Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지

The Pleiotropy of Telomerase against Cell Death

  • Sung, Young Hoon (Department of Molecular Cell Biology, Samsung Biomedical Research Institute, SungKyunkwan University School of Medicine) ;
  • Choi, Yoon Sik (Department of Molecular Cell Biology, Samsung Biomedical Research Institute, SungKyunkwan University School of Medicine) ;
  • Cheong, Cheolho (Department of Molecular Cell Biology, Samsung Biomedical Research Institute, SungKyunkwan University School of Medicine) ;
  • Lee, Han-Woong (Department of Molecular Cell Biology, Samsung Biomedical Research Institute, SungKyunkwan University School of Medicine)
  • Received : 2005.06.13
  • Accepted : 2005.06.15
  • Published : 2005.06.30
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Abstract

The end of eukaryotic genomic DNA is capped by a specialized structure called as "telomere" which consists of the repetitive array of nucleotide sequence, TTAGGG, in humans and mice, and a variety of binding proteins. Telomerase is a ribonucleoprotein (RNP) complex responsible for the elongation of telomeres to maintain the genomic integrity, and is composed of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and their associated factors regulating the catalytic activity of telomerase. Although it is now apparent that telomerase protects cells from apoptosis via the maintenance of genomic integrity by stabilizing telomeres, our understanding for the physiological role of telomerase is yet far from completion, and emerging evidence suggests that telomerase has additional extratelomeric roles in mediating cell survival and anti-apoptotic functions against various cytotoxic stresses. Here we summarize and discuss how telomerase and telomeres are involved in mediating cellular protection against apoptosis.

