Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2010 Feb 7;1(1):22–32. doi: 10.1007/s13238-010-0014-1

Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene

Jiyue Zhu 1,, Yuanjun Zhao 1, Shuwen Wang 1
PMCID: PMC3683535  NIHMSID: NIHMS470666  PMID: 21203995

Abstract

Telomerase expression and telomere maintenance are critical for long-term cell proliferation and survival, and they play important roles in development, aging, and cancer. Cumulating evidence has indicated that regulation of the rate-limiting subunit of human telomerase reverse transcriptase gene (hTERT) is a complex process in normal cells and many cancer cells. In addition to a number of transcriptional activators and repressors, the chromatin environment and epigenetic status of the endogenous hTERT locus are also pivotal for its regulation in normal human somatic cells and in tumorigenesis.

Keywords: telomerase, transcriptional regulation, chromatin, epigenetic regulation, cancer

References

  1. Aisner D.L., Wright W.E., Shay J.W. Telomerase regulation: not just flipping the switch. Curr Opin Genet Dev. 2002;12:80–85. doi: 10.1016/s0959-437x(01)00268-4. [DOI] [PubMed] [Google Scholar]
  2. Akiyama M., Hideshima T., Hayashi T., Tai Y.T., Mitsiades C.S., Mitsiades N., Chauhan D., Richardson P., Munshi N.C., Anderson K.C. Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res. 2003;63:18–21. [PubMed] [Google Scholar]
  3. Atkinson S.P., Hoare S.F., Glasspool R.M., Keith W.N. Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res. 2005;65:7585–7590. doi: 10.1158/0008-5472.CAN-05-1715. [DOI] [PubMed] [Google Scholar]
  4. Bazarov A.V., Hines W.C., Mukhopadhyay R., Beliveau A., Melodyev S., Zaslavsky Y., Yaswen P. Telomerase activation by c-Myc in human mammary epithelial cells requires additional genomic changes. Cell Cycle. 2009;8:3373–3378. doi: 10.4161/cc.8.20.9856. [DOI] [PubMed] [Google Scholar]
  5. Blackburn E.H., Chan S., Chang J., Fulton T.B., Krauskopf A., McEachern M., Prescott J., Roy J., Smith C., Wang H. Molecular manifestations and molecular determinants of telomere capping. Cold Spring Harb Symp Quant Biol. 2000;65:253–263. doi: 10.1101/sqb.2000.65.253. [DOI] [PubMed] [Google Scholar]
  6. Blasco M.A., Funk W., Villeponteau B., Greider C.W. Functional characterization and developmental regulation of mouse telomerase RNA. Science. 1995;269:1267–1270. doi: 10.1126/science.7544492. [DOI] [PubMed] [Google Scholar]
  7. Blasco M.A., Lee H.W., Hande M.P., Samper E., Lansdorp P.M., DePinho R.A., Greider C.W. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA [see comments] Cell. 1997;91:25–34. doi: 10.1016/s0092-8674(01)80006-4. [DOI] [PubMed] [Google Scholar]
  8. Blasco M.A., Rizen M., Greider C.W., Hanahan D. Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis. Nature Genetics. 1996;12:200–204. doi: 10.1038/ng0296-200. [DOI] [PubMed] [Google Scholar]
  9. Bodnar A.G., Ouellette M., Frolkis M., Holt S.E., Chiu C.P., Morin G.B., Harley C.B., Shay J.W., Lichtsteiner S., Wright W.E. Extension of life-span by introduction of telomerase into normal human cells [see comments] Science. 1998;279:349–352. doi: 10.1126/science.279.5349.349. [DOI] [PubMed] [Google Scholar]
  10. Cao Y., Bryan T.M., Reddel R.R. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci. 2008;99:1092–1099. doi: 10.1111/j.1349-7006.2008.00815.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cassar L., Li H., Pinto A.R., Nicholls C., Bayne S., Liu J.P. Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth. Cancer Res. 2008;68:9157–9166. doi: 10.1158/0008-5472.CAN-08-1323. [DOI] [PubMed] [Google Scholar]
