Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2011 Oct 6;2(9):726–738. doi: 10.1007/s13238-011-1093-3

Molecular regulation of telomerase activity in aging

Craig Nicholls 1,3, He Li 1, Jian-Qiu Wang 2, Jun-Ping Liu 1,2,3,4,
PMCID: PMC4875265  PMID: 21976062

Abstract

The process of aging is mitigated by the maintenance and repair of chromosome ends (telomeres), resulting in extended lifespan. This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase (TERT), which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy. Underpinning increased cell proliferation, telomerase is also a key factor in facilitating cancer cell immortalization. The review focuses on aspects of hormonal regulations of telomerase, and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels. In addition, the basic structure and function of two key telomerase enzyme components—the catalytic subunit TERT and the template RNA (TERC) are discussed briefly.

Keywords: telomerase, aging, telomerase reverse transcriptase (TERT)

References

  1. Akalin A., Elmore L.W., Forsythe H.L., Amaker B.A., McCollum E. D., Nelson P.S., Ware J.L., Holt S.E. A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression. Cancer Res. 2001;61:4791–4796. [PubMed] [Google Scholar]
  2. Allsopp R.C., Vaziri H., Patterson C., Goldstein S., Younglai E.V., Futcher A.B., Greider C.W., Harley C.B. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992;89:10114–10118. doi: 10.1073/pnas.89.21.10114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armanios M. Syndromes of Telomere Shortening. Annu Rev Genomics Hum Genet. 2009;10:45–61. doi: 10.1146/annurev-genom-082908-150046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armbruster B.N., Banik S.S., Guo C., Smith A.C., Counter C. M. N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo. Mol Cell Biol. 2001;21:7775–7786. doi: 10.1128/MCB.21.22.7775-7786.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Atzmon G., Cho M., Cawthon R.M., Budagov T., Katz M., Yang X., Siegel G., Bergman A., Huffman D.M., Schechter C.B., et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010;107:1710–1717. doi: 10.1073/pnas.0906191106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Autexier C., Pruzan R., Funk W.D., Greider C.W. Reconstitution of human telomerase activity and identification of a minimal functional region of the human telomerase RNA. EMBO J. 1996;15:5928–5935. [PMC free article] [PubMed] [Google Scholar]
  7. Ayouaz A., Raynaud C., Heride C., Revaud D., Sabatier L. Telomeres: hallmarks of radiosensitivity. Biochimie. 2008;90:60–72. doi: 10.1016/j.biochi.2007.09.011. [DOI] [PubMed] [Google Scholar]
  8. Bachand F., Autexier C. Functional regions of human telomerase reverse transcriptase and human telomerase RNA required for telomerase activity and RNA-protein interactions. Mol Cell Biol. 2001;21:1888–1897. doi: 10.1128/MCB.21.5.1888-1897.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bagheri S., Nosrati M., Li S., Fong S., Torabian S., Rangel J., Moore D.H., Federman S., Laposa R.R., Baehner F.L., et al. Genes and pathways downstream of telomerase in melanoma metastasis. Proc Natl Acad Sci U S A. 2006;103:11306–11311. doi: 10.1073/pnas.0510085103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Banik S.S., Guo C., Smith A.C., Margolis S.S., Richardson D.A., Tirado C.A., Counter C.M. C-terminal regions of the human telomerase catalytic subunit essential for in vivo enzyme activity. Mol Cell Biol. 2002;22:6234–6246. doi: 10.1128/MCB.22.17.6234-6246.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Banks W.A., Morley J.E., Farr S.A., Price T.O., Ercal N., Vidaurre I., Schally A.V. Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice. Proc Natl Acad Sci U S A. 2010;107:22272–22277. doi: 10.1073/pnas.1016369107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bayne S., Jones M.E., Li H., Pinto A.R., Simpson E.R., Liu J. P. Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice. Cell Res. 2008;18:1141–1150. doi: 10.1038/cr.2008.291. [DOI] [PubMed] [Google Scholar]
