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.
Cancer is a complex process involving a multi-faceted evolutionary process occurring at the cellular level within organisms. It is triggered by the second law of thermodynamics (disorder increases in a closed system) operating through mutation and cell selection. Oncology research in the past 30 years has largely focussed on how cancer disrupts the orderly structure of somatic tissues through genetic alterations that cause loss of cell cycle control and abnormal cell–cell, and cell–matrix interactions. However, telomere biology, originally studied by basic geneticists and later biochemists working with plants and invertebrates and totally unaware of a strong connection to oncology (reviewed in Blackburn and Szostak, 1989; Greider, 1996), has emerged as an entirely new field rich in relevance to cancer and other age-related diseases.
The telomere hypothesis of cell aging and immortalization
Telomeres are essential genetic elements at chromosome termini maintained in immortal cells by the enzyme telomerase (Figure 1). Our current understanding of the structure and function of telomeres and telomerase is reviewed elsewhere in this issue. The telomere hypothesis linking telomere loss to replicative senescence and telomerase activation to cell immortalization is reviewed in Figure 2. The major concepts of this hypothesis were proven correct by specific manipulation of telomerase in human cells with the cloned components of the enzyme (Bodnar et al., 1998; Feng et al., 1995; Hahn et al., 1999; Nakamura et al., 1997; Vaziri and Benchimol, 1999; Zhang et al., 1999). Moreover, it has been largely substantiated by the phenotype of the late generation telomerase knockout mouse (Gonzalez-Suarez et al., 2000; Herrera et al., 1999; Lee et al., 1998; Rudolph et al., 1999a), which shares remarkable similarities to the phenotype of the autosomal dominant form of dyskeratosis congenita, a genetic disease caused by a telomerase defect (Vulliamy et al., 2001). Telomerase-compromized mice and humans with shortened telomeres (e.g., dyskeratosis congenital) have reduced longevity, chromosome fusions, defects in highly proliferative tissues including impaired regenerative and wound-healing capacity, and an increase in incidence of certain tumors.
Exceptions to simple generalizations will always be found, especially when looking across species or in multiple cell types in varied conditions in vitro and in vivo. Although the basics of the original telomere hypothesis remain valid, important variations exist. For example, certain highly proliferative human cells are capable of expressing low or transiently high levels of telomerase upon commitment to clonal expansion, apparently slowing the net rate of telomere loss and conferring an extended, but still finite lifespan to these cells (Bodnar et al., 1996; Hiyama et al., 1995b; Taylor et al., 1996; Usselmann et al., 2001; Weng et al., 1996, 1997) (Figure 2A, line b). Also, certain transformed human cells capable of indefinite replication in culture are telomerase negative, and maintain unstable telomeres by an alternative lengthening pathway (Bryan et al., 1997). Finally, a great deal more is known about telomere associated proteins, the overall telomere structure, and the sensitivity of telomeres to DNA damaging agents. These findings point to additional factors which regulate the rate of telomere loss in the absence of telomerase, the equilibrium telomere length in telomerase positive cells, and provide insights into the consequences of aberrant (or ‘uncapped’) telomere structures or critical telomere loss (Blackburn, 2001; Goytisolo et al., 2000; Griffith et al., 1999; Hemann et al., 2001; Ranganathan et al., 2001; Smith and de Lange, 2000; Smogorzewska et al., 2000; von Zglinicki, 2000; Wong et al., 2000).
Despite these additions and variations to the telomere hypothesis, there now exists compelling cell and animal data for the potential of killing telomerase-positive cancer cells through telomerase inhibition (Gonzalez-Suarez et al., 2000, through therapeutic telomerase vaccines (Minev et al., 2000; Nair et al., 2000; Vonderheide et al., 1999), and through suicide genes driven by the telomerase promoter (Komata et al., 2001; Majumdar et al., 2001). There is also intriguing cell and animal data for the potential of telomerase activation in degenerative diseases (Funk et al., 2000; Jiang et al., 1999; Rudolph et al., 1999b), supported by the human dyskeratosis congenita genetic evidence (Vulliamy et al., 2001). However, human cells in culture and in mice do not capture human physiology, normal human aging is not phenocopied by mutations in telomerase, and man and mouse differ markedly in telomerase regulation, chromosome structure, and the stringency of checkpoint arrest mechanisms. These facts leave uncertain the complete role of telomere loss and telomerase activation in human age-related disease and cancer. Final proof for the medical relevance of these concepts will come with successful human clinical trials using drugs or genes that specifically target telomere or telomerase pathways.
