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Regulation of Telomerase Activity

Ectopic expression of c-myc fails to overcome downregulation of telomerase activity induced by herbimycin A, but ectopic hTERT expression overcomes it

Leukemia volume 14, pages 1260–1265 (2000)Cite this article

A Corrigendum to this article was published on 04 November 2015

Abstract

Telomerase plays a key role in the maintenance of chromosomal stability in tumors, but the mechanism regulating telomerase activity is still unclear. Recent studies have suggested that c-myc may be vital for regulation of hTERT mRNA expression and telomerase activity. In this study, we investigated the changes of telomerase activity and telomerase-related genes induced by herbimycin A in K562 human chronic myelogeous leukemic cells. Telomerase activity showed a biphasic pattern in herbimycin A-treated K562 cells. Initially, the telomerase activity decreased along with the decline of cells in S and G2/M phases, but it recovered slightly at the end of treatment. Expression of mRNA for the telomerase catalytic subunit (hTERT) was decreased before the decline of telomerase activity, and increased slightly before the reactivation of telomerase activity. During herbimycin A treatment, both c-myc and cyclin D1 mRNA showed transient downregulation before the increase of G1 cells. Herbimycin A treatment caused the downregulation of both telomerase activity and hTERT mRNA in cyclin D1-transfected K562 cells, while telomerase activity was partially restored in c-myc-transfected cells. In contrast, hTERT-transfected K562 cells maintained a high level of telomerase activity during herbimycin A treatment. Neither the template RNA component of telomerase (hTERC) nor telomerase-associated protein (TEP-1) were altered in any of the transfected K562 cells. These results indicate that telomerase activity is mainly regulated by hTERT, and that c-Myc protein is one of the positive regulators of hTERT in leukemic cells but is not enough to counteract the downregulation of telomerase activity by herbimycin A completely.

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References

  1. Blackburn EH . Structure and function of telomeres Nature 1991 266: 569–573

    Article  Google Scholar 

  2. Harley CB, Kim NW, Prowse KR, Weirich SL, Hirsch KS, West MD, Bacchetti S, Hirte HW, Counter CM, Greider CW, Piatyszek MA, Wright WE, Shay JW . Telomerase, cell immortality, and cancer Cold Spring Harbor Symp Quant Biol 1994 59: 307–315

    Article  CAS  Google Scholar 

  3. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PLC, Coviello GM, Wright WE, Weirich SL, Shay JW . Specific association of human telomerase activity with immortal cells and cancer Science 1994 266: 2011–2015

    Article  CAS  Google Scholar 

  4. Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S . Telomere shortening associated with chromosome instability in immortal cells which express telomerase activity EMBO J 1992 11: 1921–1929

    Article  CAS  Google Scholar 

  5. Harly CB . Telomere loss: mitotic clock or genetic time bomb? Mutat Res 1991 265: 271–282

    Article  Google Scholar 

  6. Rhyu MS . Telomeres, telomerase and immortality J Natl Cancer Inst 1995 87: 884–894

    Article  CAS  Google Scholar 

  7. Yamada O, Motoji T, Mizoguchi H . Up-regulation of telomerase activity in human lymphocytes Biochim Biophys Acta 1996 1314: 260–266

    Article  CAS  Google Scholar 

  8. Kyo S, Takakura M, Kohama T, Inoue M . Telomerase activity in human endometrium Cancer Res 1997 57: 610–614

    CAS  PubMed  Google Scholar 

  9. Feng J, Funk WD, Wang S, Weirich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J, Le S, West MD, Harley CB, Andrews WH, Greider CW, Villeponteau B . The RNA component of human telomerase Science 1995 269: 1236–1241

    Article  CAS  Google Scholar 

  10. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Linda Z, Beijerssbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA . hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization Cell 1997 90: 785–795

    Article  CAS  Google Scholar 

  11. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Linger J, Harley CB, Cech TR . Telomerase catalytic subunit homologs from fission yeast and human Science 1997 277: 955–959

    Article  CAS  Google Scholar 

  12. Nakayama J, Saito M, Nakamura H, Matsuura A, Ishikawa F . TLP-1: a gene encoding a protein component of mammalian telomerase is a novel member of WD repeats family Cell 1997 88: 875–884

    Article  CAS  Google Scholar 

  13. Harrington L, Mcphail T, Mar V, Zhou W, Oulton R, Amgen EST Program, Bass MB, Isabel A, Robinson MO . A mammalian telomerase-associated protein Science 1997 275: 973–977

    Article  CAS  Google Scholar 

  14. Yamada H, Iwase S, Nagai M, Nemoto T, Sekikawa T, Takahara S, Nakada S, Furukawa Y, Yamada HJ . Herbimycin A down-regulates messages of cyclin D1 and c-myc during erythroid differentiation of K562 Int J Hematol 1996 65: 31–40