  13. Bayne S., Li H., Jones M.E., Pinto A.R., van Sinderen M., Drummond A., Simpson E.R., Liu J.P. Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo. Protein Cell. 2011;2:333–346. doi: 10.1007/s13238-011-1033-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Britt K.L., Drummond A.E., Dyson M., Wreford N.G., Jones M.E., Simpson E.R., Findlay J.K. The ovarian phenotype of the aromatase knockout (ArKO) mouse. J Steroid Biochem Mol Biol. 2001;79:181–185. doi: 10.1016/s0960-0760(01)00158-3. [DOI] [PubMed] [Google Scholar]
  15. Britt K.L., Kerr J., O’Donnell L., Jones M.E., Drummond A.E., Davis S.R., Simpson E.R., Findlay J.K. Estrogen regulates development of the somatic cell phenotype in the eutherian ovary. FASEB J. 2002;16:1389–1397. doi: 10.1096/fj.01-0992com. [DOI] [PubMed] [Google Scholar]
  16. Browner W.S., Kahn A.J., Ziv E., Reiner A.P., Oshima J., Cawthon R.M., Hsueh W.C., Cummings S.R. The genetics of human longevity. Am J Med. 2004;117:851–860. doi: 10.1016/j.amjmed.2004.06.033. [DOI] [PubMed] [Google Scholar]
  17. Bryan T.M., Goodrich K.J., Cech T.R. Telomerase RNA bound by protein motifs specific to telomerase reverse transcriptase. Mol Cell. 2000;6:493–499. doi: 10.1016/s1097-2765(00)00048-4. [DOI] [PubMed] [Google Scholar]
  18. Calado R.T., Young N.S. Telomere diseases. N Engl J Med. 2009;361:2353–2365. doi: 10.1056/NEJMra0903373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Cha Y., Kwon S.J., Seol W., Park K.S. Estrogen receptor-alpha mediates the effects of estradiol on telomerase activity in human mesenchymal stem cells. Mol Cells. 2008;26:454–458. [PubMed] [Google Scholar]
  21. Chai W., Ford L.P., Lenertz L., Wright W.E., Shay J.W. Human Ku70/80 associates physically with telomerase through interaction with hTERT. J Biol Chem. 2002;277:47242–47247. doi: 10.1074/jbc.M208542200. [DOI] [PubMed] [Google Scholar]
  22. Chang J.T., Lu Y.C., Chen Y.J., Tseng C.P., Chen Y.L., Fang C.W., Cheng A.J. hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells. Br J Cancer. 2006;94:870–878. doi: 10.1038/sj.bjc.6603008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Chen J.L., Blasco M.A., Greider C.W. Secondary structure of vertebrate telomerase RNA. Cell. 2000;100:503–514. doi: 10.1016/s0092-8674(00)80687-x. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Colgin L.M., Wilkinson C., Englezou A., Kilian A., Robinson M.O., Reddel R.R. The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia. 2000;2:426–432. doi: 10.1038/sj.neo.7900112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Collins K. The biogenesis and regulation of telomerase holoenzymes. Nat Rev Mol Cell Biol. 2006;7:484–494. doi: 10.1038/nrm1961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Counter C.M., Meyerson M., Eaton E.N., Ellisen L.W., Caddle S. D., Haber D.A., Weinberg R.A. Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase. Oncogene. 1998;16:1217–1222. doi: 10.1038/sj.onc.1201882. [DOI] [PubMed] [Google Scholar]
  29. Cuthbert A.P., Bond J., Trott D.A., Gill S., Broni J., Marriott A., Khoudoli G., Parkinson E.K., Cooper C.S., Newbold R.F. Telomerase repressor sequences on chromosome 3 and induction of permanent growth arrest in human breast cancer cells. J Natl Cancer Inst. 1999;91:37–45. doi: 10.1093/jnci/91.1.37. [DOI] [PubMed] [Google Scholar]
  30. Dallaire F., Dupuis S., Fiset S., Chabot B. Heterogeneous nuclear ribonucleoprotein A1 and UP1 protect mammalian telomeric repeats and modulate telomere replication in vitro. J Biol Chem. 2000;275:14509–14516. doi: 10.1074/jbc.275.19.14509. [DOI] [PubMed] [Google Scholar]
