Molecular Biology

, Volume 47, Issue 4, pp 476–487 | Cite as

Possibilities and effects of telomerase activation

  • N. A. Kovalenko
  • D. D. Zhdanov
  • T. F. Kovalenko
Reviews

Abstract

The mechanisms regulating the activity of telomerase, predominantly human telomerase, are considered in brief. The localization of telomerase complex components in the cell is described, and telomerase activities unrelated to telomere elongation are discussed. Human diseases that correlate with reduced telomerase activity, short telomeres, and rapid telomere shortening are overviewed. The possibilities to activate transcription of exogenous hTERT by various natural and synthetic compounds are described along with the effects of cell transfection with active hTERT. Exogenous hTERT activation increases the cell proliferation potential and may be employed in cell therapy. It is emphasized that elevated hTERT expression may cause cell malignant transformation, especially in the case of hTERT transfection. This possibility must be considered when choosing the means of telomerase activation for therapeutic purposes.

Keywords

human telomerase telomerase activators hTERT gene 

Abbreviations

TR

telomerase RNA

HSP

heat shock protein

siRNA

short interfering RNA

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References

  1. 1.
    Griffith J.D., Comeau L., Rosenfield S., et al. 1999. Mammalian telomeres end in a large duplex loop. Cell. 97(4), 503–514.PubMedCrossRefGoogle Scholar
  2. 2.
    Blachburn E.H. 1991. Structure and function of telomeres. Nature. 350, 569–573.CrossRefGoogle Scholar
  3. 3.
    Hayflick L. 1976. The cell biology of human aging. N. Engl. J. Med. 295, 1302–1308.PubMedCrossRefGoogle Scholar
  4. 4.
    Masutomi K., Yu E.Y., Khurts S., et al. 2003. Telomerase maintains telomere structure in normal human cells. Cell. 114(2), 241–253.PubMedCrossRefGoogle Scholar
  5. 5.
    Zvereva M.E., Shcherbakova D.M., Dontsova O.A. 2010. Telomerase: Structure, functions, and activity regulation. Biochemistry (Moscow). 75(13), 1563–1583.CrossRefGoogle Scholar
  6. 6.
    Zhdanov D.D., Kovalenko N.A., Khorobrykh T.V., et al. 2009. Telomerase activity and its relationship with the expression of transcriptional variants of the HSP90α gene and human telomerase catalytic subunit gene in patients with stomach and intestine tumors. Mol. Med. (Moscow). 6, 37–41.Google Scholar
  7. 7.
    Robart A.R., Collins K. 2010. Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285, 4375–4386.PubMedCrossRefGoogle Scholar
  8. 8.
    De Boeck G., Forsyth R.G., Praet M., et al. 2009. Telomere-associated proteins: Cross-talk between telomere maintenance and telomere-lengthening mechanisms. J. Pathol. 217, 327–344.PubMedCrossRefGoogle Scholar
  9. 9.
    De Lange T. 2005. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110.PubMedCrossRefGoogle Scholar
  10. 10.
    Loayza D., De Lange T. 2003. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 423, 1013–1018.PubMedCrossRefGoogle Scholar
  11. 11.
    Smogorzewska A., van Steensel B., Bianchi A., et al. 2000. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668.PubMedCrossRefGoogle Scholar
  12. 12.
    Azzalin C.M., Reichenbach P., Khoriauli L., et al. 2007. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science. 318, 798–801.PubMedCrossRefGoogle Scholar
  13. 13.
    Bollman F.M. 2008. The many faces of telomerase: Merging extratelomeric effects. BioEssays. 30, 728–732.CrossRefGoogle Scholar
  14. 14.
    Mukherjee S., Firpo E.J., Wang Y., et al. 2011. Separation of telomerase function by reverse genetics. Proc. Natl. Acad. Sci. U. S. A. 108, E1363–E1371.PubMedCrossRefGoogle Scholar
  15. 15.
    Sharma N.K., Reyes A., Green P., et al. 2012. Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res. 40(2), 712–725.PubMedCrossRefGoogle Scholar
  16. 16.