  12. Chatagnon A., Bougel S., Perriaud L., Lachuer J., Benhattar J., Dante R. Specific association between the methyl-CpG-binding domain protein 2 and the hypermethylated region of the human telomerase reverse transcriptase promoter in cancer cells. Carcinogenesis. 2009;30:28–34. doi: 10.1093/carcin/bgn240. [DOI] [PubMed] [Google Scholar]
  13. Chiu C.P., Dragowska W., Kim N.W., Vaziri H., Yui J., Thomas T. E., Harley C.B., Lansdorp P.M. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells. 1996;14:239–248. doi: 10.1002/stem.140239. [DOI] [PubMed] [Google Scholar]
  14. Cohen S.B., Graham M.E., Lovrecz G.O., Bache N., Robinson P. J., Reddel R.R. Protein composition of catalytically active human telomerase from immortal cells. Science. 2007;315:1850–1853. doi: 10.1126/science.1138596. [DOI] [PubMed] [Google Scholar]
  15. Collins K. Mammalian telomeres and telomerase. Current Opinion in Cell Biology. 2000;12:378–383. doi: 10.1016/s0955-0674(00)00103-4. [DOI] [PubMed] [Google Scholar]
  16. Cong Y.S., Bacchetti S. Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J Biol Chem. 2000;275:35665–35668. doi: 10.1074/jbc.C000637200. [DOI] [PubMed] [Google Scholar]
  17. Cong Y.S., Wen J., Bacchetti S. The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet. 1999;8:137–142. doi: 10.1093/hmg/8.1.137. [DOI] [PubMed] [Google Scholar]
  18. Counter C.M., Botelho F.M., Wang P., Harley C.B., Bacchetti S. Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes. J Virol. 1994;68:3410–3414. doi: 10.1128/jvi.68.5.3410-3414.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Counter C.M., Hahn W.C., Wei W., Caddle S.D., Beijersbergen R. L., Lansdorp P.M., Sedivy J.M., Weinberg R.A. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci U S A. 1998;95:14723–14728. doi: 10.1073/pnas.95.25.14723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Crowe D.L., Nguyen D.C., Tsang K.J., Kyo S. E2F-1 represses transcription of the human telomerase reverse transcriptase gene. Nucleic Acids Res. 2001;29:2789–2794. doi: 10.1093/nar/29.13.2789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. de la Serna I.L., Ohkawa Y., Imbalzano A.N. Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet. 2006;7:461–473. doi: 10.1038/nrg1882. [DOI] [PubMed] [Google Scholar]
  22. Dessain S.K., Yu H., Reddel R.R., Beijersbergen R.L., Weinberg R.A. Methylation of the human telomerase gene CpG island. Cancer Res. 2000;60:537–541. [PubMed] [Google Scholar]
  23. Devereux T.R., Horikawa I., Anna C.H., Annab L.A., Afshari C.A., Barrett J.C. DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 1999;59:6087–6090. [PubMed] [Google Scholar]
  24. Ducrest A.L., Amacker M., Mathieu Y.D., Cuthbert A.P., Trott D.A., Newbold R.F., Nabholz M., Lingner J. Regulation of human telomerase activity: repression by normal chromosome 3 abolishes nuclear telomerase reverse transcriptase transcripts but does not affect c-Myc activity. Cancer Res. 2001;61:7594–7602. [PubMed] [Google Scholar]
  25. Ducrest A.L., Szutorisz H., Lingner J., Nabholz M. Regulation of the human telomerase reverse transcriptase gene. Oncogene. 2002;21:541–552. doi: 10.1038/sj.onc.1205081. [DOI] [PubMed] [Google Scholar]