  31. Dang C.V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999;19:1–11. doi: 10.1128/mcb.19.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. de Lange T. How telomeres solve the end-protection problem. Science. 2009;326:948–952. doi: 10.1126/science.1170633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Denchi E.L. Give me a break: how telomeres suppress the DNA damage response. DNA Repair (Amst) 2009;8:1118–1126. doi: 10.1016/j.dnarep.2009.04.013. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Feng J., Funk W.D., Wang S.S., Weinrich S.L., Avilion A.A., Chiu C.P., Adams R.R., Chang E., Allsopp R.C., Yu J., et al. The RNA component of human telomerase. Science. 1995;269:1236–1241. doi: 10.1126/science.7544491. [DOI] [PubMed] [Google Scholar]
  37. Fiset S., Chabot B. hnRNP A1 may interact simultaneously with telomeric DNA and the human telomerase RNA in vitro. Nucleic Acids Res. 2001;29:2268–2275. doi: 10.1093/nar/29.11.2268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Fisher C.R., Graves K.H., Parlow A.F., Simpson E.R. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A. 1998;95:6965–6970. doi: 10.1073/pnas.95.12.6965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Forsythe H.L., Jarvis J.L., Turner J.W., Elmore L.W., Holt S.E. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001;276:15571–15574. doi: 10.1074/jbc.C100055200. [DOI] [PubMed] [Google Scholar]
  40. Friedman K.L., Cech T.R. Essential functions of aminoterminal domains in the yeast telomerase catalytic subunit revealed by selection for viable mutants. Genes Dev. 1999;13:2863–2874. doi: 10.1101/gad.13.21.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Geserick C., Tejera A., González-Suárez E., Klatt P., Blasco M.A. Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-beta signaling. Oncogene. 2006;25:4310–4319. doi: 10.1038/sj.onc.1209465. [DOI] [PubMed] [Google Scholar]
  42. Gillis A.J., Schuller A.P., Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008;455:633–637. doi: 10.1038/nature07283. [DOI] [PubMed] [Google Scholar]
  43. González-Suárez E., Geserick C., Flores J.M., Blasco M.A. Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene. 2005;24:2256–2270. doi: 10.1038/sj.onc.1208413. [DOI] [PubMed] [Google Scholar]
  44. González-Suárez E., Samper E., Ramírez A., Flores J.M., Martín-Caballero J., Jorcano J.L., Blasco M.A. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 2001;20:2619–2630. doi: 10.1093/emboj/20.11.2619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Grasselli A., Nanni S., Colussi C., Aiello A., Benvenuti V., Ragone G., Moretti F., Sacchi A., Bacchetti S., Gaetano C., et al. Estrogen receptor-alpha and endothelial nitric oxide synthase nuclear complex regulates transcription of human telomerase. Circ Res. 2008;103:34–42. doi: 10.1161/CIRCRESAHA.107.169037. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Greider C.W., Blackburn E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43:405–413. doi: 10.1016/0092-8674(85)90170-9. [DOI] [PubMed] [Google Scholar]
  48. Greider C.W., Blackburn E.H. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell. 1987;51:887–898. doi: 10.1016/0092-8674(87)90576-9. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Guo C., Armbruster B.N., Price D.T., Counter C.M. In vivo regulation of hTERT expression and telomerase activity by androgen. J Urol. 2003;170:615–618. doi: 10.1097/01.ju.0000074653.22766.c8. [DOI] [PubMed] [Google Scholar]
  51. 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]
  52. Harley C.B. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991;256:271–282. doi: 10.1016/0921-8734(91)90018-7. [DOI] [PubMed] [Google Scholar]
