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:

Inactivation of hTERT transcription by Tax

Oncogene volume 22, pages 3734–3741 (2003)Cite this article

Abstract

Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, hTERT repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies.

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

Similar content being viewed by others

References

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

  • Artandi SE and DePinho RA . (2000). Curr. Opin. Genet. Dev., 10, 39–46.

  • Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA and Greider CW . (1997). Cell, 91, 25–34.

  • Buerger H, Otterbach F, Simon R, Poremba C, Diallo R, Decker T, Riethdorf L, Brinkschmidt C, Dockhorn-Dworniczak B and Boecker W . (1999). J. Pathol., 187, 396–402.

  • Cavrois M, Leclercq I, Gout O, Gessain A, Wain-Hobson S and Wattel E . (1998). Oncogene, 17, 77–82.

  • Cesarman E, Chadburn A, Inghirami G, Gaidano G and Knowles DM . (1992). Blood, 80, 3205–3216.

  • Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S . (1992). EMBO J., 11, 1921–1929.

  • Crowe DL, Nguyen DC, Tsang KJ and Kyo S . (2001). Nucleic Acids Res., 29, 2789–2794.

  • de Lange T and Jacks T . (1999). Cell, 98, 273–275.

  • Fujii M, Niki T, Mori T, Matsuda T, Matsui M, Nomura N and Seiki M . (1991). Oncogene, 6, 1023–1029.

  • Furukawa Y, Osame M, Kubota R, Tara M and Yoshida M . (1995). Blood, 85, 1865–1870.

  • Gauthier LR, Granotier C, Soria JC, Faivre S, Boige V, Raymond E and Boussin FD . (2001). Br. J. Cancer, 84, 631–635.

  • Hanon E, Hall S, Taylor GP, Saito M, Davis R, Tanaka Y, Usuku K, Osame M, Weber JN and Bangham CR . (2000). Blood, 95, 1386–1392.

  • Hollsberg P . (1999). Microbiol. Mol. Biol. Rev., 63, 308–333.

  • Horikawa I, Cable PL, Afshari C and Barrett JC . (1999). Cancer Res., 59, 826–830.

  • Inoue J, Seiki M, Taniguchi T, Tsuru S and Yoshida M . (1986). Embo J., 5, 2883–2888.

  • Itoyama T, Chaganti RS, Yamada Y, Tsukasaki K, Atogami S, Nakamura H, Tomonaga M, Ohshima K, Kikuchi M and Sadamori N . (2001). Blood, 97, 3612–3620.

  • Jeang KT, Widen SG, Semmes OT and Wilson SH . (1990). Science, 247, 1082–1084.

  • Jin DY, Spencer F and Jeang KT . (1998). Cell, 93, 81–91.

  • Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H and Inoue M . (2000). Clin. Cancer Res., 6, 1239–1247.

  • Kao SY and Marriott SJ . (1999). J. Virol., 73, 4299–4304.

  • Kitagawa Y, Kyo S, Takakura M, Kanaya T, Koshida K, Namiki M and Inoue M . (2000). Clin. Cancer Res., 6, 2868–2875.

  • Klingelhutz AJ, Foster SA and McDougall JK . (1996). Nature, 380, 79–82.

  • Knight JS, Cotter II MA and Robertson ES . (2001). J. Biol. Chem., 276, 22971–22978.

  • Kusumoto M, Ogawa T, Mizumoto K, Ueno H, Niiyama H, Sato N, Nakamura M and Tanaka M . (1999). Clin. Cancer Res., 5, 2140–2147.

  • Lee DK, Kim BC, Brady JN, Jeang KT and Kim SJ . (2002). J. Biol. Chem., 277, 33766–33775.

  • Lee M, Hak-Zoo Kim HZ, Jeong KW, Shim YS, Horikawa I, Barrett JC and Choe J . J. Biol. Chem., 277, 27748–27756.

  • Lemasson I, Robert-Hebmann V, Hamaia S, Duc Dodon M, Gazzolo L and Devaux C . (1997). J. Virol., 71, 1975–1983.

  • Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ and Weng NP . (1999). Proc Natl Acad Sci USA, 96, 5147–5152.

  • Miyake H, Suzuki T, Hirai H and Yoshida M . (1999). Virology, 253, 155–161.

  • Mortreux F, Gabet AS and Wattel E . (2003). Leukemia, 17, 26–38.

  • Mortreux F, Leclercq I, Gabet A, Leroy A, Westhof E, Gessain A, Wain-Hobson S and Wattel E . (2001). J. Natl. Cancer Inst., 93, 367–377.

  • Nagai H, Kinoshita T, Imamura J, Murakami Y, Hayashi K, Mukai K, Ikeda S, Tobinai K, Saito H, Shimoyama M and Shimotohno K. (1991). Jpn. J. Cancer Res., 82, 1421–1427.

  • Nagai M, Brennan MB, Sakai JA, Mora CA and Jacobson S . (2001). Blood, 98, 1858–1861.

  • Neuveut C, Low KG, Maldarelli F, Schmitt I, Majone F, Grassmann R and Jeang KT . (1998). Mol. Cell. Biol., 18, 3620–3632.

  • Nishimura S, Asou N, Suzushima H, Okubo T, Fujimoto T, Osato M, Yamasaki H, Lisha L and Takatsuki K . (1995). Leukemia, 9, 598–604.