    Article  CAS  Google Scholar 

  15. Wang J, Xie LY, Allan S, Beach D, Hannon GJ . Myc activates telomerase Gene Dev 1998 12: 1769–1774

    Article  CAS  Google Scholar 

  16. Cong YS, Wen J, Bacchetti S . The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promotor Hum Mol Genet 1999 8: 137–142

    Article  CAS  Google Scholar 

  17. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M . Cloning of human telomerase catalytic subunit (hTERT) gene promotor and identification of proximal core promotor sequences essential for transcriptional activation in immortalized and cancer cells Cancer Res 1999 59: 551–557

    CAS  PubMed  Google Scholar 

  18. Horikawa I, Cable PL, Afshari C, Barrett JC . Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene Cancer Res 1999 59: 826–830

    CAS  PubMed  Google Scholar 

  19. Greenberg RA, O'Hagan RC, Deng H, Xiao Q, Hann SR, Adams RR, Lichtsteiner S, Chin L, Morin GB, Depinho RA . Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation Oncogene 1999 18: 1219–1226

    Article  CAS  Google Scholar 

  20. Wick M, Zubov D, Hagen G . Genomic organization and promotor characterization of the gene encoding the human telomerase reverse transcriptase (hTERT) Gene 1999 232: 97–106

    Article  CAS  Google Scholar 

  21. Wu KJ, Grandori C, Amacker M, Vermot NS, Polack A, Linger J, Favera RD . Direct activation of TERT transcription by c-myc Nat Genet 1999 21: 220–224

    Article  CAS  Google Scholar 

  22. Akiyama M, Yamada-Horiguchi J, Saito S, Hoshi Y, Yamada O, Mizoguchi H, Yamada H . Cytostatic concentrations of anticancer agents do not affect telomerase activity of leukemic cells in vitro Eur J Cancer 1999 35: 309–315

    Article  CAS  Google Scholar 

  23. Akiyama M, Iwase S, Yamada HJ, Saito S, Furukawa Y, Yamada O, Mizoguchi H, Ohno T, Yamada H . Interferon-α repressed telomerase along with G1-accumulation of Daudi cells Cancer Lett 1999 142: 23–30

    Article  CAS  Google Scholar 

  24. Yamada H, Ochi K, Nakada S, Takahara S, Nemoto T, Sekikawa T, Horiguchi-Yamada J . Interferon modulates the messenger RNA of G1-controlling genes to suppress the G1-to-S transition in Daudi cells Mol Cell Biochem 1995 152: 149–158

    Article  CAS  Google Scholar 

  25. Surmacz E, Reiss K, Sell C, Baserga R . Cyclin D1 messenger RNA is inducible by pletelet-derived growth factor in cultured fibroblasts Cancer Res 1992 52: 4522–4525

    CAS  PubMed  Google Scholar 

  26. Iwase S, Furukawa Y, Kikuchi J, Nagai M, Terui Y, Nakamura M, Yamada H . Modulation of E2F activity is linked to interferon-induced growth suppression of hematopoietic cells J Biol Chem 1997 227: 12406–12414

    Article  Google Scholar 

  27. Kondo Y, Kondo S, Tanaka Y, Haqqi T, Barna BP, Cowell JK . Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced apoptosis Oncogene 1998 16: 2243–2248

    Article  CAS  Google Scholar 

  28. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO . Telomere shortening and apoptosis in telomerase-inhibited human tumor cells Gene Dev 1999 13: 2388–2399

    Article  CAS  Google Scholar 

  29. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar WH, Wright WE, Shay JW, Harley CB, Morin GB . Recognition of human telomerase with the template RNA component hTR and catalytic protein subunit hTRT Nat Genet 1997 17: 498–502

    Article  CAS  Google Scholar 

  30. Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E, Ide T, Ishikawa F . Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas Nat Genet 1998 18: 65–68

    Article  CAS  Google Scholar 

  31. Kang SS, Kwon T, Kwon DY, Do SL . Akt protein kinase enhances human telomerase activity through phoshorylation of telomerase reverse transcriptase subunit J Biol Chem 1999 274: 13085–13090

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the special Coordination Fund for ‘Research for the future program’ from the Science and Technology Agency and by the grant in aid of ‘High-Tech Research Center (Institute of DNA Medicine)’ from the Ministry of Education of Japan.

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Authors and Affiliations

  1. Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

    M Akiyama, M Urashima & Y Eto

  2. Department of Molecular Genetics, Jikei University School of Medicine, Tokyo, Japan

    M Akiyama, S Akita & H Yamada

  3. Department of Hematology, Tokyo Women's Medical College, Tokyo, Japan

    O Yamada & H Mizoguchi

  4. Department of Oncology, Jikei University School of Medicine, Tokyo, Japan

    J Horiguchi-Yamada & T Ohno

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Akiyama, M., Yamada, O., Akita, S. et al. Ectopic expression of c-myc fails to overcome downregulation of telomerase activity induced by herbimycin A, but ectopic hTERT expression overcomes it. Leukemia 14, 1260–1265 (2000). https://doi.org/10.1038/sj.leu.2401828

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