  53. Harley C.B. Telomerase and cancer therapeutics. Nat Rev Cancer. 2008;8:167–179. doi: 10.1038/nrc2275. [DOI] [PubMed] [Google Scholar]
  54. Heiss N.S., Knight S.W., Vulliamy T.J., Klauck S.M., Wiemann S., Mason P.J., Poustka A., Dokal I. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet. 1998;19:32–38. doi: 10.1038/ng0598-32. [DOI] [PubMed] [Google Scholar]
  55. Herbert B., Pitts A.E., Baker S.I., Hamilton S.E., Wright W.E., Shay J.W., Corey D.R. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci U S A. 1999;96:14276–14281. doi: 10.1073/pnas.96.25.14276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Herrera E., Samper E., Blasco M.A. Telomere shortening in mTR-/-embryos is associated with failure to close the neural tube. EMBO J. 1999;18:1172–1181. doi: 10.1093/emboj/18.5.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Holt S.E., Aisner D.L., Baur J., Tesmer V.M., Dy M., Ouellette M., Trager J.B., Morin G.B., Toft D.O., Shay J.W., et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 1999;13:817–826. doi: 10.1101/gad.13.7.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. 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]
  59. 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]
  60. Huard S., Moriarty T.J., Autexier C. The C terminus of the human telomerase reverse transcriptase is a determinant of enzyme processivity. Nucleic Acids Res. 2003;31:4059–4070. doi: 10.1093/nar/gkg437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Jacobs S.A., Podell E.R., Cech T.R. Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat Struct Mol Biol. 2006;13:218–225. doi: 10.1038/nsmb1054. [DOI] [PubMed] [Google Scholar]
  62. Jaskelioff M., Muller F.L., Paik J.H., Thomas E., Jiang S., Adams A.C., Sahin E., Kost-Alimova M., Protopopov A., Cadiñanos J., et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469:102–106. doi: 10.1038/nature09603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Kalantaridou S.N., Naka K.K., Bechlioulis A., Makrigiannakis A., Michalis L., Chrousos G.P. Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement. Trends Endocrinol Metab. 2006;17:101–109. doi: 10.1016/j.tem.2006.02.003. [DOI] [PubMed] [Google Scholar]
  64. 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]
  65. Kelleher C., Teixeira M.T., Förstemann K., Lingner J. Telomerase: biochemical considerations for enzyme and substrate. Trends Biochem Sci. 2002;27:572–579. doi: 10.1016/s0968-0004(02)02206-5. [DOI] [PubMed] [Google Scholar]
  66. Kiaris H., Schally A.V. Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone. Proc Natl Acad Sci U S A. 1999;96:226–231. doi: 10.1073/pnas.96.1.226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Kimura A., Ohmichi M., Kawagoe J., Kyo S., Mabuchi S., Takahashi T., Ohshima C., Arimoto-Ishida E., Nishio Y., Inoue M., et al. Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines. Oncogene. 2004;23:4505–4515. doi: 10.1038/sj.onc.1207582. [DOI] [PubMed] [Google Scholar]
  68. Kimura M., Barbieri M., Gardner J.P., Skurnick J., Cao X., van Riel N., Rizzo M.R., Paoliso G., Aviv A. Leukocytes of exceptionally old persons display ultra-short telomeres. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2210–R2217. doi: 10.1152/ajpregu.00615.2007. [DOI] [PubMed] [Google Scholar]
  69. Kimura M., Cherkas L.F., Kato B.S., Demissie S., Hjelmborg J.B., Brimacombe M., Cupples A., Hunkin J.L., Gardner J.P., Lu X., et al. Offspring’s leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 2008;4:e37. doi: 10.1371/journal.pgen.0040037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Kugoh H., Shigenami K., Funaki K., Barrett J.C., Oshimura M. Human chromosome 5 carries a putative telomerase repressor gene. Genes Chromosomes Cancer. 2003;36:37–47. doi: 10.1002/gcc.10135. [DOI] [PubMed] [Google Scholar]