    Ram R., Uziel O., Eldan O., et al. 2009. Ionizing radiation up-regulates telomerase activity in cancer cell lines by post-translational mechanism via ras/phosphatidylinositol 3-kinase/Akt pathway. Clin. Cancer Res. 15(3), 914–923.PubMedCrossRefGoogle Scholar
  17. 17.
    Büchner N., Zschauer T.-C., Lukosz M., Altschmied J., Haendeler J. 2010. Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent. Exp. Gerontol. 45(7–8), 558–562.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee J., Sung Y.H., Cheong C., Choi Y.S., Jeon H.K., Sun W., et al. 2008. TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene. 27, 3754–3760.PubMedCrossRefGoogle Scholar
  19. 19.
    Cifuentes-Rojas C., Shippen D.E. 2012. Telomerase regulation. Mutat. Res. 730, 20–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Cairney C.J., Keith W.N. 2008. Telomerase redifined: Integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochemie. 90, 13–23.CrossRefGoogle Scholar
  21. 21.
    Kyo S., Takakura M., Fujiwara T., Inoue M. 2008. Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci. 99, 1528–1538.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhu J., Zhao Y., Wang S. 2010. Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene. Protein Cell. 1, 22–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Smith L.L., Coller H.A., Roberts J.M. 2003. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nature Cell. Biol. 5, 474–479.PubMedCrossRefGoogle Scholar
  24. 24.
    Bodnar A.G., Ouellette M., Frolkis M., et al. 1998. Extension of life-span by introduction of telomerase into normal human cells. Science. 279, 349–352.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim N.W., Piatyszek M.A., Prowse K.R., et al. 1994. Specific association of human telomerase activity with immortal cells and cancer. Science. 266, 2011–2015.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhdanov D.D., Orlova E.V. 2011. Inhibitors of telomere and telomerase functions. Miol. Med. (Moscow). 2, 3–17.Google Scholar
  27. 27.
    El-Daly H., Kull M., Zimmermann S., et al. 2005. Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood. 105, 1742–1749.PubMedCrossRefGoogle Scholar
  28. 28.
    Stravopodis D.J., Margaritis L.H., Voutsinas G.E. 2007. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr. Med. Chem. 14, 3122–3138.PubMedCrossRefGoogle Scholar
  29. 29.
    Ahmed A., Tollefsbol T. 2001 Telomeres and telomerase: Basic science implications for aging. J. Am. Geriatrics Soc. 49(8), 1105–1109.CrossRefGoogle Scholar
  30. 30.
    Crabbe L., Jauch A., Naeger C.M., et al. 2007. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc. Natl. Acad. Sci. U. S. A. 104(7), 2205–2210.PubMedCrossRefGoogle Scholar
  31. 31.
    Crabbe L., Verdun R.E., Haggblom C.I., Karlseder J. 2004. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science. 306(5703), 1951–1953.PubMedCrossRefGoogle Scholar
  32. 32.
    Allsopp R.C., Vaziri H., Patterson C., et al. 1992. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl. Acad. Sci. U. S. A. 89(21), 10114–10118.PubMedCrossRefGoogle Scholar
  33. 33.
    Vaziri H., Schächter F., Uchida I., et al. 1993. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am. J. Hum. Genet. 52(4), 661–667.PubMedGoogle Scholar
  34. 34.
    Marrone A., Stevens D., Vulliamy T., et al. 2004. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood. 104(13), 3936–3942.PubMedCrossRefGoogle Scholar
  35. 35.
    Franco S., van de Vrugt H.J., Fernández P., et al. 2004. Telomere dynamics in Fancg-deficient mouse and human cells. Blood. 104(13), 3927–3935.PubMedCrossRefGoogle Scholar
  36. 36.
    Nelson N.D., Bertuch A.A. 2012. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat. Res. 730(1–2), 43–51.PubMedGoogle Scholar
  37. 37.
    Armanios M., Chen J.L., Chang Y.P., et al. 2005. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital. Proc. Natl. Acad. Sci. U. S. A. 102(44), 15960–15964.PubMedCrossRefGoogle Scholar