  26. Dwyer J., Li H., Xu D., Liu J.P. Transcriptional regulation of telomerase activity: roles of the the Ets transcription factor family. Ann N Y Acad Sci. 2007;1114:36–47. doi: 10.1196/annals.1396.022. [DOI] [PubMed] [Google Scholar]
  27. Ferber M.J., Montoya D.P., Yu C., Aderca I., McGee A., Thorland E.C., Nagorney D.M., Gostout B.S., Burgart L.J., Boix L., et al. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003;22:3813–3820. doi: 10.1038/sj.onc.1206528. [DOI] [PubMed] [Google Scholar]
  28. Forsyth N.R., Elder F.F., Shay J.W., Wright W.E. Lagomorphs (rabbits, pikas and hares) do not use telomere-directed replicative aging in vitro. Mech Ageing Dev. 2005;126:685–691. doi: 10.1016/j.mad.2005.01.003. [DOI] [PubMed] [Google Scholar]
  29. Fujimoto K., Kyo S., Takakura M., Kanaya T., Kitagawa Y., Itoh H., Takahashi M., Inoue M. Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit (hTERT) gene promoter: possible role of MZF-2 in transcriptional repression of hTERT. Nucleic Acids Res. 2000;28:2557–2562. doi: 10.1093/nar/28.13.2557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Günes C., Lichtsteiner S., Vasserot A.P., Englert C. Expression of the hTERT gene is regulated at the level of transcriptional initiation and repressed by Mad1. Cancer Res. 2000;60:2116–2121. [PubMed] [Google Scholar]
  31. Ge, Z., Li, W., Wang, N., Liu, C., Zhu, Q., Bjorkholm, M., Gruber, A., and Xu, D. (2009). Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase. Faseb J. In press. [DOI] [PubMed]
  32. Ge Z., Liu C., Bjorkholm M., Gruber A., Xu D. Mitogen-activated protein kinase cascade-mediated histone H3 phosphorylation is critical for telomerase reverse transcriptase expression/telomerase activation induced by proliferation. Mol Cell Biol. 2006;26:230–237. doi: 10.1128/MCB.26.1.230-237.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Goueli B.S., Janknecht R. Upregulation of the Catalytic Telomerase Subunit by the Transcription Factor ER81 and Oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol. 2004;24:25–35. doi: 10.1128/MCB.24.1.25-35.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Greenberg R.A. Telomeres, crisis and cancer. Curr Mol Med. 2005;5:213–218. doi: 10.2174/1566524053586590. [DOI] [PubMed] [Google Scholar]
  35. Greenberg R.A., Allsopp R.C., Chin L., Morin G.B., DePinho R.A. Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene. 1998;16:1723–1730. doi: 10.1038/sj.onc.1201933. [DOI] [PubMed] [Google Scholar]
  36. Greenberg R.A., O’Hagan R.C., Deng H., Xiao Q., Hann S.R., Adams R.R., Lichtsteiner S., Chin L., Morin G.B., DePinho R.A. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene. 1999;18:1219–1226. doi: 10.1038/sj.onc.1202669. [DOI] [PubMed] [Google Scholar]
  37. Guilleret I., Benhattar J. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Exp Cell Res. 2003;289:326–334. doi: 10.1016/s0014-4827(03)00281-7. [DOI] [PubMed] [Google Scholar]
  38. Guilleret I., Yan P., Grange F., Braunschweig R., Bosman F.T., Benhattar J. Int J Cancer. 2002;101:335–341. doi: 10.1002/ijc.10593. [DOI] [PubMed] [Google Scholar]
  39. Hahn W.C., Counter C.M., Lundberg A.S., Beijersbergen R.L., Brooks M.W., Weinberg R.A. Creation of human tumour cells with defined genetic elements [see comments] Nature. 1999;400:464–468. doi: 10.1038/22780. [DOI] [PubMed] [Google Scholar]
  40. Hahn W.C., Stewart S.A., Brooks M.W., York S.G., Eaton E., Kurachi A., Beijersbergen R.L., Knoll J.H., Meyerson M., Weinberg R.A. Inhibition of telomerase limits the growth of human cancer cells. Nat Med. 1999;5:1164–1170. doi: 10.1038/13495. [DOI] [PubMed] [Google Scholar]