  71. 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]
  72. 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]
  73. LaBranche H., Dupuis S., Ben-David Y., Bani M.R., Wellinger R.J., Chabot B. Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nat Genet. 1998;19:199–202. doi: 10.1038/575. [DOI] [PubMed] [Google Scholar]
  74. Lai C.K., Mitchell J.R., Collins K. RNA binding domain of telomerase reverse transcriptase. Mol Cell Biol. 2001;21:990–1000. doi: 10.1128/MCB.21.4.990-1000.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Laviolette L.A., Garson K., Macdonald E.A., Senterman M.K., Courville K., Crane C.A., Vanderhyden B.C. 17betaestradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer. Endocrinology. 2010;151:929–938. doi: 10.1210/en.2009-0602. [DOI] [PubMed] [Google Scholar]
  76. Lee H.W., Blasco M.A., Gottlieb G.J., Horner J.W., 2nd, Greider C. W., DePinho R.A. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392:569–574. doi: 10.1038/33345. [DOI] [PubMed] [Google Scholar]
  77. Li H., Pinto A.R., Duan W., Li J., Toh B.H., Liu J.P. Telomerase down-regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signalling. J Neurochem. 2005;95:891–901. doi: 10.1111/j.1471-4159.2005.03439.x. [DOI] [PubMed] [Google Scholar]
  78. Li H., Zhao L., Yang Z., Funder J.W., Liu J.P. Telomerase is controlled by protein kinase Calpha in human breast cancer cells. J Biol Chem. 1998;273:33436–33442. doi: 10.1074/jbc.273.50.33436. [DOI] [PubMed] [Google Scholar]
  79. Lin J., Kroenke C.H., Epel E., Kenna H.A., Wolkowitz O.M., Blackburn E., Rasgon N.L. Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline. Brain Res. 2011;1379:224–231. doi: 10.1016/j.brainres.2010.10.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Ling S., Zhou L., Li H., Dai A., Liu J.P., Komesaroff P.A., Sudhir K. Effects of 17beta-estradiol on growth and apoptosis in human vascular endothelial cells: influence of mechanical strain and tumor necrosis factor-alpha. Steroids. 2006;71:799–808. doi: 10.1016/j.steroids.2006.05.010. [DOI] [PubMed] [Google Scholar]
  81. Liu J.P., Chen S.M., Cong Y.S., Nicholls C., Zhou S.F., Tao Z.Z., Li H. Regulation of telomerase activity by apparently opposing elements. Ageing Res Rev. 2010;9:245–256. doi: 10.1016/j.arr.2010.03.002. [DOI] [PubMed] [Google Scholar]
  82. Loayza D., De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 2003;423:1013–1018. doi: 10.1038/nature01688. [DOI] [PubMed] [Google Scholar]
  83. Lopatina N.G., Poole J.C., Saldanha S.N., Hansen N.J., Key J.S., Pita M.A., Andrews L.G., Tollefsbol T.O. Control mechanisms in the regulation of telomerase reverse transcriptase expression in differentiating human teratocarcinoma cells. Biochem Biophys Res Commun. 2003;306:650–659. doi: 10.1016/s0006-291x(03)01033-7. [DOI] [PubMed] [Google Scholar]
  84. Martínez P., Thanasoula M., Muñoz P., Liao C., Tejera A., McNees C., Flores J.M., Fernández-Capetillo O., Tarsounas M., Blasco M.A. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23:2060–2075. doi: 10.1101/gad.543509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. McNees C.J., Tejera A.M., Martínez P., Murga M., Mulero F., Fernandez-Capetillo O., Blasco M.A. ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase. J Cell Biol. 2010;188:639–652. doi: 10.1083/jcb.200908136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Meeker A.K., Sommerfeld H.J., Coffey D.S. Telomerase is activated in the prostate and seminal vesicles of the castrated rat. Endocrinology. 1996;137:5743–5746. doi: 10.1210/endo.137.12.8940411. [DOI] [PubMed] [Google Scholar]