  38. 38.
    Marrone A., Dokal I. 2004. Dyskeratosis congenita: Molecular insights into telomerase function, ageing and cancer. Exper. Rev. Mol. Med. 6(26), 1–23.Google Scholar
  39. 39.
    Demissie S., Levi D., Bendjamin E.J., et al. 2006. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framinghem heart study. Aging Cell. 5, 325–330.PubMedCrossRefGoogle Scholar
  40. 40.
    Starr J.M., McGurn B., Harris S.E., et al. 2007. Association between telomere length and heart disease in a narrow age cohort of older people. Exp. Gerontol. 42, 571–573.PubMedCrossRefGoogle Scholar
  41. 41.
    Valdes A.M., Richards J.B., Gardner J.P., et al. 2007. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int. 18, 1203–1210.PubMedCrossRefGoogle Scholar
  42. 42.
    Harley C.B. 2005. Telomerase therapeutics for degenerative diseases. Curr. Mol. Med. 5, 205–211.PubMedCrossRefGoogle Scholar
  43. 43.
    Valenzuela H.F., Effros R.B. 2002. Divergent telomerase patterns in human CD4 and CD8 T cells follwing repeated encounters with the same antigenic stimulus. Clin. Immunol. 105, 117–125.PubMedCrossRefGoogle Scholar
  44. 44.
    Harley C.B. 2002. Telomerase is not an oncogene. Oncogene. 21, 494–502.PubMedCrossRefGoogle Scholar
  45. 45.
    Natarajan S., Chen Z., Wancewicz E.V., et al. 2004. Telomerase reverse transcriptase (hTERT) mRNA and telomerase RNA (hTR) as targets for downregulation of telomerase activity. Oligonucleotides. 14, 263–273.PubMedCrossRefGoogle Scholar
  46. 46.
    Konnikova L., Simeone M.C., Kruger M.M., et al. 2005. Signal transducer and activator of transcription 3 (STAT3) regulates human telomerase reverse transcriptase (hTERT) expression in human cancer and primary cells. Cancer Res. 65, 6516–6520.PubMedCrossRefGoogle Scholar
  47. 47.
    Soder A.I., Hoare S.F., Muir S., et al. 1997. Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer. Oncogene. 14, 1013–1021.PubMedCrossRefGoogle Scholar
  48. 48.
    Saretzki G., Petersen S., Petersen I., et al. 2002. hTERT gene dosage correlates with telomerase activity in human lung cancer cell lines. Cancer Lett. 176, 81–91.PubMedCrossRefGoogle Scholar
  49. 49.
    Khavinson V.Kh., Shataeva L.K., Chernova A.A. Effect of regulatory peptides on gene transcription. Bull. Exp. Biol. Med. 136(3), 288–290.Google Scholar
  50. 50.
    Guilleret I., Yan P., Grange F., et al. 2002. Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. Int. J. Cancer. 101, 335–341.PubMedCrossRefGoogle Scholar
  51. 51.
    Renaud S., Loukinov D., Abdullaev Z., et al. 2007. Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res. 35(4), 1245–1256.PubMedCrossRefGoogle Scholar
  52. 52.
    Renaud S., Loukinov D., Bosman F.T., et al. 2005. CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res. 33, 6850–6860.PubMedCrossRefGoogle Scholar
  53. 53.
    Wojtyla A., Gladych M., Rubis B. 2011. Human telomerase activity regulation. Mol. Biol. Rep. 38(5), 3339–3349.PubMedCrossRefGoogle Scholar
  54. 54.
    Prokhorchouk A.V., Ruzov A.S., 2000. Genome methylation and its role in the functioning of eukaryotic organisms. Russ. J. Genet. 36(11), 1239–1248.Google Scholar
  55. 55.
    Devereux T.R., Horikawa I., Anna C.H., et al. 1999. DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 59, 6087–6090.PubMedGoogle Scholar
  56. 56.
    Jakob S., Altschmied J., Haendeler J. 2009. “Shping 2” different cellular localizations: a potential new player in aging processes. Aging. 1(7), 664–668.PubMedGoogle Scholar
  57. 57.
    Santos J.H., Meyer J.N., Van Houten B. 2006. Mitochondrial localization of hTERT as a determinant for hydrogen peroxide-induced mtDNA damage and apoptosis. Hum. Mol. Genet. 15, 1757–1768.PubMedCrossRefGoogle Scholar
  58. 58.
    Tajrishi M.M., Tuteja R., Tuteja N. 2011. Nucleolin: The most abundant multifunctional phosphoprotein of nucleolus. Commun. Integ. Biol. 4(3), 267–275.CrossRefGoogle Scholar