Keywords

Acknowledgement

Supported by : MOST, KOSEF

References

  1. Akiyama, M., Hideshima, T., Hayashi, T., Tai, Y. T., Mitsiades, C. S., et al. (2003) Nuclear factor-${\kappa}B$ p65 mediates tumor necrosis factor ${\alpha}$-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res. 63, 18-21
  2. Akiyama, M., Yamada, O., Hideshima, T., Yanagisawa, T., Yokoi, K., et al. (2004) $TNF{\alpha}$ induces rapid activation and nuclear translocation of telomerase in human lymphocytes. Biochem. Biophys. Res. Commun. 316, 528-532 https://doi.org/10.1016/j.bbrc.2004.02.080
  3. Bachand, F., Boisvert, F. M., Cote, J., Richard, S., and Autexier, C. (2002) The product of the survival of motor neuron (SMN) gene is a human telomerase-associated protein. Mol. Biol. Cell 13, 3192-3202 https://doi.org/10.1091/mbc.E02-04-0216
  4. Blackburn, E. H. (1991) Structure and function of telomeres. Nature 350, 569-573 https://doi.org/10.1038/350569a0
  5. Blackburn, E. H. (2001) Switching and signaling at the telomere. Cell 106, 661-673 https://doi.org/10.1016/S0092-8674(01)00492-5
  6. Blasco, M. A. (2003) Telomeres and cancer: a tale with many endings. Curr. Opin. Genet. Dev. 13, 70-76 https://doi.org/10.1016/S0959-437X(02)00011-4
  7. Blasco, M. A. and Hahn, W. C. (2003) Evolving views of telomerase and cancer. Trends Cell Biol. 13, 289-294 https://doi.org/10.1016/S0962-8924(03)00085-0
  8. Cao, Y., Li, H., Deb, S., and Liu, J. P. (2002) TERT regulates cell survival independent of telomerase enzymatic activity. Oncogene 21, 3130-3138 https://doi.org/10.1038/sj.onc.1205419
  9. Caporaso, G. L., Lim, D. A., Alvarez-Buylla, A., and Chao, M. V. (2003) Telomerase activity in the subventricular zone of adult mice. Mol. Cell. Neurosci. 23, 693-702 https://doi.org/10.1016/S1044-7431(03)00103-9
  10. Chan, S. W. and Blackburn, E. H. (2002) New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21, 553-563 https://doi.org/10.1038/sj.onc.1205082
  11. Chan, S. L., Tammariello, S. P., Estus, S., and Mattson, M. P. (1999) Prostate apoptosis response-4 mediates trophic factor withdrawal-induced apoptosis of hippocampal neurons: actions prior to mitochondrial dysfunction and caspase activation. J. Neurochem. 73, 502-512 https://doi.org/10.1046/j.1471-4159.1999.0730502.x
  12. Chang, J. Y. (2004) Telomerase: a potential molecular marker and therapeutic target for cancer. Surg. Oncol. 87, 1-3 https://doi.org/10.1002/jso.20076
  13. Cheong, C., Hong, K. U., and Lee, H. W. (2003) Mouse models for telomere and telomerase biology. Exp. Mol. Med. 35, 141-153 https://doi.org/10.1038/emm.2003.20
  14. Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S. L., et al. (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527-538 https://doi.org/10.1016/S0092-8674(00)80762-X
  15. Choi, D. W. (1985) Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci. Lett. 58, 293-297 https://doi.org/10.1016/0304-3940(85)90069-2
  16. Chung, H. K., Cheong, C., Song, J., and Lee, H. W. (2005) Extratelomeric functions of telomerase. Curr. Mol. Med. 5, 233-241 https://doi.org/10.2174/1566524053586635
  17. Dudognon, C., Pendino, F., Hillion, J., Saumet, A., Lanotte, M., et al. (2004) Death receptor signaling regulatory function for telomerase: hTERT abolishes TRAIL-induced apoptosis, independently of telomere maintenance. Oncogene 23, 7469- 7474 https://doi.org/10.1038/sj.onc.1208029
  18. Etheridge, K. T., Banik, S. S., Armbruster, B. N., Zhu, Y., Terns, R. M., et al. (2002) The nucleolar localization domain of the catalytic subunit of human telomerase. J. Biol. Chem. 277, 24764-24770 https://doi.org/10.1074/jbc.M201227200
  19. Feng, J., Funk, W. D., Wang, S. S., Weinrich, S. L., Avilion, A. A., et al. (1995) The RNA component of human telomerase. Science 269, 1236–1241 https://doi.org/10.1126/science.7544491
  20. Fu, W., Killen, M., Culmsee, C., Dhar, S., Pandita, T. K., et al. (2000) The catalytic subunit of telomerase is expressed in developing brain neurons and serves a cell survivalpromoting function. J. Mol. Neurosci. 14, 3-15 https://doi.org/10.1385/JMN:14:1-2:003
  21. Fu, W., Lu, C., and Mattson, M. P. (2002) Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons. J. Neurosci. 22, 10710-10719
  22. Haendeler, J., Hoffmann, J., Brandes, R. P., Zeiher, A. M., and Dimmeler, S. (2003) Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family- dependent phosphorylation of tyrosine 707. Mol. Cell Biol. 23, 4598-4610 https://doi.org/10.1128/MCB.23.13.4598-4610.2003
  23. Herbert, B. S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., et al. (1999) Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl. Acad. Sci. USA 96, 14276-14281
  24. Kang, H. J., Choi, Y. S., Hong, S. B., Kim, K. W., Woo, R. S., et al. (2004) Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J. Neurosci. 24, 1280-1287 https://doi.org/10.1523/JNEUROSCI.4082-03.2004
  25. Khurts, S., Masutomi, K., Delgermaa, L., Arai, K., Oishi, N., et al. (2004) Nucleolin interacts with telomerase. J. Biol. Chem. 279, 51508 https://doi.org/10.1074/jbc.M407643200
  26. Kim, M. M., Rivera, M. A., Botchkina, I. L., Shalaby, R., Thor, A. D., et al. (2001) A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc. Natl. Acad. Sci. USA 98, 7982-7987