  87. Misiti S., Nanni S., Fontemaggi G., Cong Y.S., Wen J., Hirte H.W., Piaggio G., Sacchi A., Pontecorvi A., Bacchetti S., et al. Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol. 2000;20:3764–3771. doi: 10.1128/mcb.20.11.3764-3771.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Mitchell M., Gillis A., Futahashi M., Fujiwara H., Skordalakes E. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat Struct Mol Biol. 2010;17:513–518. doi: 10.1038/nsmb.1777. [DOI] [PubMed] [Google Scholar]
  89. Moehren U., Papaioannou M., Reeb C.A., Grasselli A., Nanni S., Asim M., Roell D., Prade I., Farsetti A., Baniahmad A. Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development. FASEB J. 2008;22:1258–1267. doi: 10.1096/fj.07-9360com. [DOI] [PubMed] [Google Scholar]
  90. Murnane J.P. Telomere loss as a mechanism for chromosome instability in human cancer. Cancer Res. 2010;70:4255–4259. doi: 10.1158/0008-5472.CAN-09-4357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. 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. Science. 1997;277:955–959. doi: 10.1126/science.277.5328.955. [DOI] [PubMed] [Google Scholar]
  92. Nesbit C.E., Tersak J.M., Prochownik E.V. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18:3004–3016. doi: 10.1038/sj.onc.1202746. [DOI] [PubMed] [Google Scholar]
  93. Njajou O.T., Cawthon R.M., Damcott C.M., Wu S.H., Ott S., Garant M.J., Blackburn E.H., Mitchell B.D., Shuldiner A.R., Hsueh W.C. Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci U S A. 2007;104:12135–12139. doi: 10.1073/pnas.0702703104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Njajou O.T., Hsueh W.C., Blackburn E.H., Newman A.B., Wu S.H., Li R., Simonsick E.M., Harris T.M., Cummings S.R., Cawthon R.M., the Health ABC study Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a populationbased cohort study. J Gerontol A Biol Sci Med Sci. 2009;64:860–864. doi: 10.1093/gerona/glp061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Oh S., Song Y.H., Yim J., Kim T.K. Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene. 2000;19:1485–1490. doi: 10.1038/sj.onc.1203439. [DOI] [PubMed] [Google Scholar]
  96. Oh W., Ghim J., Lee E.W., Yang M.R., Kim E.T., Ahn J.H., Song J. PML-IV functions as a negative regulator of telomerase by interacting with TERT. J Cell Sci. 2009;122:2613–2622. doi: 10.1242/jcs.048066. [DOI] [PubMed] [Google Scholar]
  97. Ornish D., Lin J., Daubenmier J., Weidner G., Epel E., Kemp C., Magbanua M.J., Marlin R., Yglecias L., Carroll P.R., et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9:1048–1057. doi: 10.1016/S1470-2045(08)70234-1. [DOI] [PubMed] [Google Scholar]
  98. Park J.I., Venteicher A.S., Hong J.Y., Choi J., Jun S., Shkreli M., Chang W., Meng Z., Cheung P., Ji H., et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009;460:66–72. doi: 10.1038/nature08137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Peng Y., Mian I.S., Lue N.F. Analysis of telomerase processivity: mechanistic similarity to HIV-1 reverse transcriptase and role in telomere maintenance. Mol Cell. 2001;7:1201–1211. doi: 10.1016/s1097-2765(01)00268-4. [DOI] [PubMed] [Google Scholar]
  100. Pinto A.R., Li H., Nicholls C., Liu J.P. Telomere protein complexes and interactions with telomerase in telomere maintenance. Front Biosci. 2011;16:187–207. doi: 10.2741/3683. [DOI] [PubMed] [Google Scholar]
  101. Ramírez R., Carracedo J., Jiménez R., Canela A., Herrera E., Aljama P., Blasco M.A. Massive telomere loss is an early event of DNA damage-induced apoptosis. J Biol Chem. 2003;278:836–842. doi: 10.1074/jbc.M206818200. [DOI] [PubMed] [Google Scholar]
  102. Ravindranath N., Ioffe S.L., Marshall G.R., Ramaswamy S., Plant T.M., Dym M. Androgen depletion activates telomerase in the prostate of the nonhuman primate, Macaca mulatta. Prostate. 2001;49:79–89. doi: 10.1002/pros.1120. [DOI] [PubMed] [Google Scholar]