  41. Harrington L., McPhail T., Mar V., Zhou W., Oulton R., Bass M.B., Arruda I., Robinson M.O. A mammalian telomerase-associated protein [see comments] Science. 1997;275:973–977. doi: 10.1126/science.275.5302.973. [DOI] [PubMed] [Google Scholar]
  42. Horikawa I., Cable P.L., Afshari C., Barrett J.C. Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 1999;59:826–830. [PubMed] [Google Scholar]
  43. Horikawa I., Cable P.L., Mazur S.J., Appella E., Afshari C.A., Barrett J.C. 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. 2002;13:2585–2597. doi: 10.1091/mbc.E01-11-0107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Horikawa I., Chiang Y.J., Patterson T., Feigenbaum L., Leem S.H., Michishita E., Larionov V., Hodes R.J., Barrett J.C. Differential cis-regulation of human versus mouse TERT gene expression in vivo: identification of a human-specific repressive element. Proc Natl Acad Sci U S A. 2005;102:18437–18442. doi: 10.1073/pnas.0508964102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Horikawa I., Oshimura M., Barrett J.C. Repression of the telomerase catalytic subunit by a gene on human chromosome 3 that induces cellular senescence. Mol Carcinog. 1998;22:65–72. doi: 10.1002/(sici)1098-2744(199806)22:2<65::aid-mc1>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  46. Hornsby P.J. Senescence as an anticancer mechanism. J Clin Oncol. 2007;25:1852–1857. doi: 10.1200/JCO.2006.10.3101. [DOI] [PubMed] [Google Scholar]
  47. Hou M., Wang X., Popov N., Zhang A., Zhao X., Zhou R., Zetterberg A., Bjorkholm M., Henriksson M., Gruber A., et al. The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells. Exp Cell Res. 2002;274:25–34. doi: 10.1006/excr.2001.5462. [DOI] [PubMed] [Google Scholar]
  48. Janknecht R. On the road to immortality: hTERT upregulation in cancer cells. FEBS Lett. 2004;564:9–13. doi: 10.1016/S0014-5793(04)00356-4. [DOI] [PubMed] [Google Scholar]
  49. Jenuwein T., Allis C.D. Translating the histone code.[see comment] Science. 2001;293:1074–1080. doi: 10.1126/science.1063127. [DOI] [PubMed] [Google Scholar]
  50. Kaeser M.D., Emerson B.M. Remodeling plans for cellular specialization: unique styles for every room. Curr Opin Genet Dev. 2006;16:508–512. doi: 10.1016/j.gde.2006.08.001. [DOI] [PubMed] [Google Scholar]
  51. Kang S.S., Kwon T., Kwon D.Y., Do S.I. Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem. 1999;274:13085–13090. doi: 10.1074/jbc.274.19.13085. [DOI] [PubMed] [Google Scholar]
  52. Kim N.W., Piatyszek M.A., Prowse K.R., Harley C.B., West M.D., Ho P.L., Coviello G.M., Wright W.E., Weinrich S.L., Shay J. W. Specific association of human telomerase activity with immortal cells and cancer [see comments] Science. 1994;266:2011–2015. doi: 10.1126/science.7605428. [DOI] [PubMed] [Google Scholar]
  53. Klingelhutz A.J., Foster S.A., McDougall J.K. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature. 1996;380:79–82. doi: 10.1038/380079a0. [DOI] [PubMed] [Google Scholar]
  54. 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. doi: 10.1111/j.1349-7006.2008.00878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kyo S., Takakura M., Kanaya T., Zhuo W., Fujimoto K., Nishio Y., Orimo A., Inoue M. Estrogen activates telomerase. Cancer Res. 1999;59:5917–5921. [PubMed] [Google Scholar]
