59: 5456–5460.

  • Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D and Wynshaw-Boris A. . 1996 Cell. 86: 159–171.

  • Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, Barlow C, Baltimore D, Wynshaw-Boris A, Kastan MB and Wang JY. . 1997 Nature 387: 516–519.

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

  • Calaf G and Hei TK. . 2000 Carcinogenesis 21: 769–776.

  • Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB and Siliciano JD. . 1998 Science 281: 1677–1679.

  • Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan Q, Lu RS, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD and Zhou BB. . 1999 Oncogene 18: 4047–4054.

  • Cortez D, Wang Y, Qin J and Elledge SJ. . 1999 Science 286: 1162–1166.

  • Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP and Rheinwald JG. . 2000 Mol. Cell. Biol. 20: 1436–1447.

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubeli I, Pereira-Smith O, Peacocke M and Campisi J. . 1995 Proc. Natl. Acad. Sci. USA 92: 9363–9367.

  • Easton DF. . 1994 Int. J. Radiat. Biol. 66: S177–S182.

  • Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J and Leder P. . 1996 Proc. Natl. Acad. Sci. USA 93: 13084–13089.

  • Fu W, Killen M, Culmsee C, Dhar S, Pandita TK and Mattson MP. . 2000 J. Mol. Neuro. 10: 3–15.

  • Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B and Petes TD. . 1995 Cell. 82: 823–829.

  • Greider CW. . 1996 Annu. Rev. Biochem. 65: 337–365.

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW and Weinberg RA. . 1999 Nature 400: 464–468.

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

  • Harley CB and Sherwood SW. . 1997 Cancer Surv. 29: 263–284.

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

  • Harnden DG. . 1994 Int. J. Radiat. Biol. 66: S13–S19.

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

  • Hecht F and Hecht BK. . 1990 Cancer Genet. Cytogenet. 46: 9–19.

  • Holt SE, Shay JW and Wright WE. . 1996 Nat. Biotechnol. 14: 836–839.

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

  • Jung M, Zhang Y, Lee S and Dritschilo A. . 1995 Science 268: 1619–1621.

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW. . 1994 Science 266: 2011–2015.

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

  • Knudsen ES, Buckmaster C, Chen TT, Feramisco JR and Wang JY. . 1998 Genes Dev. 12: 2278–2292.

  • Kojis TL, Gatti RA and Sparkes RS. . 1991 Cancer Genet. Cytogenet. 56: 143–156.

  • Lavin MF and Khanna KK. . 1999 Int. J. Radiat. Biol. 75: 1201–1214.

  • Lavin MF and Shiloh Y. . 1997 Annu. Rev. Immunol. 15: 177–202.

  • Lee SJ, Dimtchev A, Lavin MF, Dritschilo A and Jung M. . 1998 Oncogene 17: 1821–1826.

  • Lim DS, Kim ST, Xu B, Maser RS, Lin J, Petrini JH and Kastan MB. . 2000 Nature 404: 613–617.

  • Matsuoka S, Huang M and Elledge SJ. . 1998 Science 282: 1893–1897.

  • Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ and Taylor AM. . 1996 Nat. Genet. 13: 350–353.

  • Meyn MS. . 1995 Cancer Res. 55: 5991–6001.

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

  • Morgan SE and Kastan MB. . 1997 Adv. Cancer Res. 71: 1–25.

  • Ouellette MM, Aisner DL, Savre-Train I, Wright WE and Shay JW. . 1999 Biochem. Biophys. Res. Commun. 254: 795–803.

  • Painter RB and Young BR. . 1980 Proc. Natl. Acad. Sci. USA 77: 7315–7317.

  • Pandita TK and Geard CR. . 1996 Radiat. Res. 145: 730–739.

  • Pandita TK, Hall EJ, Hei TK, Piatyszek MA, Wright WE, Piao CQ, Pandita RK, Willey JC, Geard CR, Kastan MB and Shay JW. . 1996 Oncogene 13: 1423–1430.

  • Pandita TK, Lieberman HB, Lim DS, Dhar S, Zheng W, Taya Y and Kastan MB. . 2000 Oncogene 19: 1386–1391.

  • Pandita TK, Pathak S and Geard CR. . 1995 Cytogenet. Cell. Genet. 71: 86–93.

