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:

TAK1 represses transcription of the human telomerase reverse transcriptase gene

Oncogene volume 26, pages 5258–5266 (2007)Cite this article

Abstract

In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor β (TGF-β) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-β-activated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.

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

Similar content being viewed by others

References

  • Aisner DL, Wright WE, Shay JW . (2002). Telomerase regulation: not just flipping the switch. Curr Opin Genet Dev 12: 80–85.

    Article  CAS  PubMed  Google Scholar 

  • Cong YS, Bacchetti S . (2000). Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J Biol Chem 275: 35665–35668.

    Article  CAS  PubMed  Google Scholar 

  • Cong YS, Wen J, Bacchetti S . (1999). The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet 8: 137–142.

    Article  CAS  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363–9367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ducrest AL, Szutorisz H, Lingner J, Nabholz M . (2002). Regulation of the human telomerase reverse transcriptase gene. Oncogene 21: 541–552.

    Article  CAS  PubMed  Google Scholar 

  • Emami KH, Navarre WW, Smale ST . (1995). Core promoter specificities of the Sp1 and VP16 transcriptional activation domains. Mol Cell Biol 15: 5906–5916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. (1998). Identification of c-MYC as a target of the APC pathway. Science 281: 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  • Horikawa I, Cable PL, Afshari C, Barrett JC . (1999). Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res 59: 826–830.

    CAS  PubMed  Google Scholar 

  • Horikawa I, Cable PL, Mazur SJ, Appella E, Afshari CA, Barrett JC . (2002). Downstream E-box-mediated regulation of the human telomerase reverse transcriptase (hTERT) gene transcription: evidence for an endogenous mechanism of transcriptional repression. Mol Biol Cell 13: 2585–2597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou M, Wang X, Popov N, Zhang A, Zhao X, Zhou R et al. (2002). The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells. Exp Cell Res 274: 25–34.

    Article  CAS  PubMed  Google Scholar 

  • Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N et al. (1999). The TAK1-NLK-MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF. Nature 399: 798–802.

    Article  CAS  PubMed  Google Scholar 

  • Katakura Y, Nakata E, Miura T, Shirahata S . (1999). Transforming growth factor β triggers two independent-senescence programs in cancer cells. Biochem Biophys Res Commun 255: 110–115.

    Article  CAS  PubMed  Google Scholar 

  • Katakura Y, Yoshizaki K, Yasuda T, Tsunematsu T, Uehara N, Miura T et al. (2005). Functional impairment of telomerase in sublines derived from human lung adenocarcinoma exposed to mild oxidative stress. Biochem Biophys Res Commun 334: 450–459.

    Article  CAS  PubMed  Google Scholar 

  • Kyo S, Inoue M . (2002). Complex regulatory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene 21: 688–697.

    Article  CAS  PubMed  Google Scholar 

  • Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N et al. (1996). TAB1: an activator of the TAK1 MAPKKK in TGF-β signal transduction. Science 272: 1179–1182.

    Article  CAS  PubMed  Google Scholar 

  • Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M et al. (1999). Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res 59: 551–557.

    CAS  PubMed  Google Scholar 

  • Takakura M, Kyo S, Sowa Y, Wang Z, Yatabe N, Maida Y et al. (2001). Telomerase activation by histone deacetylase inhibitor in normal cells. Nucleic Acids Res 29: 3006–3011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tzukerman M, Shachaf C, Ravel Y, Braunstein I, Cohen-Barak O, Yalon-Hacohen M et al. (2000). Identification of a novel transcription factor binding element involved in the regulation by differentiation of the human telomerase (hTERT) promoter. Mol Biol Cell 11: 4381–4391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Won J, Yim J, Kim TK . (2002). Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells. J Biol Chem 277: 38230–38238.

    Article  CAS  PubMed  Google Scholar 

  • Xu D, Popov N, Hou M, Wang Q, Bjorkholm M, Gruber A et al. (2001). Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc Natl Acad Sci USA 98: 3826–3831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N et al. (1995). Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270: 2008–2011.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr K Matsumoto (Nagoya University, Japan) for providing us with pCMV-TAK1, pCMV-TAK1 (K63W), and pCMV-TAB1 (Yamaguchi et al., 1995; Shibuya et al., 1996); Dr RA Weinberg (Massachusetts Institute of Technology, MA, USA), for providing pCI-Neo-hTERT; Dr R Tjian (Howard Hughes Medical Institute), for providing pBS-Sp1-FL; Dr ST Smale (UCLA, Los Angeles, CA, USA), for providing GAL4-Sp1 (83−778); and Dr K Takahashi (Nihon University, Japan), for her technical advice. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

Author information

Author notes

  1. T Fujiki and T Miura: These two authors equally contributed to this work.

Authors and Affiliations

  1. Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan

    T Fujiki, T Miura, M Maura, H Shiraishi, S Nishimura, Y Imada, N Uehara, K Tashiro, S Shirahata & Y Katakura

Authors
  1. T Fujiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Maura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Shiraishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Imada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Uehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Tashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Shirahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y Katakura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Katakura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujiki, T., Miura, T., Maura, M. et al. TAK1 represses transcription of the human telomerase reverse transcriptase gene. Oncogene 26, 5258–5266 (2007). https://doi.org/10.1038/sj.onc.1210331

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210331

Keywords

This article is cited by

Search

Advanced search

Quick links