  56. Kyo S., Takakura M., Taira T., Kanaya T., Itoh H., Yutsudo M., Ariga H., Inoue M. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT) Nucleic Acids Res. 2000;28:669–677. doi: 10.1093/nar/28.3.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Li H., Liu J.P. Mechanisms of action of TGF-beta in cancer: evidence for Smad3 as a repressor of the hTERT gene. Ann N Y Acad Sci. 2007;1114:56–68. doi: 10.1196/annals.1396.016. [DOI] [PubMed] [Google Scholar]
  58. Li H., Xu D., Li J., Berndt M.C., Liu J.P. Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem. 2006;281:25588–25600. doi: 10.1074/jbc.M602381200. [DOI] [PubMed] [Google Scholar]
  59. Lin S.Y., Elledge S.J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell. 2003;113:881–889. doi: 10.1016/s0092-8674(03)00430-6. [DOI] [PubMed] [Google Scholar]
  60. Lingner J., Hughes T.R., Shevchenko A., Mann M., Lundblad V., Cech T.R. Reverse transcriptase motifs in the catalytic subunit of telomerase [see comments] Science. 1997;276:561–567. doi: 10.1126/science.276.5312.561. [DOI] [PubMed] [Google Scholar]
  61. Liu C., Fang X., Ge Z., Jalink M., Kyo S., Bjorkholm M., Gruber A., Sjoberg J., Xu D. The telomerase reverse transcriptase (hTERT) gene is a direct target of the histone methyltransferase SMYD3. Cancer Res. 2007;67:2626–2631. doi: 10.1158/0008-5472.CAN-06-4126. [DOI] [PubMed] [Google Scholar]
  62. Liu L., Lai S., Andrews L.G., Tollefsbol T.O. Genetic and epigenetic modulation of telomerase activity in development and disease. Gene. 2004;340:1–10. doi: 10.1016/j.gene.2004.06.011. [DOI] [PubMed] [Google Scholar]
  63. Martin-Rivera L., Herrera E., Albar J.P., Blasco M.A. Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc Natl Acad Sci U S A. 1998;95:10471–10476. doi: 10.1073/pnas.95.18.10471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Maser R.S., DePinho R.A., Masera G. Connecting chromosomes, crisis, and cancer. Science. 2002;297:565–569. doi: 10.1126/science.297.5581.565. [DOI] [PubMed] [Google Scholar]
  65. Masutomi K., Yu E.Y., Khurts S., Ben-Porath I., Currier J.L., Metz G.B., Brooks M.W., Kaneko S., Murakami S., DeCaprio J.A., et al. Telomerase maintains telomere structure in normal human cells. Cell. 2003;114:241–253. doi: 10.1016/s0092-8674(03)00550-6. [DOI] [PubMed] [Google Scholar]
  66. Meyerson M., Counter C.M., Eaton E.N., Ellisen L.W., Steiner P., Caddle S.D., Ziaugra L., Beijersbergen R.L., Davidoff M.J., Liu Q., et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795. doi: 10.1016/s0092-8674(00)80538-3. [DOI] [PubMed] [Google Scholar]
  67. Morin G.B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989;59:521–529. doi: 10.1016/0092-8674(89)90035-4. [DOI] [PubMed] [Google Scholar]
  68. Nakamura T.M., Morin G.B., Chapman K.B., Weinrich S.L., Andrews W.H., Lingner J., Harley C.B., Cech T.R. Telomerase catalytic subunit homologs from fission yeast and human [see comments] Science. 1997;277:955–959. doi: 10.1126/science.277.5328.955. [DOI] [PubMed] [Google Scholar]
  69. Nash S.R., Giros B., Kingsmore S.F., Kim K.M., el-Mestikawy S., Dong Q., Fumagalli F., Seldin M.F., Caron M.G. Cloning, gene structure and genomic localization of an orphan transporter from mouse kidney with six alternatively-spliced isoforms. Receptors Channels. 1998;6:113–128. [PubMed] [Google Scholar]
  70. Oh S., Song Y., Yim J., Kim T.K. The Wilms’ tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J Biol Chem. 1999;274:37473–37478. doi: 10.1074/jbc.274.52.37473. [DOI] [PubMed] [Google Scholar]
