Telomerase is not an oncogene

Harley, Calvin B.

doi:10.1038/sj.onc.1205076

Cited by 164 publications

(119 citation statements)

References 86 publications

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“…Forced telomerase expression in ALT models confers growth advantages under all tested conditions, including limited cellular cross-talk, low seeding number and in anchorageindependent growth assays. This growth promotion is only apparent with the inactivation of growth inhibitory signals and the absence of tumor suppressor gene functions, as constitutive telomerase activation in primary human cells did not result in changes to their growth characteristics (Kiyono et al, 1998;Harley, 2002).…”

Section: Discussionmentioning

confidence: 98%

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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Constitutive telomerase activity maintains telomere length and confers immortal phenotypes to human cancers. The prevalence of telomerase, rather than a homologous recombination-based mechanism, in telomere length maintenance suggests that telomerase also has auxiliary roles in tumorigenesis. Here, we investigate growth advantages provided by the telomerase enzyme in oncogene-transformed human cells that do not require telomerase activity for telomere length control. Our data suggest that in oncogene-transformed cells, telomerase activity accelerates cell growth kinetics in a cell cycle phase-specific manner and promotes anchorage-independent growth. Coculture experiments demonstrated that this growth advantage conferred by telomerase activity is not due to increased cellular cross-talk. Growth advantages provided by telomerase required all functional aspects of the enzyme. Dissociation-of-activity-in-telomerase mutants and other functionally defective versions of telomerase were unable to promote oncogene-transformed cell growth, suggesting that canonical telomerase activities may be involved. We conclude that telomerase provides advantages to oncogene-transformed human cells, thereby supporting the development of telomerasebased anticancer chemotherapies targeting these growthpromoting effects.

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Section: Discussionmentioning

confidence: 98%

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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“…Telomerase activity has been demonstrated in high levels in over 85% of all malignancies ). Although telomerase is not an oncogene (Harley, 2002), transfection of hTERT into normal epithelial or endothelial cells transformed with SV40 large T antigen and N-ras oncogene allows cells to bypass crisis and ultimately achieve malignancy, confirming the role of telomerase in cellular immortalisation and tumorigenesis .…”

mentioning

confidence: 85%

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines

et al. 2005

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Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 mM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.

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“…Although cellular immortalization in the vast majority of human tumors relies on derepression of the native cellular hTERT gene, telomerase is itself not widely believed to be an oncogene that is independently capable of inducing tumor formation (35). The overexpression of telomerase activity in cultured cells has failed to result in malignant change in a number of cell types, including fibroblasts (12,33), endothelial cells (15,33), skeletal muscle cells (36), and esophageal squamous cells (31).…”

Section: Discussionmentioning

confidence: 99%

Relevance and safety of telomerase for human tissue engineering

Klinger

Blum

Hearn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase upregulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.tumorigenicity ͉ smooth muscle cells ͉ vascular graft

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Telomerase is not an oncogene

Cited by 164 publications

References 86 publications

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines

Relevance and safety of telomerase for human tissue engineering

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