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Telomerase is not an oncogene

Abstract

In the decade since the telomere hypothesis of cellular aging was proposed, the two essential genes for human telomerase were cloned and characterized, allowing experimental proof of the causal relationships between telomere loss and replicative senescence, and telomerase activation and immortalization. These relationships were established using a variety of cultured human cell types from both normal and tumor tissues, and were largely confirmed in the telomerase knockout mouse. Taken together, the data provide strong support for the potential utility of telomerase detection and inhibition for cancer, and telomerase activation for degenerative diseases. The specificity of the promoter for the telomerase catalytic gene and the antigenicity of the protein product, hTERT, provide additional strategies for killing telomerase-positive tumor cells. Unfortunately, the strong link between telomerase and cancer has led some to confuse telomerase activation with cancer, and others to overstate the cancer risk of telomerase activation therapies for degenerative diseases. This review clarifies the difference between telomerase, which does not cause growth deregulation, and oncogenes, which do. It also addresses the concept of telomerase repression as a tumor suppressor mechanism early in life, with detrimental tissue degeneration and tumor-promoting consequences late in life. This extended view of the telomere hypothesis helps explain how telomerase inhibition can be therapeutic in cancer patients, while controlled telomerase activation for degenerative diseases may actually reduce, rather than increase, the frequency of age-related tumorigenesis.

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References

  • Amit M, Carpenter MK, Inokuma MS, Chiu C-P, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA . 2000 Dev. Biol. 227: 271–278

  • Bandyopadhyay D, Timchenko N, Suwa T, Hornsby PJ, Campisi J, Medrano EE . 2001 Exp. Gerontol. 36: 1265–1275

  • Blackburn EH . 2001 Cell 106: 661–673

  • Blackburn EH, Szostak JW . 1989 Ann. Rev. Genet. 23: 163–194

  • Bodnar A, Kim NW, Effros RB, Chiu C-P . 1996 Exp. Cell Res. 228: 58–64

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu C-P, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE . 1998 Science 279: 349–352

  • Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR . 1997 Hum. Mol. Gen. 6: 1–16

  • Campisi J . 1997 Eur. J. Cancer 33: 703–709

  • Chen J-L, Blasco MA, Greider CW . 2000 Cell 100: 503–514

  • Choi D, Whittier PS, Oshima J, Funk WD . 2001 FASEB J. 15: 1014–1020

  • Cong YS, Bachetti S . 2000 J. Biol. Chem. 275: 35665–35668

  • Dessain SK, Yu H, Reddel RR, Beijersbergen RL, Weinberg RA . 2000 Cancer Res. 60: 537–541

  • Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP, Rheinwald JG . 2000 Mol. Cell. Biol. 20: 1436–1447

  • Effros RB, Allsopp R, Chiu C-P, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV . 1996 AIDS 10: F17–F22

  • Engelhardt M, Mackenzie K, Drullinsky P, Silver RT, Moore MA . 2000 Cancer Res. 60: 610–617

  • Farwell DG, Shera KA, Koop JI, Bonnet GA, Matthews CP, Reuther GW, Coltrera MD, McDougall JK, Klingelhutz AJ . 2000 Am. J. Pathol. 156: 1537–1547

  • Feng J, Funk WD, Wang S-S, Weinrich SL, Avilion AA, Chiu C-P, Adams RR, Chang E, Yu J, Le S, West MD, Harley CB, Andrews WH, Greider CW, Villeponteau B . 1995 Science 269: 1236–1241

  • Franco S, MacKenzie KL, Dias S, Alvarez S, Rafii S, Moore MA . 2001 Exp. Cell Res. 268: 14–25

  • Funk WD, Wang CK, Shelton DN, Harley CB, Pagon GD, Hoeffler WK . 2000 Exp. Cell. Res. 258: 270–278

  • Gonzalez-Suarez E, Samper E, Flores JM, Blasco MA . 2000 Nat. Genet. 26: 114–117

  • Goytisolo FA, Samper E, Martin-Caballero J, Finnon P, Herrera E, Flores JM, Bouffler SD, Blasco MA . 2000 J. Exp. Med. 192: 1625–1636

  • Greider CW . 1996 Annu. Rev. Biochem. 65: 337–365

  • Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T . 1999 Cell 97: 503–514

  • Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JHM, Meyerson M, Weinberg RA . 1999 Nat. Med. 5: 1164–1170