  59. 59.
    Khurts S., Masutomi K., Delgermaa L., et al. 2004. Nucleolin interact with telomerase. J. Biol. Chem. 279, 51508–51515.PubMedCrossRefGoogle Scholar
  60. 60.
    Ha G.H., Kim H.S., Go H., et al. 2012. Tankyrase1 function at telomeres and during mitosis is regulated by Polo-like kinase 1-mediated phosphorylation. Cell. Death Differ. 19(2), 321–332.PubMedCrossRefGoogle Scholar
  61. 61.
    Gao J., Zhang J., Long Y., et al. 2011. Expression of tankyrase 1 in gastric cancer and its correlation with telomerase activity. Pathol. Oncol. Res. 17(3), 685–690.PubMedCrossRefGoogle Scholar
  62. 62.
    Tang B., Wang J., Fang J., Jiang B., et al. 2012. Expression of TNKS1 is correlated with pathologic grade and Wnt/β-catenin pathway in human astrocytomas. J. Clin. Neurosci. 19(1), 139–143.PubMedCrossRefGoogle Scholar
  63. 63.
    Karner C.M., Merkel C.E., Dodge M., et al. 2010. Tankyrase is necessary for canonical Wnt signaling during kidney development. Dev. Dyn. 239(7), 2014–2023.PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang H., Yang M.N., Zhao J.J., et al. 2010. Inhibition of tankyrase-1 in human gastric cancer cells enhances telomere shortening by telomerase inhibitors. Oncol. Res. 24(4), 1059–1065.Google Scholar
  65. 65.
    Sbodio J.I., Lodish H.F., Chi N.W. 2002. Tankyrase-2 oligimerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor1) and IRAP (insulinresponsive aminopeptidase). Biochem. J. 361(3), 451–459.PubMedCrossRefGoogle Scholar
  66. 66.
    Chang Y.J., Hsiao S.J., Yver D., et al. 2008. Tankyrase-1 and tankyrase-2 are essential but redundant for mouse embryonic development. PloS ONE. 3(7), e2639.CrossRefGoogle Scholar
  67. 67.
    Stefanou N., Papanikolaou V., Furukawa Y., et al. 2010. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase. BMC Cancer. 10, 442–452.PubMedGoogle Scholar
  68. 68.
    Sikand K., Kaul D., Varma N. 2006. Receptor Ckdependent signaling regulates hTERT gene transcription. BMC Cell Biol. 7, 2–14.PubMedCrossRefGoogle Scholar
  69. 69.
    Fajas L., Debril M.B., Auwerx J. 2001. Peroxisome proliferators-activaded receptor-γ: From adipogenesis to carcinogenesis. J. Mol. Endocrinol. 27, 1–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Parish S.T., Kim S., Sekhon R.K., et al. 2010. Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. J. Immunol. 184, 2847–2854.PubMedCrossRefGoogle Scholar
  71. 71.
    Ren Sh., Mandani K., Boedeker A.L., et al. 2007. Regulation of telomerase in Arabidopsis by BT2, an apparent target of telomersse activator 1. Plant Cell. 19, 23–31.PubMedCrossRefGoogle Scholar
  72. 72.
    Khavinson V.Kh., Bondarev I.E., Butyugov A.A. 2003. Epitalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull. Exp. Biol. Med. 135(6), 590–592.PubMedCrossRefGoogle Scholar
  73. 73.
    Khavinson V.Kh., Bondarev I.E., Butyugov A.A., Smirnova T.D. 2004. The peptide promotes the overcoming of the limit of somatic human cell division. Bull. Exp. Biol. Med. 137(5), 573–577.CrossRefGoogle Scholar
  74. 74.
    Zhu J., Lee S., Ho M.K., et al. 2010. In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator. Drug Metab. Pharmacokinet. 25(5), 477–486.PubMedCrossRefGoogle Scholar
  75. 75.
    Roth A., Yssel H., Pene J., et al. 2003. Telomerase levels control the lifespan of human T lymphocytes. Blood. 102, 849–857.PubMedCrossRefGoogle Scholar
  76. 76.
    Bodnar A.G., Kim N.W., Effros R.B., Chiu C.P. 1996. Mechanism of telomerase induction during T cell activation. Exp. Cell. Res. 228, 58–64.PubMedCrossRefGoogle Scholar
  77. 77.
    Fauce S.R., Jamieson B.D., Chin A.C., et al. 2008. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J. Immunol. 181(10), 7400–7406.PubMedGoogle Scholar
  78. 78.