  71. Palmqvist R., Zhang A., Xu D., Golovleva I., Norrback K.F., Gruber A., Oberg A., Stenling R., Roos G. hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer. Int J Cancer. 2005;116:395–400. doi: 10.1002/ijc.21020. [DOI] [PubMed] [Google Scholar]
  72. Pirker C., Holzmann K., Spiegl-Kreinecker S., Elbling L., Thallinger C., Pehamberger H., Micksche M., Berger W. Chromosomal imbalances in primary and metastatic melanomas: over-representation of essential telomerase genes. Melanoma Res. 2003;13:483–492. doi: 10.1097/00008390-200310000-00007. [DOI] [PubMed] [Google Scholar]
  73. Prowse K.R., Greider C.W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci U S A. 1995;92:4818–4822. doi: 10.1073/pnas.92.11.4818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Renaud S., Bosman F.T., Benhattar J. Implication of the exon region in the regulation of the human telomerase reverse transcriptase gene promoter. Biochem Biophys Res Commun. 2003;300:47–54. doi: 10.1016/s0006-291x(02)02775-4. [DOI] [PubMed] [Google Scholar]
  75. Renaud S., Loukinov D., Bosman F.T., Lobanenkov V., Benhattar J. CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res. 2005;33:6850–6860. doi: 10.1093/nar/gki989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Ritz J.M., Kuhle O., Riethdorf S., Sipos B., Deppert W., Englert C., Gunes C. A novel transgenic mouse model reveals humanlike regulation of an 8-kbp human TERT gene promoter fragment in normal and tumor tissues. Cancer Res. 2005;65:1187–1196. doi: 10.1158/0008-5472.CAN-04-3046. [DOI] [PubMed] [Google Scholar]
  77. Rudolph K.L., Chang S., Lee H.W., Blasco M., Gottlieb G.J., Greider C., DePinho R.A. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96:701–712. doi: 10.1016/s0092-8674(00)80580-2. [DOI] [PubMed] [Google Scholar]
  78. Shay J.W., Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer. 1997;33:787–791. doi: 10.1016/S0959-8049(97)00062-2. [DOI] [PubMed] [Google Scholar]
  79. Shay J.W., Wright W.E. Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen. Exp Cell Res. 1989;184:109–118. doi: 10.1016/0014-4827(89)90369-8. [DOI] [PubMed] [Google Scholar]
  80. Shippen-Lentz D., Blackburn E.H. Functional evidence for an RNA template in telomerase. Science. 1990;247:546–552. doi: 10.1126/science.1689074. [DOI] [PubMed] [Google Scholar]
  81. Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.[see comment] Cell. 2007;131:861–872. doi: 10.1016/j.cell.2007.11.019. [DOI] [PubMed] [Google Scholar]
  82. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.[see comment] Cell. 2006;126:663–676. doi: 10.1016/j.cell.2006.07.024. [DOI] [PubMed] [Google Scholar]
  83. Takakura M., Kyo S., Inoue M., Wright W.E., Shay J.W. Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells. Mol Cell Biol. 2005;25:8037–8043. doi: 10.1128/MCB.25.18.8037-8043.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Takakura M., Kyo S., Kanaya T., Hirano H., Takeda J., Yutsudo M., Inoue M. 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. 1999;59:551–557. [PubMed] [Google Scholar]
  85. Takakura M., Kyo S., Sowa Y., Wang Z., Yatabe N., Maida Y., Tanaka M., Inoue M. Telomerase activation by histone deacetylase inhibitor in normal cells. Nucleic Acids Res. 2001;29:3006–3011. doi: 10.1093/nar/29.14.3006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Takuma Y., Nouso K., Kobayashi Y., Nakamura S., Tanaka H., Matsumoto E., Fujikawa T., Suzuki M., Hanafusa T., Shiratori Y. Telomerase reverse transcriptase gene amplification in hepatocellular carcinoma. J Gastroenterol Hepatol. 2004;19:1300–1304. doi: 10.1111/j.1440-1746.2004.03447.x. [DOI] [PubMed] [Google Scholar]