  • Halvorsen RL, Leibowitz G, Levine F . 1999 Mol. Cell. Biol. 19: 1864–1870

  • Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F . 2000 J. Endrocrinol. 166: 103–109

  • Harley CB . 1991 Mut. Res. 256: 271–282

  • Harley CB, Futcher AB, Greider CW . 1990 Nature 345: 458–460

  • Harley CB, Kim NW, Prowse KR, Weinrich SL, Hirsch KS, West MD, Bacchetti S, Hirte HW, Counter CM, Greider CW, Wright WE, Shay JW . 1994 Cold Spring Harbor Symp. Quant. Biol. 59: 307–315

  • Hemann M, Strong M, Hao L, Greider C . 2001 Cell 107: 67–77

  • Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee H-W, Blasco MA . 1999 EMBO J. 18: 2950–2960

  • Hiyama E, Hiyama K, Yokoyama T, Mitsuura Y, Piatyszek MA, Shay JW . 1995a Nature Med. 1: 249–255

  • Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyamas E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M . 1995b J. Immunol. 155: 3711–3715

  • Hooijberg E, Ruizendaal JJ, Snijders PJF, Kueter EWM, Walboomers JMM, Spits H . 2000 J. Immunol. 165: 4239–4245

  • Jiang X-R, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, Beeche M, Bodnar AG, Wahl GM, Tlsty TD, Chiu C-P . 1999 Nat. Genet. 21: 111–114

  • Jones CJ, Kipling D, Morris M, Hepburn P, Skinner J, Bounacer A, Wyllie FS, Ivan M, Bartek J, Wynford-Thomas D, Bond JA . 2000 Mol. Cell. Biol. 20: 5690–5699

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PLC, Coviello GM, Wright WE, Weinrich SL, Shay JW . 1994 Science 266: 2011–2014

  • Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ . 1998 Nature 396: 84–88

  • Komata T, Kondo Y, Kanzawa T, Hirohata S, Koga S, Sumiyohi H, Srinivasula S, Barna B, Germano I, Takakura M, Inoue M, Alnemri E, Shay JW, Kyo S, Kondo S . 2001 Cancer Res. 61: 5796–5802

  • Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J . 2001 Proc. Natl. Acad. Sci. USA 98: 12072–12077

  • Lee H-W, Blasco MA, Gottlieb G, Horner II JW, Greider CW, DePinho RA . 1998 Nature 392: 569–574

  • MacKenzie KL, Franco S, May C, Sadelain M, Moore MAS . 2000 Exp. Cell. Res. 259: 336–350

  • Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP . 2001 Gene Ther. 8: 568–578

  • Matsunaga H, Handa JT, Aotaki-Keen A, Sherwood SW, West MD, Hjelmeland LM . 1999 Invest. Ophtalmol. Vis. Sci. 40: 197–202

  • McSharry BP, Jones CJ, Skinner JW, Kipling D, Wilkinson GWG . 2001 J. Gen. Virol. 82: 855–863

  • Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA . 1997 Cell 90: 785–795

  • Migliaccio M, Amacker M, Just T, Reichenbach P, Valmori D, Cerottini J-C, Romero P, Nabholz M . 2000 J. Immunol. 165: 4978–4984

  • Minev B, Hipp J, Firat H, Schmidt H, Langlade-Demoyen P, Zanetti M . 2000 Proc. Natl. Acad. Sci. USA 97: 4796–4801

  • Mitchell JR, Collins K . 2000 Mol. Cell. 6: 361–371

  • Nair SK, Hiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski J, Vieweg J, Gilboa E . 2000 Nat. Med. 6: 1011–1017

  • Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR . 1997 Science 277: 955–959

  • O'Hare MJ, Bond J, Clarke C, Takeuchi Y, Atherton AJ, Berry C, Moody J, Silver ARJ, Davies DC, Alsop AE, Neville AM, Jat PS . 2001 PNAS 98: 646–651

  • Ouellette MM, McDaniel LD, Wright WE, Shay JW, Schultz RA . 2000 Hum. Mol. Gen. 9: 403–411

  • Poole JC, Andrews LG, Tollefsbol TO . 2001 Gene 269: 1–12

  • Ramirez RD, Morales CP, Herbert B-S, Rohde J, Passons C, Shay JW, Wright WE . 2001 Genes Dev. 15: 398–403