    Dagarag M., Evazyan T., Rao N., Effros R.B. 2004. Genetic manipulation of telomerase in HIV-specific CD8+ T cells: Enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J. Immunol. 173, 6303–311.PubMedGoogle Scholar
  79. 79.
    Zhao Z., Wang W., Wang F., et al. 2009. Effects of astragaloside IV on heart failure in rats. Chin. Med. 4, 6–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Lv L., Wu S.Y., Wang G.F., et al. 2010. Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Phytother. Res. 24(2), 219–224.PubMedGoogle Scholar
  81. 81.
    Zhang W.D., Chen H., Zhang C., et al.. 2006. Astragaloside IV from Astragalus membranaceus shows cardio-protection during myocardial ischemia in vivo and in vitro. Planta Med. 72(1), 4–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Harley C.B., Liu W., Blasco M., et al. 2011. A natural product telomerase activator as part of a health maintenance program. Rejuv. Res. 14(1), 45–56.CrossRefGoogle Scholar
  83. 83.
    de Jesus B.B., Schneeberger K., Vera E., et al. 2011. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell. 10(4), 604–621.CrossRefGoogle Scholar
  84. 84.
    Chan M.N., El Touny L.H., Yagadeesh S., Baneryee P.P. 2007. Physiologically achievable concentration of genistein enhance telomerase activity in prostate cancer cells via the activation of STAT3. Carcinogenesis. 28(11), 2282–2290.CrossRefGoogle Scholar
  85. 85.
    Lanzilli G., Euggetta M.P., Tricarico M., et al. 2006. Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. Int. J. Oncol. 28, 642–648.Google Scholar
  86. 86.
    Pears V.P., Sherrell J., Lou Z., et al. 2008. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene. 27, 2365–2374.CrossRefGoogle Scholar
  87. 87.
    Xia L., Wang X.X., Hu X.S., et al. 2008. Resveratrol reduces endotelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanism. Br. J. Pharmacol. 155, 387–394.PubMedCrossRefGoogle Scholar
  88. 88.
    Satoh M., Minami Y., Takahashi Y., et al. 2009. Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease. Clin. Sci. (London). 116(11), 827–835.CrossRefGoogle Scholar
  89. 89.
    Sprouse A.A., Steding C.E., Herbert B.S. 2012. Pharmaceutical regulation of telomerase and its clinical potential. J. Cell. Mol. Med. 16(1), 1–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Stenderup K., Justesen J., Clausen C., Kassem M. 2003. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 33, 919–926.PubMedCrossRefGoogle Scholar
  91. 91.
    Zimmermann S., Voss M., Kaiser S., et al. 2003. Lack of telomerase activity in human mesenchymal stem cells. Leukemia. 17, 1146–1149.PubMedCrossRefGoogle Scholar
  92. 92.
    Banfi A., Muraglia A., Dozin B., et al. 2000. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp. Hematol. 28, 707–755.PubMedCrossRefGoogle Scholar
  93. 93.
    DiGirolamo C.M., Stokes D., Colter D., et al. 1999. Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br. J. Haematol. 107, 275–281.PubMedCrossRefGoogle Scholar
  94. 94.
    Böcker W., Yin Zh., Drosse I., et al. 2008. Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer. J. Cell. Mol. Med. 12(4), 1347–1359.CrossRefGoogle Scholar
  95. 95.
    Huang G., Zheng Q., Sun J., et al. 2008. Stabilization of cellular properties and differentiation mutilpotential of human mesenchymal stem cells transduced with hTERT gene in a long-term culture. J. Cell. Biochem. 103, 1256–1269.PubMedCrossRefGoogle Scholar
  96. 96.
    Honma T., Honmou O., Iihoshi S., et al. 2006. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp. Neurol. 199(1), 56–66.PubMedCrossRefGoogle Scholar
  97. 97.
    Huang G.P., Pan Z.J., Huang J.P., et al. 2008. Proteomic analysis of human bone marrow mesenchymal stem cells transduced with human telomerase reverse transcriptase gene during proliferation. Cell Prolif. 41, 625–644.PubMedCrossRefGoogle Scholar
  98. 98.