  • Nishizaki T, DeVries S, Chew K, Goodson III WH, Ljung BM, Thor A and Waldman FM . (1997). Genes Chromosomes Cancer, 19, 267–272.

  • Nordeen SK . (1988). Biotechniques, 6, 454–458.

  • Oh S, Song YH, Yim J and Kim TK . (2000). Oncogene, 19, 1485–1490.

  • Philpott SM and Buehring GC . (1999). J. Natl. Cancer Inst., 91, 933–942.

  • Pise-Masison CA, Mahieux R, Radonovich MF, Jiang H and Brady JN . (2000). J. Biol. Chem., 276, 200–205.

  • PiseMasison CA, Choi KS, Radonovich M, Dittmer J, Kim SJ and Brady JN . (1998). J. Virol., 72, 1165–1170.

  • Reid RL, Lindholm PF, Mireskandari A, Dittmer J and Brady JN . (1993). Oncogene, 8, 3029–3036.

  • Riou P, Bex F and Gazzolo L . (2000). J. Biol. Chem., 275, 10551–10560.

  • Royer-Leveau C, Mordelet E, Delebecque F, Gessain A, Charneau P and Ozden S . (2002). J. Virol. Methods, 105, 133.

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

  • Sakashita A, Hattori T, Miller CW, Suzushima H, Asou N, Takatsuki K and Koeffler HP . (1992). Blood, 79, 477–480.

  • Santiago F, Clark E, Chong S, Molina C, Mozafari F, Mahieux R, Fujii M, Azimi N and Kashanchi F . (1999). J. Virol., 73, 9917–9927.

  • Saretzki G, Sitte N, Merkel U, Wurm RE and von Zglinicki T . (1999). Oncogene, 18, 5148–5158.

  • Smith MR and Greene WC . (1990). Genes Dev., 4, 1875–1885.

  • Suzuki T, Kitao S, Matsushime H and Yoshida M . (1996). EMBO J., 15, 1607–1614.

  • Takemoto S, Trovato R, Cereseto A, Nicot C, Kislyakova T, Casareto L, Waldmann T, Torelli G and Franchini G . (2000). Blood, 95, 3939–3944.

  • Tzukerman M, Shachaf C, Ravel Y, Braunstein I, Cohen-Barak O, Yalon-Hacohen M and Skorecki KL . (2000). Mol. Biol. Cell, 11, 4381–4391.

  • Uchida N, Otsuka T, Arima F, Shigematsu H, Fukuyama T, Maeda M, Sugio Y, Itoh Y and Niho Y . (1999). Leuk. Res., 23, 311–316.

  • Uittenbogaard MN, Giebler HA, Reisman D and Nyborg JK . (1995). J. Biol. Chem., 270, 28503–28506.

  • Webster K, Parish J, Pandya M, Stern PL, Clarke AR and Gaston K . (2000). J. Biol. Chem., 275, 87–94.

  • Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J and Dalla-Favera R . (1999). Nat. Genet., 21, 220–224.

  • Yoshida M . (2001). Annu. Rev. Immunol., 19, 475–496.

  • Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L and Charneau P . (2000). Cell, 101, 173–185.

Download references

Acknowledgements

We thank P Jalinot and E Gilson for their critical review of this manuscript, C Pinatel, A Lançon, C Paul and MD Reynaud for technical assistance; KJ Wu and R Dalla-Favera for TERTLuc800, pMT2TMyc, SM and DM constructs; WC Greene for pCMV-Tax plasmid and P Jalinot for the Tax monoclonal antibody HY474. ASG is supported by the Centre Léon Bérard, FM by the Ministère de l'Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale and PR by the Ministère de l'Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale. This work was supported by grants from the Ministère de l'Éducation Nationale, de la Recherche et de la Technologie (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires), from the Association pour la Recherche sur le Cancer, from the Fondation Contre la Leucémie and from the comité départemental de la Saône et Loire de la Ligue Nationale Contre le Cancer.

Author information

Author notes

  1. Franck Mortreux and Pierre Charneau: These two authors equally contributed to the work

Authors and Affiliations

  1. Unité d'Oncogenèse Virale-CNRS UMR 5537, Centre Léon Bérard, 28 rue Laennec, Lyon, Cedex 08, 69373, France

    Anne-Sophie Gabet, Franck Mortreux & Eric Wattel

  2. Groupe de Virologie Moléculaire et Vectorologie, Institut Pasteur, 28 rue du Dr Roux,  Paris, Cedex 1, 75724, France

    Pierre Charneau

  3. Immuno-Virologie Moléculaire et Cellulaire-CNRS UMR 5537, Faculté de Médecine Lyon Laennec, Lyon, Cedex 8, 69372, France

    Patrice Riou & Madeleine Duc-Dodon

  4. Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

    Yalin Wu & Kuan-Teh Jeang

  5. Service d'Hématologie, Pavillon E, Hôpital Edouard Herriot, Place d'Arsonval, Lyon, Cedex 03, 69437, France

    Eric Wattel

Authors
  1. Anne-Sophie Gabet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franck Mortreux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Charneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrice Riou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Madeleine Duc-Dodon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yalin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kuan-Teh Jeang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric Wattel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Wattel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gabet, AS., Mortreux, F., Charneau, P. et al. Inactivation of hTERT transcription by Tax. Oncogene 22, 3734–3741 (2003). https://doi.org/10.1038/sj.onc.1206468

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206468

Keywords

This article is cited by

Search

Advanced search

Quick links