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 Article
  • Published:

Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

Oncogene volume 25, pages 4310–4319 (2006)Cite this article

Abstract

Here, we show that ectopic expression of the catalytic subunit of mouse telomerase (mTert) confers a growth advantage to primary murine embryonic fibroblasts (MEFs), which have very long telomeres, as well as facilitates their spontaneous immortalization and increases their colony-forming capacity upon activation of oncogenes. We demonstrate that these telomere length-independent growth-promoting effects of mTert overexpression require catalytically active mTert, as well as the formation of mTert/Terc complexes. The gene expression profile of mTert-overexpressing MEFs indicates that telomerase enhances growth in these cells through the repression of growth-inhibiting genes of the transforming growth factor-beta (TGF-β) signaling network. We functionally validate this result by showing that mTert abrogates the growth-inhibitory effect of TGF-β in MEFs, thus demonstrating that telomerase increments the proliferative potential of primary mouse embryonic fibroblasts by targeting the TGF-β pathway.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  • Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA et al. (2002). Proc Natl Acad Sci USA 99: 8191–8196.

  • Balasubramanian S, Efimova T, Eckert RL . (2002). J Biol Chem 277: 1828–1836.

  • Blackburn EH . (2001). Cell 106: 661–673.

  • Blasco MA . (2002). Nat Rev Cancer 2: 627–633.

  • Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA et al. (1997). Cell 91: 25–34.

  • Blasco MA, Rizen M, Greider CW, Hanahan D . (1996). Nat Genet 12: 200–204.

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB et al. (1998). Science 279: 349–352.

  • Canela A, Martin-Caballero J, Flores JM, Blasco MA . (2004). Mol Cell Biol 24: 4275–4293.

  • Cayuela ML, Flores JM, Blasco MA . (2005). EMBO Rep 6: 268–274.

  • Chen ZY, Tseng CC . (2005). Mol Pharmacol 68: 1203–1213.

  • Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H et al. (2003). J Clin Endocrinol Metab 88: 3913–3920.

  • Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M et al. (2005). Nature 436: 642.

  • Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW . (2003). Oncogene 22: 3424–3430.

  • de Lange T . (2002). Oncogene 21: 532–540.

  • Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA et al. (2000). Mol Cell Biol 20: 1436–1447.

  • Flores I, Cayuela ML, Blasco MA . (2005). Science 309: 1253–1256.

  • Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A . (2003). Am J Pathol 162: 1807–1815.

  • Furukawa T, Yatsuoka T, Youssef EM, Abe T, Yokoyama T, Fukushige S et al. (1998). Cytogenet Cell Genet 82: 156–159.

  • Gonzalez-Suarez E, Flores JM, Blasco MA . (2002). Mol Cell Biol 22: 7291–7301.

  • Gonzalez-Suarez E, Geserick C, Flores JM, Blasco MA . (2005). Oncogene 24: 2256–2270.

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

  • Gonzalez-Suarez E, Samper E, Ramirez A, Flores JM, Martin-Caballero J, Jorcano JL et al. (2001). EMBO J 20: 2619–2630.

  • Goytisolo FA, Blasco MA . (2002). Oncogene 21: 584–591.

  • Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J . (1998). J Biol Chem 273: 31327–31336.

  • Hu Y, Sun H, Drake J, Kittrell F, Abba MC, Deng L et al. (2004). Cancer Res 64: 7748–7755.

  • Huang Q, Raya A, DeJesus P, Chao SH, Quon KC, Caldwell JS et al. (2004). Proc Natl Acad Sci USA 101: 3456–3461.

  • Javelaud D, Mauviel A . (2005). Oncogene 24: 5742–5750.

  • Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS et al. (2003). Development 130: 411–423.

  • Keeton AB, Bortoff KD, Bennett WL, Franklin JL, Venable DY, Messina JL . (2003). Endocrinology 144: 5402–5410.

  • Kondratyev AD, Chung KN, Jung MO . (1996). Cancer Res 56: 1498–1502.

  • Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP et al. (1996). Lab Invest 74: 991–1003.

  • Krag S, Osterby R, Chai Q, Nielsen CB, Hermans C, Wogensen L . (2000). Lab Invest 80: 1855–1868.

  • Kuribara R, Kinoshita T, Miyajima A, Shinjyo T, Yoshihara T, Inukai T et al. (1999). Mol Cell Biol 19: 2754–2762.

  • Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD et al. (2000). Science 289: 1159–1164.

  • Liao L, Zeng XM, Gao PJ, Zhu DL, Mei YA . (2005). Biochem Biophys Res Commun 336: 854–859.

  • Lim JY, Park SJ, Hwang HY, Park EJ, Nam JH, Kim J et al. (2005). J Mol Cell Cardiol 39: 627–636.

  • Lim RW, Zhu CY, Stringer B . (1995). Biochim Biophys Acta 1266: 91–100.

  • Liu J, Rich CB, Buczek-Thomas JA, Nugent MA, Panchenko MP, Foster JA . (2003). Am J Physiol Lung Cell Mol Physiol 285: L1106–L1115.

  • Martin-Rivera L, Herrera E, Albar JP, Blasco MA . (1998). Proc Natl Acad Sci USA 95: 10471–10476.