    García-Escudero V., García-Gomez A., Gargini R., et al. 2010. Prevention of senescence progression in reversibly immortalized human ensheathing glia permits their survival after deimmortalization. Mol. Ther. 18(2), 394–403.PubMedCrossRefGoogle Scholar
  99. 99.
    Huang Q., Chen M., Liang S., et al. 2007. Improving cell therapy: Experiments using transplanted telomerase-immortalized cells in immunodeficient mice. Mech. Ageing Dev. 128(1), 25–30.PubMedCrossRefGoogle Scholar
  100. 100.
    Song J.S., Murase N., Demetris A.J., et al. 2007. Protection from acute cellular injury using sleeping beauty mediated telomerase gene transfer. Biochem. Biophys. Res. Commun. 363(2), 253–256.PubMedCrossRefGoogle Scholar
  101. 101.
    Oh H., Taffet G.E., Youker K.A., et al. 2001. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc. Natl. Acad. Sci. U. S. A. 98, 10308–10313.PubMedCrossRefGoogle Scholar
  102. 102.
    Masutomi K., Possemato R., Wong J.M., et al. 2005. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl. Acad. Sci. U. S. A. 102(23), 8222–8227.PubMedCrossRefGoogle Scholar
  103. 103.
    Geserick C., Tejera A., Gonzalez-Suarez E., et al. 2006. Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-beta signaling. Oncogene. 25, 4310–4319.PubMedCrossRefGoogle Scholar
  104. 104.
    Astandi S.E., Alson S., Tietze M.K., et al. 2002. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. U. S. A. 99(12), 8191–8196.CrossRefGoogle Scholar
  105. 105.
    Kipling D., Cooke H.J. 1990. Hypervariable ultralong telomeres in mice. Nature. 347(6291), 400–402.PubMedCrossRefGoogle Scholar
  106. 106.
    Blasco M.A. 1997. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 91, 25–34.PubMedCrossRefGoogle Scholar
  107. 107.
    Greenberg R.A., Allsopp R.C., Chin L., et al. 1998. Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene. 16, 1723–1730.PubMedCrossRefGoogle Scholar
  108. 108.
    Park J.I., Venteicher A.S., Hong J.Y., et al. 2009. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 460, 66–72.PubMedCrossRefGoogle Scholar
  109. 109.
    Barker N., Hurlstone A., Musisi H., Miles A., Bienz M., Clevers H. 2001. The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J. 20, 4935–4943.PubMedCrossRefGoogle Scholar
  110. 110.
    Okamoto N., Yasukawa M., Nguyen C., Kasim V., Maida Y., Possemato R., et al. 2011. Maintenance of tumor initiating cells of defined genetic composition by nucleostemin. Proc. Natl. Acad. Sci. U. S. A. 108, 20388–20393.PubMedCrossRefGoogle Scholar
  111. 111.
    Hoffmeyer K., Raggioli A., Rudloff S., et al. 2012. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 336, 1549–1554.PubMedCrossRefGoogle Scholar
  112. 112.
    Shkreli M., Sarin K.Y., Pech M.F., et al. 2012. Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nature Med. 18, 111–119.Google Scholar
  113. 113.
    Bernardes de Jesus B., Vera E., Schneeberger K., et al. 2012. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol. Med. 4, 691–704.PubMedCrossRefGoogle Scholar
  114. 114.
    Park J.I., Venteicher A.S., Hong J. Y. 2009. Telomerase modulates Wnt signaling by association with target gene chromatin. Nature. 460(7251), 66–72.PubMedCrossRefGoogle Scholar
  115. 115.
    Lee J., Sung Y. H., Cheong C., et al. 2008. TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene. 27(26), 3754–3760.PubMedCrossRefGoogle Scholar
  116. 116.
    Rahman R., Latonen L., Wiman K.G. 2005. hTERT antagonizes p53-induced apoptosis independently of telomerase activity. Oncogene. 24(8), 1320–1327.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  • N. A. Kovalenko
    • 1
  • D. D. Zhdanov
    • 2
  • T. F. Kovalenko
    • 3
  1. 1.RF Ministry of HealthSechenov First Moscow State Medical UniversityMoscowRussia
  2. 2.Orekhovich Institute of Biomedical ChemistryRussian Academy of Medical SciencesMoscowRussia
  3. 3.Shemyakin and Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia

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