  87. Veldman T., Liu X., Yuan H., Schlegel R. Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc Natl Acad Sci U S A. 2003;100:8211–8216. doi: 10.1073/pnas.1435900100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Venteicher A.S., Abreu E.B., Meng Z., McCann K.E., Terns R.M., Veenstra T.D., Terns M.P., Artandi S.E. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science. 2009;323:644–648. doi: 10.1126/science.1165357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Wang J., Xie L.Y., Allan S., Beach D., Hannon G.J. Myc activates telomerase. Genes Dev. 1998;12:1769–1774. doi: 10.1101/gad.12.12.1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Wang S., Hu C., Zhu J. Transcriptional silencing of a novel hTERT reporter locus during in vitro differentiation of mouse embryonic stem cells. Mol Biol Cell. 2007;18:669–677. doi: 10.1091/mbc.E06-09-0840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Wang S., Robertson G.P., Zhu J. A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers. Gene. 2004;343:69–78. doi: 10.1016/j.gene.2004.09.006. [DOI] [PubMed] [Google Scholar]
  92. Wang S., Zhao Y., Hu C., Zhu J. Differential repression of human and mouse TERT genes during cell differentiation. Nucleic Acids Res. 2009;37:2618–2629. doi: 10.1093/nar/gkp125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Wang S., Zhu J. Evidence for a relief of repression mechanism for activation of the human telomerase reverse transcriptase promoter. J Biol Chem. 2003;278:18842–18850. doi: 10.1074/jbc.M209544200. [DOI] [PubMed] [Google Scholar]
  94. Wang S., Zhu J. The hTERT gene is embedded in a nuclease-resistant chromatin domain. J Biol Chem. 2004;279:55401–55410. doi: 10.1074/jbc.M411352200. [DOI] [PubMed] [Google Scholar]
  95. Weng N.P., Levine B.L., June C.H., Hodes R.J. Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med. 1996;183:2471–2479. doi: 10.1084/jem.183.6.2471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Wernig M., Meissner A., Cassady J.P., Jaenisch R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008;2:10–12. doi: 10.1016/j.stem.2007.12.001. [DOI] [PubMed] [Google Scholar]
  97. Wick M., Zubov D., Hagen G. Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT) Gene. 1999;232:97–106. doi: 10.1016/s0378-1119(99)00108-0. [DOI] [PubMed] [Google Scholar]
  98. Won J., Yim J., Kim T.K. Sp1 and Sp3 Recruit Histone Deacetylase to Repress Transcription of Human Telomerase Reverse Transcriptase (hTERT) Promoter in Normal Human Somatic Cells. J Biol Chem. 2002;277:38230–38238. doi: 10.1074/jbc.M206064200. [DOI] [PubMed] [Google Scholar]
  99. Wright W.E., Piatyszek M.A., Rainey W.E., Byrd W., Shay J.W. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996;18:173–179. doi: 10.1002/(SICI)1520-6408(1996)18:2<173::AID-DVG10>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  100. Wu K.J., Grandori C., Amacker M., Simon-Vermot N., Polack A., Lingner J., Dalla-Favera R. Direct activation of TERT transcription by c-MYC. Nat Genet. 1999;21:220–224. doi: 10.1038/6010. [DOI] [PubMed] [Google Scholar]