  • Ranganathan V, Heine WF, Ciccone DN, Rudolph KL, Wu X, Chang S, Hai H, Ahearn IM, Livingston DM, Resnick I, Rosen F, Seemanova E, Jarolim P, DePinho RA, Weaver DT . 2001 Curr. Biol. 11: 962–966

  • Reynolds CP, Zuo JJ, Kim NW, Wang H, Lukens J, Matthay KK, Seeger RC . 1997 Eur. J. Cancer 33: 1929–1931

  • Rudolph KL, Chang S, Lee H-W, Blasco M, Goettlieb GJ, Greider C, DePinho RA . 1999a Cell 96: 701–712

  • Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA . 1999b Science 287: 1253–1258

  • Rudolph KL, Millard M, Bosenberg MW, DePinho RA . 2001 Nat. Genet. 28: 155–159

  • Salmon P, Oberholzer J, Occhiodoro T, Morel P, Lou J, Trono D . 2000 Mol. Ther. 2: 404–414

  • Seigneurin-Venin S, Bernard V, Ouellette MM, Mouly V, Wright WE, Tremblay J . 2000a Biochem. Biophys. Res. Commun. 7: 362–369

  • Seigneurin-Venin S, Bernard V, Tremblay JP . 2000b Gene Thera. 7: 619–623

  • Smith S, de Lange T . 2000 Curr. Biol. 10: 1299–1302

  • Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T . 2000 Mol. Cell. Biol. 20: 1659–1668

  • Taylor RS, Ramirez RD, Ogoshi M, Chaffins M, Piatyszek MA, Shay JW . 1996 J. Invest. Dermatol. 106: 759–765

  • Thomas M, Yang L, Hornsby PJ . 2000 Nat. Biotech. 18: 39–42

  • Ulaner GA, Giudice LC . 1997 Mol. Hum. Reprod. 3: 769–773

  • Ulaner GA, Hu J-F, Hu TH, Giudice LC, Hoffman AR . 1998 Cancer Res. 58: 4168–4172

  • Usselmann B, Newbold M, Morris AG, Nwokolo CU . 2001 Am. J. Gastroenterol. 96: 1106–1112

  • Vaziri H, Benchimol S . 1999 Oncogene 18: 7676–7680

  • von Zglinicki T . 2000 Ann. NY Acad. Sci. 99–110

  • Vonderheide RH, Hahn WC, Schultze JL, Nadler LM . 1999 Immunity 10: 673–679

  • Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I . 2001 Nature 413: 432–435

  • Weng N-P, Granger L, Hodes RJ . 1997 Proc. Natl. Acad. Sci. USA 94: 10827–10832

  • Weng N-P, Levine BL, June CH, Hodes RJ . 1996 J. Exp. Med. 183: 2471–2479

  • Wong K-K, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C, Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW, DePinho RA . 2000 Nat. Gen. 26: 85–88

  • Wood LD, Halvorsen TL, Dhar S, Baur JA, Pandita RK, Wright WE, Hande MP, Calaf G, Hei TK, Levine F, Shay JW, Wang JJ, Pandita TK . 2001 Oncogene 20: 278–288

  • Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW . 1996 Dev. Genet. 18: 173–179

  • Wright WE, Shay JW . 2001 Curr. Opin. Genet. Dev. 11: 98–103

  • Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RGA, Kipling D . 2000 Nat. Genet. 24: 16–17

  • Yang J, Chang E, Cherry AM, Bangs CD, Oei Y, Bodnar A, Bronstein A, Chiu C-P, Herron GS . 1999 J. Biol. Chem. 274: 26141–26148

  • Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T . 2001 J. Bone Miner. Res. 16: 1453–1464

  • Zhang X, Mar V, Harrington L, Robinson MO . 1999 Genes Dev. 13: 2388–2399

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Acknowledgements

I thank my Geron colleagues for helpful discussion, and David Karpf, Tom Okarma and Jane Lebkowski for critical comments on this paper. I also thank Gregg Morin and Melissa Fischer for creation of the telomerase schematic upon which Figure 1 was based.

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Correspondence to Calvin B Harley.

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Harley, C. Telomerase is not an oncogene. Oncogene 21, 494–502 (2002). https://doi.org/10.1038/sj.onc.1205076

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Keywords

  • telomere
  • telomerase
  • aging
  • cancer
  • immortalization
  • genetic instability

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