  103. Rochette P.J., Brash D.E. Human telomeres are hypersensitive to UV-induced DNA Damage and refractory to repair. PLoS Genet. 2010;6:e1000926. doi: 10.1371/journal.pgen.1000926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. 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]
  105. Seimiya H., Sawada H., Muramatsu Y., Shimizu M., Ohko K., Yamane K., Tsuruo T. Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO J. 2000;19:2652–2661. doi: 10.1093/emboj/19.11.2652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Seth A., Watson D.K. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 2005;41:2462–2478. doi: 10.1016/j.ejca.2005.08.013. [DOI] [PubMed] [Google Scholar]
  107. Sfeir A., Kosiyatrakul S.T., Hockemeyer D., MacRae S.L., Karlseder J., Schildkraut C.L., de Lange T. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138:90–103. doi: 10.1016/j.cell.2009.06.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Sharma H.W., Sokoloski J.A., Perez J.R., Maltese J.Y., Sartorelli A.C., Stein C.A., Nichols G., Khaled Z., Telang N.T., Narayanan R. Differentiation of immortal cells inhibits telomerase activity. Proc Natl Acad Sci U S A. 1995;92:12343–12346. doi: 10.1073/pnas.92.26.12343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. 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]
  110. Smith L.L., Coller H.A., Roberts J.M. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol. 2003;5:474–479. doi: 10.1038/ncb985. [DOI] [PubMed] [Google Scholar]
  111. Soda H., Raymond E., Sharma S., Lawrence R., Davidson K., Oka M., Kohno S., Izbicka E., Von Hoff D.D. Effects of androgens on telomerase activity in normal and malignant prostate cells in vitro. Prostate. 2000;43:161–168. doi: 10.1002/(sici)1097-0045(20000515)43:3<161::aid-pros1>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  112. Stewart S.A., Hahn W.C., O’Connor B.F., Banner E.N., Lundberg A.S., Modha P., Mizuno H., Brooks M.W., Fleming M., Zimonjic D.B., et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc Natl Acad Sci U S A. 2002;99:12606–12611. doi: 10.1073/pnas.182407599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. 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]
  114. 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]
  115. Tang L., Sawers R.S. Twin pregnancy in premature ovarian failure after estrogen treatment: a case report. Am J Obstet Gynecol. 1989;161:172–173. doi: 10.1016/0002-9378(89)90258-5. [DOI] [PubMed] [Google Scholar]
  116. Teixeira M.T., Arneric M., Sperisen P., Lingner J. Telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states. Cell. 2004;117:323–335. doi: 10.1016/s0092-8674(04)00334-4. [DOI] [PubMed] [Google Scholar]
  117. Terry D.F., Nolan V.G., Andersen S.L., Perls T.T., Cawthon R. Association of longer telomeres with better health in centenarians. J Gerontol A Biol Sci Med Sci. 2008;63:809–812. doi: 10.1093/gerona/63.8.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Theimer C.A., Feigon J. Structure and function of telomerase RNA. Curr Opin Struct Biol. 2006;16:307–318. doi: 10.1016/j.sbi.2006.05.005. [DOI] [PubMed] [Google Scholar]
  119. Ting N.S., Pohorelic B., Yu Y., Lees-Miller S.P., Beattie T.L. The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res. 2009;37:6105–6115. doi: 10.1093/nar/gkp636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Ting N.S., Yu Y., Pohorelic B., Lees-Miller S.P., Beattie T.L. Human Ku70/80 interacts directly with hTR, the RNA component of human telomerase. Nucleic Acids Res. 2005;33:2090–2098. doi: 10.1093/nar/gki342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Tomás-Loba A., Flores I., Fernández-Marcos P.J., Cayuela M.L., Maraver A., Tejera A., Borrás C., Matheu A., Klatt P., Flores J. M., et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell. 2008;135:609–622. doi: 10.1016/j.cell.2008.09.034. [DOI] [PubMed] [Google Scholar]