  101. Xu D., Dwyer J., Li H., Duan W., Liu J.P. Ets2 maintains hTERT gene expression and breast cancer cell proliferation by interacting with c-Myc. J Biol Chem. 2008;283:23567–23580. doi: 10.1074/jbc.M800790200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Xu D., Popov N., Hou M., Wang Q., Bjorkholm M., Gruber A., Menkel A.R., Henriksson M. 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 U S A. 2001;98:3826–3831. doi: 10.1073/pnas.071043198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Xu M., Luo W., Elzi D.J., Grandori C., Galloway D.A. NFX1 interacts with mSin3A/histone deacetylase to repress hTERT transcription in keratinocytes. Mol Cell Biol. 2008;28:4819–4828. doi: 10.1128/MCB.01969-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Yasumoto S., Kunimura C., Kikuchi K., Tahara H., Ohji H., Yamamoto H., Ide T., Utakoji T. Telomerase activity in normal human epithelial cells. Oncogene. 1996;13:433–439. [PubMed] [Google Scholar]
  105. Yaswen P., Stampfer M.R. Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells. Int J Biochem Cell Biol. 2002;34:1382–1394. doi: 10.1016/s1357-2725(02)00047-x. [DOI] [PubMed] [Google Scholar]
  106. Yi X., Shay J.W., Wright W.E. Quantitation of telomerase components and hTERT mRNA splicing patterns in immortal human cells. Nucleic Acids Res. 2001;29:4818–4825. doi: 10.1093/nar/29.23.4818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Yu J., Vodyanik M.A., Smuga-Otto K., Antosiewicz-Bourget J., Frane J.L., Tian S., Nie J., Jonsdottir G.A., Ruotti V., Stewart R., et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920. doi: 10.1126/science.1151526. [DOI] [PubMed] [Google Scholar]
  108. Zhang A., Zheng C., Hou M., Lindvall C., Wallin K.L., Angstrom T., Yang X., Hellstrom A.C., Blennow E., Bjorkholm M., et al. Amplification of the telomerase reverse transcriptase (hTERT) gene in cervical carcinomas. Genes Chromosomes Cancer. 2002;34:269–275. doi: 10.1002/gcc.10071. [DOI] [PubMed] [Google Scholar]
  109. Zhang A., Zheng C., Lindvall C., Hou M., Ekedahl J., Lewensohn R., Yan Z., Yang X., Henriksson M., Blennow E., et al. Frequent amplification of the telomerase reverse transcriptase gene in human tumors. Cancer Res. 2000;60:6230–6235. [PubMed] [Google Scholar]
  110. Zhang Z., Reese J.C. Redundant mechanisms are used by Ssn6-Tup1 in repressing chromosomal gene transcription in Saccharomyces cerevisiae. J Biol Chem. 2004;279:39240–39250. doi: 10.1074/jbc.M407159200. [DOI] [PubMed] [Google Scholar]
  111. Zhao, Y., Wang, S., Popova, E., Grigoryev, S., and Zhu, J. (2009). Rearrangement of Upstream Sequences of the hTERT Gene during Cellular Immortalization. Genes Chromosomes Cancer. In press. [DOI] [PMC free article] [PubMed]
  112. Zhu J., Wang H., Bishop J.M., Blackburn E.H. Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening [see comments] Proc Natl Acad Sci U S A. 1999;96:3723–3728. doi: 10.1073/pnas.96.7.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Zhu Q., Liu C., Ge Z., Fang X., Zhang X., Straat K., Bjorkholm M., Xu D. Lysine-specific demethylase 1 (LSD1) Is required for the transcriptional repression of the telomerase reverse transcriptase (hTERT) gene. PLoS One. 2008;3:e1446. doi: 10.1371/journal.pone.0001446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Zinn R.L., Pruitt K., Eguchi S., Baylin S.B., Herman J.G. hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res. 2007;67:194–201. doi: 10.1158/0008-5472.CAN-06-3396. [DOI] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES