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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1

Leukemia volume 23, pages 2081–2089 (2009)Cite this article

Abstract

Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loop-helix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ–JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.

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References

  1. Gilson E, Geli V . How telomeres are replicated. Nat Rev Mol Cell Biol 2007; 8: 825–838.

    Article  CAS  Google Scholar 

  2. Harley CB . Telomerase and cancer therapeutics. Nat Rev Cancer 2008; 8: 167–179.

    Article  CAS  Google Scholar 

  3. Cogulu O, Kosova B, Karaca E, Gunduz C, Ozkinay F, Aksoylar S et al. Evaluation of telomerase mRNA (hTERT) in childhood acute leukemia. Leuk Lymphoma 2004; 45: 2477–2480.

    Article  CAS  Google Scholar 

  4. Kubuki Y, Suzuki M, Sasaki H, Toyama T, Yamashita K, Maeda K et al. Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia. Leuk Lymphoma 2005; 46: 393–399.

    Article  CAS  Google Scholar 

  5. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 1997; 17: 498–502.

    Article  CAS  Google Scholar 

  6. Koyanagi Y, Kobayashi D, Yajima T, Asanuma K, Kimura T, Sato T et al. Telomerase activity is down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC during the differentiation of leukemic cells. Anticancer Res 2000; 20 (2A): 773–778.

    CAS  PubMed  Google Scholar 

  7. Ohyashiki JH, Ohyashiki K, Fujimura T, Kawakubo K, Shimamoto T, Iwabuchi A et al. Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes. Cancer Res 1994; 54: 3557–3560.

    CAS  PubMed  Google Scholar 

  8. Kyo S, Takakura M, Fujiwara T, Inoue M . Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci 2008; 99: 1528–1538.

    Article  CAS  Google Scholar 

  9. Hao H, Nancai Y, Lei F, Xiong W, Wen S, Guofu H et al. siRNA directed against c-Myc inhibits proliferation and downregulates human telomerase reverse transcriptase in human colon cancer Colo 320 cells. J Exp Clin Cancer Res 2008; 27: 27.

    Article  Google Scholar 

  10. Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M et al. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res 2000; 28: 669–677.

    Article  CAS  Google Scholar 

  11. Lebel R, McDuff FO, Lavigne P, Grandbois M . Direct visualization of the binding of c-Myc/Max heterodimeric b-HLH-LZ to E-box sequences on the hTERT promoter. Biochemistry 2007; 46: 10279–10286.

    Article  CAS  Google Scholar 

  12. Xu D, Popov N, Hou M, Wang Q, Bjorkholm M, Gruber A et al. 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 2001; 98: 3826–3831.

    Article  CAS  Google Scholar 

  13. Gabet AS, Mortreux F, Charneau P, Riou P, Duc-Dodon M, Wu Y et al. Inactivation of hTERT transcription by Tax. Oncogene 2003; 22: 3734–3741.

    Article  CAS  Google Scholar 

  14. Kuhlmann AS, Villaudy J, Gazzolo L, Castellazzi M, Mesnard JM, Duc Dodon M . HTLV-1 HBZ cooperates with JunD to enhance transcription of the human telomerase reverse transcriptase gene (hTERT). Retrovirology 2007; 4: 92.

    Article  Google Scholar 

  15. O'Neil J, Shank J, Cusson N, Murre C, Kelliher M . TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell 2004; 5: 587–596.

    Article  CAS  Google Scholar 

  16. Terme JM, Wencker M, Favre-Bonvin A, Bex F, Gazzolo L, Duc Dodon M et al. Cross talk between expression of the human T-cell leukemia virus type 1 Tax transactivator and the oncogenic bHLH transcription factor TAL1. J Virol 2008; 82: 7913–7922.

    Article  CAS  Google Scholar 

  17. Palomero T, Odom DT, O'Neil J, Ferrando AA, Margolin A, Neuberg DS et al. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia. Blood 2006; 108: 986–992.

    Article  CAS  Google Scholar 

  18. Lecuyer E, Hoang T . SCL: from the origin of hematopoiesis to stem cells and leukemia. Exp Hematol 2004; 32: 11–24.

    Article  CAS  Google Scholar 

  19. Huang S, Brandt SJ . mSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor. Mol Cell Biol 2000; 20: 2248–2259.

    Article  CAS  Google Scholar 

  20. Huang S, Qiu Y, Stein RW, Brandt SJ . p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein. Oncogene 1999; 18: 4958–4967.

    Article  CAS  Google Scholar 

  21. Lecuyer E, Herblot S, Saint-Denis M, Martin R, Begley CG, Porcher C et al. The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1. Blood 2002; 100: 2430–2440.

    Article  CAS  Google Scholar 

  22. Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH . Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc Natl Acad Sci USA 1995; 92: 9585–9589.

    Article  CAS  Google Scholar 

  23. Valge-Archer VE, Osada H, Warren AJ, Forster A, Li J, Baer R et al. The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. Proc Natl Acad Sci USA 1994; 91: 8617–8621.

    Article  CAS  Google Scholar 

  24. Yao J, Grant C, Harhaj E, Nonnemacher M, Alefantis T, Martin J et al. Regulation of human T-cell leukemia virus type 1 gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III. DNA Cell Biol 2006; 25: 262–276.