  122. Toogun O.A., Dezwaan D.C., Freeman B.C. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol Cell Biol. 2008;28:457–467. doi: 10.1128/MCB.01417-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Toogun O.A., Zeiger W., Freeman B.C. The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation. Proc Natl Acad Sci U S A. 2007;104:5765–5770. doi: 10.1073/pnas.0701442104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Ulaner G.A., Hu J.F., Vu T.H., Giudice L.C., Hoffman A.R. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998;58:4168–4172. [PubMed] [Google Scholar]
  125. Ulaner G.A., Hu J.F., Vu T.H., Giudice L.C., Hoffman A.R. Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int J Cancer. 2001;91:644–649. [PubMed] [Google Scholar]
  126. Verdun R.E., Karlseder J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell. 2006;127:709–720. doi: 10.1016/j.cell.2006.09.034. [DOI] [PubMed] [Google Scholar]
  127. 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]
  128. 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]
  129. Won J., Yim J., Kim T.K. Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. FASEB J. 2002;16:1943–1945. doi: 10.1096/fj.02-0311fje. [DOI] [PubMed] [Google Scholar]
  130. 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]
  131. Wong J.M., Collins K. Telomere maintenance and disease. Lancet. 2003;362:983–988. doi: 10.1016/S0140-6736(03)14369-3. [DOI] [PubMed] [Google Scholar]
  132. 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]
  133. Wymenga L.F., Wisman G.B., Veenstra R., Ruiters M.H., Mensink H.J. Telomerase activity in needle biopsies from prostate cancer and benign prostates. Eur J Clin Invest. 2000;30:330–335. doi: 10.1046/j.1365-2362.2000.00636.x. [DOI] [PubMed] [Google Scholar]
  134. Xia J., Peng Y., Mian I.S., Lue N.F. Identification of functionally important domains in the N-terminal region of telomerase reverse transcriptase. Mol Cell Biol. 2000;20:5196–5207. doi: 10.1128/mcb.20.14.5196-5207.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Xin H., Liu D., Wan M., Safari A., Kim H., Sun W., O’Connor M.S., Songyang Z. TPP1 is a homologue of ciliate TEBPbeta and interacts with POT1 to recruit telomerase. Nature. 2007;445:559–562. doi: 10.1038/nature05469. [DOI] [PubMed] [Google Scholar]
  136. 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]
  137. Xu D., Popov N., Hou M., Wang Q., Björkholm 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]
  138. 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]
  139. Yu C.C., Lo S.C., Wang T.C. Telomerase is regulated by protein kinase C-zeta in human nasopharyngeal cancer cells. Biochem J. 2001;355:459–464. doi: 10.1042/0264-6021:3550459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  140. Zaug A.J., Podell E.R., Nandakumar J., Cech T.R. Functional interaction between telomere protein TPP1 and telomerase. Genes Dev. 2010;24:613–622. doi: 10.1101/gad.1881810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  141. Zhang Q.S., Manche L., Xu R.M., Krainer A.R. hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA. 2006;12:1116–1128. doi: 10.1261/rna.58806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Zhang W., Kapusta L.R., Slingerland J.M., Klotz L.H. Telomerase activity in prostate cancer, prostatic intraepithelial neoplasia, and benign prostatic epithelium. Cancer Res. 1998;58:619–621. [PubMed] [Google Scholar]
  143. Zhang X., Mar V., Zhou W., Harrington L., Robinson M.O. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 1999;13:2388–2399. doi: 10.1101/gad.13.18.2388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. 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