  27. Kondo, S., Tanaka, Y., Kondo, Y., Hitomi, M., Barnett, G. H., et al. (1998) Antisense telomerase treatment: induction of two distinct pathways, apoptosis and differentiation. FASEB J. 12, 801-811
  28. Kyo, S., Masutomi, K., Maida, Y., Kanaya, T., Yatabe, N., et al. (2003) Significance of immunological detection of human telomerase reverse transcriptase: re-evaluation of expression and localization of human telomerase reverse transcriptase. Am. J. Pathol. 163, 859-867 https://doi.org/10.1016/S0002-9440(10)63446-3
  29. Lee, H. W., Blasco, M. A., Gottlieb, G. J., Horner, J. W. 2nd, Greider, C. W., et al. (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569-574 https://doi.org/10.1038/33345
  30. Li, S., Rosenberg, J. E., Donjacour, A. A., Botchkina, I. L., Hom, Y. K., et al. (2004) Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant- template telomerase RNA and anti-telomerase shortinterfering RNA. Cancer Res. 64, 4833-4840 https://doi.org/10.1158/0008-5472.CAN-04-0953
  31. Li, S., Crothers, J., Haqq, C. M., and Blackburn, E. H. (2005) Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference- mediated depletion of telomerase RNA. J. Biol. Chem. [Epub ahead of print]
  32. Martinou, J. C., Dubois-Dauphin, M., Staple, J. K., Rodriguez, I., Frankowski, H., et al. (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13, 1017–1030 https://doi.org/10.1016/0896-6273(94)90266-6
  33. Martin-Rivera, L., Herrera, E., Albar, J. P., and Blasco, M. A. (1998) Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc. Natl. Acad. Sci. USA 95, 10471-10476
  34. Masutomi, K., Yu, E. Y., Khurts, S., Ben-Porath, I., Currier, J. L., et al. (2003) Telomerase maintains telomere structure in normal human cells. Cell 114, 241-253 https://doi.org/10.1016/S0092-8674(03)00550-6
  35. Murphy, A. N., Bredesen, D. E., Cortopassi, G., Wang, E., and Fiskum, G. (1996) Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc. Natl. Acad. Sci. USA 93, 9893-9898
  36. Pendino, F., Flexor, M., Delhommeau, F., Buet, D., Lanotte, M., et al. (2001) Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation. Proc. Natl. Acad. Sci. USA 98, 6662-6667
  37. Prowse, K. R. and Greider, C. W. (1995) Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl. Acad. Sci. USA 92, 4818-4822
  38. Rahman, R., Latonen, L., and Wiman, K. G. (2005) hTERT antagonizes p53-induced apoptosis independently of telomerase activity. Oncogene 24, 1320-1327 https://doi.org/10.1038/sj.onc.1208232
  39. Ren, J. G., Xia, H. L., Just, T., and Dai, Y. R. (2001a) Hydroxyl radical-induced apoptosis in human tumor cells is associated with telomere shortening but not telomerase inhibition and caspase activation. FEBS Lett. 488, 123-132 https://doi.org/10.1016/S0014-5793(00)02377-2
  40. Ren, J. G., Xia, H. L., Tian, Y. M., Just, T., Cai, G. P., et al. (2001b) Expression of telomerase inhibits hydroxyl radicalinduced apoptosis in normal telomerase negative human lung fibroblasts. FEBS Lett. 488, 133-138 https://doi.org/10.1016/S0014-5793(00)02397-8
  41. Rizzuto, R., Pinton, P., Ferrari, D., Chami, M., Szabadkai, G., et al. (2003) Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619-8627 https://doi.org/10.1038/sj.onc.1207105
  42. Saretzki, G., Ludwig, A., von Zglinicki, T., and Runnebaum, I. B. (2001) Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells. Cancer Gene Ther. 8, 827-834 https://doi.org/10.1038/sj.cgt.7700383
  43. Seimiya, H., Sawada, H., Muramatsu, Y., Shimizu, M., Ohko, K., et al. (2000) Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO J. 19, 2652-2661 https://doi.org/10.1093/emboj/19.11.2652
  44. Smith, L. L., Coller, H. A., and Roberts, J. M. (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat. Cell Biol. 5, 474-479 https://doi.org/10.1038/ncb985
  45. von Zglinicki, T., Pilger, R., and Sitte, N. (2000) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic. Biol. Med. 28, 64-74 https://doi.org/10.1016/S0891-5849(99)00207-5
  46. Wang, S. and El-Deiry W. S. (2003) TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628-8633 https://doi.org/10.1038/sj.onc.1207232
  47. Wong, J. M., Kusdra, L., and Collins, K. (2002) Subnuclear shuttling of human telomerase induced by transformation and DNA damage. Nat. Cell Biol. 4, 731-736 https://doi.org/10.1038/ncb846
  48. Wong, K. K., Chang, S., Weiler, S. R., Ganesan, S., Chaudhuri, J., et al. (2000) Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat. Genet. 26, 85-88 https://doi.org/10.1038/79232
  49. Xu, D., Wang, Q., Gruber, A., Bjorkholm, M., Chen, Z., et al. (2000) Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells. Oncogene 19, 5123-5133 https://doi.org/10.1038/sj.onc.1203890
  50. Yan, P., Benhattar, J., Seelentag, W., Stehle, J. C., and Bosman, F. T. (2004) Immunohistochemical localization of hTERT protein in human tissues. Histochem. Cell Biol. 121, 391-397 https://doi.org/10.1007/s00418-004-0645-5
  51. Zhang, P., Chan, S. L., Fu, W., Mendoza, M., and Mattson, M. P. (2003) TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein-binding ability. FASEB J. 17, 767-769
  52. Zhu, H., Fu, W., and Mattson, M. P. (2000) The catalytic subunit of telomerase protects neurons against amyloid betapeptide- induced apoptosis. J. Neurochem. 75, 117-124 https://doi.org/10.1046/j.1471-4159.2000.0750117.x