Cancer, growth control and cell immortality
The primary hallmark of tumor cells, common to all cancers and representing one of the first detectable signs of tissue disorder, is loss of growth control leading to dysplasia and ultimately anaplasia. The two main contributors to this are uncorrected gain-of-function mutations in proto-oncogenes, and loss-of-function mutations in tumor suppressor genes. A second hallmark of tumor cells, common to almost all malignant cancers, is cellular immortality. Whereas normal somatic cells have a finite replicative capacity, some evolving tumor cells appear capable of indefinite replication in vivo and in vitro. There is strong selective pressure on tumor cells for replicative immortality, since a large number of divisions are exhausted in accumulating the 5–10 independent mutations and clonal expansions typically needed to generate a malignant growth (reviewed in Harley et al., 1994).
In human tumors, cell immortalization almost always involves derepression of the gene for the catalytic subunit of telomerase, hTERT (human telomerase reverse transcriptase) (Meyerson et al., 1997; Nakamura et al., 1997). Transcriptional repression of hTERT early in human development (in utero), post-transcriptional processing events, epigenetic changes in the gene, and perhaps other factors which prevent functional telomerase formation, are responsible for the ‘mortalization’ of normal somatic cells (Cong and Bachetti, 2000; Dessain et al., 2000; Poole et al., 2001; Ulaner and Giudice, 1997; Ulaner et al., 1998; Wright et al., 1996). Multiple pathways for stringent repression or controlled regulation of telomerase probably account for the extreme rarity of spontaneous immortalization of normal human cells.
Oncogenes, i.e. mutated or otherwise deregulated proto-oncogenes, are typically regarded as genes that promote the uncontrolled growth of cells. In this context, telomerase is clearly not an oncogene. hTERT and telomerase activity are expressed in normal immortal human embryonic stem cells (Amit et al., 2000), in germline cells (Kim et al., 1994; Wright et al., 1996), and in dozens of somatic cells immortalized by hTERT transduction (Table 1), all without signs of aberrant growth control. Conversely, there are severely growth deregulated, malignant, metastatic tumor cells, such as in neuroblastoma stage IV-S, which are telomerase negative (Hiyama et al., 1995a; Reynolds et al., 1997). Growth deregulation and cell immortalization are conceptually and physiologically separate processes (Figure 3).
Are there conditions under which telomerase would be considered a proto-oncogene, and the genes controlling cell mortality, i.e. the telomerase repressors, would be considered tumor suppressors? If proto-oncogenes and tumor suppressor genes are restricted to those involved in the active control of cell proliferation, which when altered by gain-of-function or loss-of-function, respectively, give rise to uncontrolled, as opposed to unlimited growth, then the answer is ‘no’. But this classical definition of oncogenes and tumor suppressors may be overly narrow. Cellular replicative senescence is generally regarded as a tumor suppressive or protective mechanism. Thus, inactivation of ‘growth limiting’ genes or deregulated expression of telomerase could increase the frequency of cancer, and hence, by a broader definition linked to cancer risk, the answer would be ‘yes’. This argument notwithstanding, telomerase is clearly not a ‘classical’ oncogene due to the distinction between growth deregulation and immortalization.
To further confound the question of whether telomerase could be considered an oncogene, genetic instability caused by telomere dysfunction resulting from a lack of telomerase is now clearly implicated in tumor initiation in mice. Some evidence also points to a role for this mechanism in humans (Campisi, 1997; Vulliamy et al., 2001; Krtolica et al., 2001). How can telomerase inhibition be therapeutic in cancer, yet lack of telomerase trigger cancer? The answer to this question is relatively simple: Genetic instability caused by critical telomere loss at cell crisis can contribute to growth deregulating mutations, i.e. transforming events, which may initiate tumor formation. This situation may be particularly acute in rodents, which lack a strong pre-crisis senescence checkpoint. However, in humans, the age-dependent increase in cancer attributable to telomere biology may relate more to loss of normal tissue barriers and diminishing immune function due to senescence, than to genetic instability and mutation.
Progression of telomerase-negative tumors with short telomeres is clearly compromized in telomerase knockout mice (Rudolph et al., 2001), as it appears to be in humans. Thus, in patients with malignant telomerase-positive tumors with short telomeres, telomerase inhibition is expected to have a dramatic therapeutic benefit. We do not expect telomerase inhibition therapy to increase the frequency of tumor initiation elsewhere in a human patient, since most normal somatic cells are telomerase negative anyway. The impact of telomerase inhibitors on telomerase competent stem cells should be relatively minor, given (1) their generally long telomeres, (2) normal precrisis checkpoints, and (3) the transient nature of telomerase expression in a subpopulation of stem cells, associated with the initial phases of clonal expansion.
