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Telomerase Activity is Constitutively Expressed in the Murine $CD8^+$ T Cells and Controlled Transcriptionally and Post-Translationally

  • Kim, SoJung (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University) ;
  • Kim, MiHyung (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University) ;
  • Kim, KilHyoun (Division of Molecular Life Sciences and College of Pharmacy, Ewha Womans University)
  • Published : 2004.09.30
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Abstract

Background: Telomerase, a ribonucleoprotein enzyme capable of synthesizing telomeric repeats, attracts attention for its possible role in determining the replicative capacity of normal somatic cells, transformed cells, and cells of the germline lineage. Differently from normal somatic cells with no telomerase activity, normal lymphocytes has been reported to have telomerase activity comparable to that found in transformed cells during development and activation, which substantiate a role in supporting the capacity of lymphocytes for extensive clonal expansion. Methods: Here, in order to define the telomerase regulation in murine T lymphocytes, telomerase activity in cloned murine $CD8^+$ T cells and naive $CD8^+$ T cells isolated from C57BL/6 mice was examined. Next, the regulatory mechanism of telomerase activity at transcriptional and post- translational levels was investigated by determining the expression level of the TERT protein, a key component for telomerase activity. Results: It was demonstrated that telomerase activity was expressed in an inactivated state as well as in an activated state in the murine $CD8^+$ T lymphocytes by using TRAP assay. The increase of telomerase activity was partially dependent on the net increase of TERT expression. Also, telomerase activity was decreased after treatment with protein kinase inhibitors, indicating that telomerase activation was prevented by inhibition of phosphorylation. Conclusion: Therefore, these results suggest that telomerase activity is constitutively expressed in the murine resting T lymphocytes and controlled by both transcriptional regulation and post- ranslational modifications.

Keywords

References

  1. Blackburn EH: Telomerases. Annu Rev Biochem 61;113-131, 1992 https://doi.org/10.1146/annurev.bi.61.070192.000553
  2. Harley CB, Villeponteau B: Telomeres and telomerase in aging and cancer. Curr Opin Genet Dev 5;249-256, 1995 https://doi.org/10.1016/0959-437X(95)80016-6
  3. Blackburn EH: Structure and function of telomeres. Nature 350;569-571, 1991 https://doi.org/10.1038/350569a0
  4. Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature 345;458-460, 1990 https://doi.org/10.1038/345458a0
  5. Liu J-P: Studies of the molecular machnisms in the regulation of telomerase activity. FASEB J 13;2091-2104, 1999 https://doi.org/10.1096/fasebj.13.15.2091
  6. Kojo S, Elenitoba-Johnson J: Complex regulation of telomerase activity. Am J Pathol 159: 405-410, 2001 https://doi.org/10.1016/S0002-9440(10)61710-5
  7. Weng NP, Levine BL, June CH, Hodes RJ: Regulation of telomerase RNA template expression in human T lymphocyte development and activation. J Immunol 158;3215-3220, 1997
  8. Liu YB, Snow E, Hande MP, Yeung D, Erdmann NJ, Wakeham A, Itie A, Siderovski DP, Lansdorp PM, Harrington L: The telomerase reverse trandcriptase is limiting and necessary for telomerase function in vivo. Curr Biol 10;1459-1462, 2000 https://doi.org/10.1016/S0960-9822(00)00805-8
  9. Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ, Weng NP: Constitutive and regulated expression of telomerase reverse trascriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci 96;5147-5152, 1999
  10. Migliaccio M, Amacker M, Just T, Reichenbach P, Valmori D, Cerottini J-C, Romero P, Nabholz M: Ectopic human telomerase catalytic subunit expression maintains telomere length but is not sufficient for CD8+ T lymphocyte immortalization. J Immunol 165;4978-4984, 2000 https://doi.org/10.4049/jimmunol.165.9.4978
  11. Hooijberg E, Ruizendaal JJ, Snijders PJF, Kueter EW, Walboomers, JMM, Spits H: Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 165;4239-4245, 2000 https://doi.org/10.4049/jimmunol.165.8.4239
  12. Li H, Zhao L, Yang Z, Funder JW, Liu JP: Telomerase is controlled by protein kinase C$\alpha$ in human breast cancer cells. J Biol Chem 273;33436-33442, 1998 https://doi.org/10.1074/jbc.273.50.33436
  13. Kang SS, Kwon T, Kwon DY, Do SI: Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem 274;13085-13090, 1999. https://doi.org/10.1074/jbc.274.19.13085
  14. Li H, Zhao LL, Funder JW, Liu JP: Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells. J Biol Chem 272;16729-16732, 1997 https://doi.org/10.1074/jbc.272.27.16729
  15. Liu K, Hodes RJ, Weng NP: Telomerase activation in human T lymphocytes does not require increase in telomerase reverse trascriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation. J Immunol 166;4826-4830, 2001 https://doi.org/10.4049/jimmunol.166.8.4826
  16. Scollay R: T-cell subset relationships in thymocyte development. Curr Opin Immunol 3;204-209, 1991 https://doi.org/10.1016/0952-7915(91)90051-2
  17. Robey E, Fowlkes BJ: Selective events in T cell development. Annu Rev Immunol 12;675-705, 1994 https://doi.org/10.1146/annurev.iy.12.040194.003331
  18. Effros RB, Pawelec G.: Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion. Immunol Today 18;450-454, 1997 https://doi.org/10.1016/S0167-5699(97)01079-7
  19. Weng NP, Hathcock KS, Hodes RJ: Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity 9151-157, 1998
  20. Weng NP, Palmer LD, Levine BL, Lane HC, June CH, Hodes RJ: Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging. Immunol Rev 160;43-54, 1997 https://doi.org/10.1111/j.1600-065X.1997.tb01026.x
  21. Lundblad V: A tale of ends. Nature 403;149-151, 2000 https://doi.org/10.1038/35003085
  22. Bodnar AG, Kim NW, Effros RB, Chiu CP: Mechanism of telomerase induction during T cell activation. Exp Cell Res 228;58-64, 1996 https://doi.org/10.1006/excr.1996.0299
  23. Weng NP, Levine BL, June CH, Hodes RJ: Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183;2471-2479, 1996 https://doi.org/10.1084/jem.183.6.2471
  24. Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M: Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155;3711-3715, 1995
  25. Monteiro J, Batliwalla F, Ostrer H, Gregersen PK: Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 156;3587-3590, 1996
  26. Weng NP, Levine BL, June CH, Hodes RJ: Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 92;11091-11094, 1995 https://doi.org/10.1073/pnas.92.24.11091
  27. Kim NW, Wu F; Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res 25;2595-2597, 1997 https://doi.org/10.1093/nar/25.13.2595
  28. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW: Specific association of human telomerase activity with immortal cells and cancer. Science 266;2011-2015, 1994 https://doi.org/10.1126/science.7605428
  29. Ogoshi M, Takashima A, Taylor RS: Mechanisms regulating telomerase activity in murine T cells. J Immunol 158;622-628, 1997
  30. Hathcock KS, Weng NP, Merica R, Jenkins MK, Hodes RJ: Antigen-dependent regulation of telomerase activity in murine T cells. J Immunol 160;5702-5706, 1998
  31. Pircher H, Burki K, Lang R, Hengartner H, Zinkernagel RM: Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342;559-61, 1989 https://doi.org/10.1038/342559a0