  • Mechta F, Lallemand D, Pfarr CM, Yaniv M . (1997). Oncogene 14: 837–847.

  • Montagnoli A, Guardavaccaro D, Starace G, Tirone F . (1996). Cell Growth Differ 7: 1327–1336.

  • Mulsow JJ, Watson RW, Fitzpatrick JM, O'Connell PR . (2005). Ann Surg 242: 880–887, discussion 887–889.

  • Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y et al. (2003). Biochem Biophys Res Commun 308: 251–256.

  • Palmero I, Serrano M . (2001). Methods Enzymol 333: 247–256.

  • Pantoja C, Serrano M . (1999). Oncogene 18: 4974–4982.

  • Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . (2003). Nat Cell Biol 5: 741–747.

  • Passegué E, Wagner EF . (2000). EMBO J 19: 2969–2979.

  • Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW et al. (2001). Genes Dev 15: 398–403.

  • Reinholz MM, An MW, Johnsen SA, Subramaniam M, Suman VJ, Ingle JN et al. (2004). Breast Cancer Res Treat 86: 75–88.

  • Rittling SR . (1996). Exp Cell Res 229: 7–13.

  • Rouault JP, Falette N, Guehenneux F, Guillot C, Rimokh R, Wang Q et al. (1996). Nat Genet 14: 482–486.

  • Rowland BD, Bernards R, Peeper DS . (2005). Nat Cell Biol 6: 1074–1082.

  • Ryu MS, Lee MS, Hong JW, Hahn TR, Moon E, Lim IK . (2004). Exp Cell Res 299: 159–170.

  • Sachsinger J, Gonzalez-Suarez E, Samper E, Heicappell R, Muller M, Blasco MA . (2001). Cancer Res 61: 5580–5586.

  • Serrano M, Blasco MA . (2001). Curr Opin Cell Biol 13: 748–753.

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

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . (1997). Cell 88: 593–602.

  • Sharma K, Ziyadeh FN . (1994). Am J Physiol 266: F829–F842.

  • Shay JW, Wright WE . (2002). Cancer Cell 2: 257–265.

  • Shields JM, Christy RJ, Yang VW . (1996). J Biol Chem 271: 20009–20017.

  • Simmen RC, Eason RR, McQuown JR, Linz AL, Kang TJ, Chatman Jr L et al. (2004). J Biol Chem 279: 29286–29294.

  • Smith LL, Coller HA, Roberts JM . (2003). Nat Cell Biol 5: 474–479.

  • Smith TG, Sweetman D, Patterson M, Keyse SM, Munsterberg A . (2005). Development 132: 1305–1314.

  • Stampfer MR, Bodnar A, Garbe J, Wong M, Pan A, Villeponteau B et al. (1997). Mol Biol Cell 8: 2391–2405.

  • Stampfer MR, Garbe J, Levine G, Lichtsteiner S, Vasserot AP, Yaswen P . (2001). Proc Natl Acad Sci USA 98: 4498–4503.

  • Sun L, Gong R, Wan B, Huang X, Wu C, Zhang X et al. (2003). Mol Biol Rep 30: 249–253.

  • Unoki M, Nakamura Y . (2001). Oncogene 20: 4457–4465.

  • Wang J, Feng H, Huang XQ, Xiang H, Mao YW, Liu JP et al. (2005a). J Biol Chem 280: 22776–22787.

  • Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN, Wu M . (2002). World J Gastroenterol 8: 966–970.

  • Wang T, Hu YC, Dong S, Fan M, Tamae D, Ozeki M et al. (2005b). J Biol Chem 280: 12593–12601.

  • Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC et al. (2005). Cancer Res 65: 2746–2754.

  • Yoon YS, Lee JH, Hwang SC, Choi KS, Yoon G . (2005). Oncogene 24: 1895–1903.

  • Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B et al. (2002). J Clin Endocrinol Metab 87: 1262–1267.

  • Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW . (2004). Oncogene 23: 395–402.

Download references

Acknowledgements

We thank A Benguría and the CNB Affymetrix Core Facility for technical assistance, R Serrano for mouse care, E Santos for genotyping, and M Serrano for critical comments on the manuscript. MA Blasco's laboratory is funded by MCyT (SAF2001-1869, GEN2001-4856-C13-08), CAM (08.1/0054/01), European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842), and the Josef Steiner Award 2003. CG is supported by a Marie Curie Fellowship within the 6th EU Framework Program.

Author information

Authors and Affiliations

  1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro, Madrid, Spain

    C Geserick, A Tejera, E González-Suárez, P Klatt & M A Blasco

Authors
  1. C Geserick
    View author publications

    Search author on:PubMed Google Scholar

  2. A Tejera
    View author publications

    Search author on:PubMed Google Scholar

  3. E González-Suárez
    View author publications

    Search author on:PubMed Google Scholar

  4. P Klatt
    View author publications

    Search author on:PubMed Google Scholar

  5. M A Blasco
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to M A Blasco.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Geserick, C., Tejera, A., González-Suárez, E. et al. Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling. Oncogene 25, 4310–4319 (2006). https://doi.org/10.1038/sj.onc.1209465

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1209465

Keywords

This article is cited by

Search

Advanced search

Quick links