  • Pandita TK, Westphal CH, Anger M, Sawant SG, Geard CR, Pandita RK and Scherthan H. . 1999 Mol. Cell. Biol. 19: 5096–5105.

  • Picksley SM and Lane DP. . 1994 Curr. Opin. Cell. Biol. 6: 853–858.

  • Robles SJ and Adami GR. . 1998 Oncogene 16: 1113–1123.

  • Rotman G and Shiloh Y. . 1999 Oncogene 18: 6135–6144.

  • Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S and et al. 1995a Science 268: 1749–1753.

  • Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y and Rotman G. . 1995b Hum. Mol. Genet. 4: 2025–2032.

  • Sawant SG, Gregoire V, Dhar S, Umbricht CB, Cvilic S, Sukumar S and Pandita TK. . 1999 FASEB J. 13: 1047–1054.

  • Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, Hobson K, Gatei M, Zhang N, Watters D, Egerton M, Shiloh Y, Kharbanda S, Kufe D and Lavin MF. . 1997 Nature 387: 520–523.

  • Shay JW, Werbin H and Wright WE. . 1996 Leukemia 10: 1255–1261.

  • Shiloh Y. . 1995 Eur. J. Hum. Genet. 3: 116–138.

  • Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E and Kastan MB. . 1997 Genes Dev. 11: 3471–3481.

  • Smilenov LB, Dhar S and Pandita TK. . 1999 Mol. Cell. Biol. 19: 6963–6971.

  • Smilenov LB, Mellado W, Rao PH, Sawant SG, Umbricht CB, Sukumar S and Pandita TK. . 1998 Oncogene 17: 2137–2142.

  • Smilenov LB, Morgan SE, Mellado W, Sawant SG, Kastan MB and Pandita TK. . 1997 Oncogene 15: 2659–2665.

  • Tominaga K, Morisaki H, Kaneko Y, Fujimoto A, Tanaka T, Ohtsubo M, Hirai M, Okayama H, Ideka K and Nakanishi M. . 1999 J. Biol. Chem. 274: 31463–31467.

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

  • 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 LY, Allan S, Beach D and Hannon GJ. . 1998 Genes Dev. 12: 1769–1774.

  • Wang JY. . 2000 Nature 405: 404–405.

  • Xu Y and Baltimore D. . 1996 Genes Dev. 10: 2401–2410.

  • Zhou BB, Chaturvedi P, Spring K, Scott SP, Johanson RA, Mishra R, Mattern MR, Winkler JD and Khanna KK. . 2000 J. Biol. Chem. 275: 10342–10348.

Download references

Acknowledgements

This work was supported by grants from NIH, Grant NS34746 to TK Pandita, Grant CA43054 to JJY Wang, Grant DK55065 to F Levine and ACS fellowship PF4462 to LD Wood. JW Shay is a senior scholar of the Ellison Medical Foundation.

Author information

Authors and Affiliations

  1. Department of Biology, University of California San Diego, La Jolla, 92093-0322, California, CA, USA

    Lauren D Wood & Jean JY Wang

  2. Cancer Center, University of California San Diego, La Jolla, 92093-0322, California, CA, USA

    Lauren D Wood, Tanya L Halvorsen, Fred Levine & Jean JY Wang

  3. Center for Radiological Research, Columbia University, New York, 10032, NY, USA

    Sonu Dhar, M Prakash Hande, Gloria Calaf, Tom K Hei & Tej K Pandita

  4. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, 75390-9039, Texas, TX, USA

    Joseph A Baur, Woodring E Wright & Jerry W Shay

  5. Albert Einstein College of Medicine, Bronx, 10461, New York, NY, USA

    Raj K Pandita

Authors
  1. Lauren D Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanya L Halvorsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonu Dhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph A Baur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raj K Pandita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Woodring E Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Prakash Hande
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gloria Calaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tom K Hei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fred Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jerry W Shay
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean JY Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tej K Pandita
    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

Wood, L., Halvorsen, T., Dhar, S. et al. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene 20, 278–288 (2001). https://doi.org/10.1038/sj.onc.1204072

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204072

Keywords

This article is cited by

Search

Advanced search

Quick links