These points help answer the related evolutionary question of how telomerase repression apparently evolved as a tumor suppressor mechanism, whereas telomere dysfunction at senescence, or crisis, apparently contributes to tumor initiation. Mus musculus, with extremely long telomeres and lack of stringent telomerase repression in most tissues, does not use a division counting mechanism for tumor suppression (Wright and Shay, 2001) and should not be analysed in this light. In humans, with relatively short telomeres and stringent telomerase repression, it is easy to argue that early in life (when telomeres are not limiting and normal fully functional cells predominate) a telomere-dependent senescence checkpoint in rare growth deregulated cells is a tumor suppressive mechanism and, hence, confers a survival advantage. Even if transformed cells bypass senescence and reach crisis, the instability of these cells in the context of normal tissue and immune function in young individuals more likely triggers their destruction than contributes to lethal tumor progression. This beneficial effect of telomerase repression early in life could offset a multitude of detrimental consequences late in life, beyond the normal period of reproductive fitness, when evolutionary selective pressures are greatly diminished. However, there is no quantitative or even theoretical analysis on this issue, to my knowledge.
The detrimental late-onset consequences of early telomerase repression fall into three categories. First, the telomere-dependent aging of normal cells, especially in areas of chronic stress, is expected to contribute to loss of function in all tissues containing or supported by proliferative cells. Second, aging cells may also contribute to an increased frequency of tumors through stimulating the proliferation of surrounding cells or through loss of tumor-restraining or tumor-killing functions. Finally, in old age the increasing fraction of senescent cells or transformed cells at crisis may also contribute to tumor initiation due to telomere dysfunction and genetic instability, as described in the telomerase knockout mouse, and suggested by the progression of myelodysplastic syndrome (Engelhardt et al., 2000) and the phenotype of dyskeratosis congenita.
Controlled telomerase activation therapies should not pose an unacceptable risk of cancer
The potential benefits of telomerase inhibition for cancer patients was described earlier and is reviewed elsewhere in this issue. However, the links between telomerase activation and tumor progression in animal models and humans raises the question of whether telomerase activation directed towards treatment of degenerative, age-related diseases, will pose an unacceptable risk of cancer. The answer of course depends upon many factors, including how telomerase is activated, in what cells or tissues it is activated, the duration of the activation, the magnitude of the potential benefit, and the alternatives for the patient; in brief, the risk/benefit ratio. The most obvious way to minimize the potential risk of immortalizing a telomerase-negative tumor cell that might reside in the tissue targeted for telomerase therapy is to use transient or conditional telomerase activation. This would be possible with a pharmacological agent that stimulates telomerase in telomerase-competent cells, or with an hTERT gene therapy strategy that utilizes transient or regulated vector systems. The tumor risk could be further reduced by targeting tissues in which tumor progression is rare, and the risk/benefit ratio would be improved by targeting diseases for which effective, durable, alternative therapies are lacking. Targeting fibroblasts or keratinocytes in chronic skin ulcers, retinal pigmented epithelial cells in macular degeneration (Matsunaga et al., 1999), and certain immune cells in AIDS (Effros et al., 1996) has been considered.
The growing evidence that telomere-dependent replicative senescence may facilitate tumor initiation directly or indirectly, argues that telomerase activation may actually have a protective effect on tumor initiation or progression in elderly patients. Thus, telomerase activation could have a net beneficial effect when directed to cells in degenerative diseases, or even to immune cells in non-hematologic cancers. However, a cautious approach to telomerase activation therapy is still warranted until we more fully evaluate the risks through empirical data.
Telomerase is the critical enzyme in overcoming growth limitations due to telomere dysfunction, but it does not cause growth deregulation and hence is not an oncogene. There are, in fact, dozens of normal cell types that have been immortalized with telomerase without signs of cancerous changes, without altering differentiation capacity, and without altering pre-existing genetic abnormalities. These observations suggest a range of opportunities for the use of telomerase immortalized cells in research, disease modeling, and drug discovery, as well as telomerase activation for treatment of certain age-related diseases. Even though telomerase-mediated prevention of cell senescence and/or genetic instability of pre-crisis cells may reduce the initiation or progression of cancers, caution is still warranted in telomerase activation therapies, as the theoretical risk of immortalizing or extending the lifespan of existing tumor cells must be weighed against the potential benefits.
Killing tumor cells in cancer patients with telomerase-based strategies has never before looked so promising. Despite the complexities of telomere dynamics on cancer initiation and progression in mice, and unresolved questions in humans, it seems clear that ‘remortalizing’ a lethal tumor through effective and specific telomerase inhibition, especially for tumors with short telomeres, will improve a patient's prognosis. While advances continue to be made in the discovery of telomerase inhibitors, other approaches to specifically killing telomerase-positive tumor cells have achieved experimental support. hTERT promoter-driven suicide genes have proven effective in vitro and in animal models, and therapeutic hTERT vaccine strategies are now in human clinical studies.
Although further research in this exciting new area of biology will undoubtedly help clarify mechanisms of action and point to better, safer, and more cost-effective therapeutic approaches, it is gratifying to finally see the light at the end of the tunnel for the development of much-needed medicines based upon the telomere hypothesis of cell aging and immortalization.
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
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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Harley, C. Telomerase is not an oncogene. Oncogene 21, 494–502 (2002). https://doi.org/10.1038/sj.onc.1205076
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