Telomerase: regulation, function and transformation

Dong, Carolyn K.; Masutomi, Kenkichi; Hahn, William C.

doi:10.1016/j.critrevonc.2004.12.005

Cited by 85 publications

(73 citation statements)

References 130 publications

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“…Functional rescue of TERT knockdown cells was accomplished using the DAT mutants but not the catalytically dead TERT variant , suggesting that this novel telomerase function is working in a non-canonical manner, separate from its role in telomere length maintenance. Corroborating this observation, functional segregation of TERT has been previously described in mouse as well as human cell models (Chang and DePinho, 2002;Dong et al, 2005). In contrast, our mutagenesis studies showed that none of the tested TERT mutants, including the same DAT mutants and other RNA-binding-deficient TERT variants, support advantageous growth kinetics, nor do they promote anchorage-independent growth in the VA13 ALT model.…”

Section: Discussionsupporting

confidence: 83%

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: Discussionsupporting

confidence: 83%

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

Fleisig

Wong

2011

Oncogene

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“…Moreover, initial tumor formation can occur independently from telomerase activation. 43 We investigated the effects of rhadinoviral vector-mediated hTERT expression on the life span and the phenotype of transduced T cells in comparison with mock-infected controls (Figure 4). Therefore, Dorf1RT-and mock-infected cells were cultivated with or without stimulation for 10 weeks.…”

Section: Ectopic Telomerase Expression Does Not Lead To Growth Transfmentioning

confidence: 99%

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

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The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T-cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression.

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“…Telomerase is able to elongate telomeres (Greider & Blackburn, 1985); however, it often has diminished activity in adults, particularly in long‐lived species (Dong, Masutomi, & Hahn, 2005; Haussmann et al., 2007; Hornsby, 2007; Stewart et al., 2002; Tollefsbol & Andrews, 2001). There is some evidence that telomerase may be more active in bone marrow, gonads, and intestine cell lines in adult birds of long‐lived species ( Sterna hirundo; Oceanodroma leucorhoa ) compared to short‐lived ones ( Taeniopygia guttata; Tachycineta bicolor ) (Haussmann et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone

Cerchiara

Risques

Prunkard

et al. 2017

Ecology and Evolution

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All species should invest in systems that enhance longevity; however, a fundamental adult life‐history trade‐off exists between the metabolic resources allocated to maintenance and those allocated to reproduction. Long‐lived species will invest more in reproduction than in somatic maintenance as they age. We investigated this trade‐off by analyzing correlations among telomere length, reproductive effort and output, and basal corticosterone in Magellanic penguins (Spheniscus magellanicus). Telomeres shorten with age in most species studied to date, and may affect adult survival. High basal corticosterone is indicative of stressful conditions. Corticosterone, and stress, has been linked to telomere shortening in other species. Magellanic penguins are a particularly good model organism for this question as they are an unusually long‐lived species, exceeding their mass‐adjusted predicted lifespan by 26%. Contrary to our hypothesis, we found adults aged 5 years to over 24 years of age had similar telomere lengths. Telomeres of adults did not shorten over a 3‐year period, regardless of the age of the individual. Neither telomere length, nor the rate at which the telomeres changed over these 3 years, correlated with breeding frequency or investment. Older females also produced larger volume clutches until approximately 15 years old and larger eggs produced heavier fledglings. Furthermore, reproductive success (chicks fledged/eggs laid) is maintained as females aged. Basal corticosterone, however, was not correlated with telomere length in adults and suggests that low basal corticosterone may play a role in the telomere maintenance we observed. Basal corticosterone also declined during the breeding season and was positively correlated with the age of adult penguins. This higher basal corticosterone in older individuals, and consistent reproductive success, supports the prediction that Magellanic penguins invest more in reproduction as they age. Our results demonstrate that telomere maintenance may be a component of longevity even with increased reproductive effort, investment, and basal corticosterone.

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Telomerase: regulation, function and transformation

Cited by 85 publications

References 130 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

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone

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