    Article  CAS  Google Scholar 

  25. Riou P, Bex F, Gazzolo L . The human T cell leukemia/lymphotropic virus type 1 Tax protein represses MyoD-dependent transcription by inhibiting MyoD-binding to the KIX domain of p300. A potential mechanism for Tax-mediated repression of the transcriptional activity of basic helix-loop-helix factors. J Biol Chem 2000; 275: 10551–10560.

    Article  CAS  Google Scholar 

  26. Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM . The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol 2002; 76: 12813–12822.

    Article  CAS  Google Scholar 

  27. Sibon D, Gabet AS, Zandecki M, Pinatel C, Thete J, Delfau-Larue MH et al. HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death. J Clin Invest 2006; 116: 974–983.

    Article  CAS  Google Scholar 

  28. Aplan PD, Lombardi DP, Reaman GH, Sather HN, Hammond GD, Kirsch IR . Involvement of the putative hematopoietic transcription factor SCL in T-cell acute lymphoblastic leukemia. Blood 1992; 79: 1327–1333.

    CAS  PubMed  Google Scholar 

  29. Macintyre EA, Smit L, Ritz J, Kirsch IR, Strominger JL . Disruption of the SCL locus in T-lymphoid malignancies correlates with commitment to the T-cell receptor alpha beta lineage. Blood 1992; 80: 1511–1520.

    CAS  PubMed  Google Scholar 

  30. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002; 1: 75–87.

    Article  CAS  Google Scholar 

  31. Cairney CJ, Keith WN . Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochimie 2008; 90: 13–23.

    Article  CAS  Google Scholar 

  32. Kleideiter E, Bangerter U, Schwab M, Boukamp P, Koscielniak E, Klotz U et al. Telomeres and telomerase in paediatric patients with T-cell acute lymphoblastic leukaemia (T-ALL). Leukemia 2005; 19: 296–298.

    Article  CAS  Google Scholar 

  33. Furukawa Y, Kubota R, Tara M, Izumo S, Osame M . Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia. Blood 2001; 97: 987–993.

    Article  CAS  Google Scholar 

  34. Miyazaki M, Yasunaga J, Taniguchi Y, Tamiya S, Nakahata T, Matsuoka M . Preferential selection of human T-cell leukemia virus type 1 provirus lacking the 5′ long terminal repeat during oncogenesis. J Virol 2007; 81: 5714–5723.

    Article  CAS  Google Scholar 

  35. Takeda S, Maeda M, Morikawa S, Taniguchi Y, Yasunaga J, Nosaka K et al. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer 2004; 109: 559–567.

    Article  CAS  Google Scholar 

  36. Satou Y, Yasunaga J, Yoshida M, Matsuoka M . HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci USA 2006; 103: 720–725.

    Article  CAS  Google Scholar 

  37. Usui T, Yanagihara K, Tsukasaki K, Murata K, Hasegawa H, Yamada Y et al. Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells. Retrovirology 2008; 5: 34.

    Article  Google Scholar 

  38. Matsumoto J, Ohshima T, Isono O, Shimotohno K . HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein. Oncogene 2005; 24: 1001–1010.

    Article  CAS  Google Scholar 

  39. Nie L, Wu H, Sun XH . Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. J Biol Chem 2008; 283: 684–692.

    Article  CAS  Google Scholar 

  40. Sharma VM, Draheim KM, Kelliher MA . The Notch1/c-Myc pathway in T cell leukemia. Cell Cycle 2007; 6: 927–930.

    Article  CAS  Google Scholar 

  41. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20: 2096–2109.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Katie Flaig, Saturo Kyo, Louis Gazzolo, Daniele Mathieu and Jean-Michel Mesnard for generously providing us with expression vectors and antibodies. We also thank Armelle Roisin for help with cell culture, Eric Gilson's team for assistance with telomerase activity measurement, Sevanna Shahbazian and Thomas Barber for a critical reading of the paper. This work was supported by Association pour la Recherche sur le Cancer (grant and VM fellowship), by the comité du Rhône de la Ligue Nationale contre le Cancer and by the Fondation pour la Recherche Médicale (J-M T fellowships).

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Authors and Affiliations

  1. Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Institut Fédératif de Recherche 128 Biosciences Lyon Gerland, Lyon cedex 07, France

    J-M Terme, V Mocquet & P Jalinot

  2. Virologie Humaine, Unité 758, Institut National de la Santé et de la Recherche Médicale, Ecole Normale Supérieure de Lyon, Institut Fédératif de Recherche 128 Biosciences Lyon Gerland, Lyon cedex 07, France

    A-S Kuhlmann & M Duc Dodon

  3. Unité d'Oncovirologie et de Biothérapies, Formation de Recherche en Evolution 3011, Centre National de la Recherche Scientifique, Centre Léon Bérard, Lyon cedex 03, France

    L Zane, F Mortreux & E Wattel

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Correspondence to P Jalinot.

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Terme, JM., Mocquet, V., Kuhlmann, AS. et al. Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1. Leukemia 23, 2081–2089 (2009). https://doi.org/10.1038/leu.2009.131

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