Telomerase activity level, but not hTERT mRNA and hTR level, regulates telomere length in telomerase-reconstituted primary fibroblasts

Swiggers, Susan J. J.; Nibbeling, H.Arno J; Zeilemaker, Annelieke; Kuijpers, Marianne A.; Mattern, Karin; Zijlmans, J. M. J. M.

doi:10.1016/j.yexcr.2004.03.028

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…In nontransformed human cells telomere length is longer in cells with higher telomerase activity levels (Yi et al, 2001;Swiggers et al, 2004). In cancer cells, however, telomere length is mostly shorter in cells with higher telomerase activity or not related to telomerase levels at all (Yan et al, 2002).…”

Section: Discussionmentioning

confidence: 95%

“…corresponds to a telomeric restriction fragment (TRF) size of $7 kb. This calculation was based on a telomere length analysis of 24 telomerase-positive fibroblast clones using both Q-FISH (data not shown) and flow-FISH methods and TRF analysis (Swiggers et al, 2004). Notably, AML with loss or gain of chromosome parts was invariably characterized by critical shortening of telomeric DNA (Fig.…”

Section: Aml With Loss or Gain Of Chromosome Parts Is Characterized Bmentioning

confidence: 99%

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Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes

Swiggers

Kuijpers

Cort

et al. 2005

Genes Chromosomes & Cancer

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Telomeres, nucleoprotein complexes at chromosome ends, protect chromosomes against end-to-end fusion. Previous in vitro studies in human fibroblast models indicated that telomere dysfunction results in chromosome instability. Loss of telomere function can result either from critical shortening of telomeric DNA or from loss of distinct telomere-capping proteins. It is less clear whether telomere dysfunction has an important role in human cancer development in vivo. Acute myeloid leukemia (AML) is a good model to study mechanisms that generate chromosome instability in human cancer development because distinct groups of AML are characterized either by aberrations that theoretically could result from telomere dysfunction (terminal deletions, gains/losses of chromosome parts, nonreciprocal translocations), or aberrations that are unlikely to result from telomere dysfunction (e.g., reciprocal translocations or inversions). Here we demonstrate that AML with multiple chromosome aberrations that theoretically could result from telomere dysfunction is invariably characterized by critically short telomeres. Short telomeres in this group are not associated with low telomerase activity or decreased expression of essential telomeric capping proteins TRF2 and POT1. In contrast, telomerase activity levels are significantly higher in AML with short telomeres. Notably, short telomeres in the presence of high telomerase may relate to significantly higher expression of TRF1, a negative regulator of telomere length. Our observations suggest that, consistent with previous in vitro fibroblast models, age-related critical telomere shortening may have a role in generating chromosome instability in human AML development.

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Section: Discussionmentioning

confidence: 95%

Section: Aml With Loss or Gain Of Chromosome Parts Is Characterized Bmentioning

confidence: 99%

Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes

Swiggers

Kuijpers

Cort

et al. 2005

Genes Chromosomes & Cancer

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“…Significant discrepancies between TERT mRNA expression and telomerase activity have also been identified in soft tissue sarcomas [87] and non-small cell lung cancer [88]. Additionally, expression levels of TERT mRNA do not regulate telomerase activity in telomerase-reconstituted primary human fibroblast clones [89].…”

Section: Discussionmentioning

confidence: 99%

Acute Exercise Leads to Regulation of Telomere-Associated Genes and MicroRNA Expression in Immune Cells

Chilton

Marques

West³

et al. 2014

PLoS ONE

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Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.

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“…These studies may indicate that telomerase expression is increased early at BE stage, however levels of hTR and hTERT do not reflect telomerase activity, the ability of enzyme to add telomeric repeats. Although hTERT mRNA expression correlates with telomerase activity in many cancers, it does not measure telomerase activity,(45) which depends on posttranscriptional and posttranslational modifications of hTERT including phosphorylation of hTERT protein, assembly into telomerase holoenzyme, and its association with other proteins, such as hsp90 and p23 etc. (6, 20)…”

Section: Introductionmentioning

confidence: 99%

Telomere Maintenance in Laser Capture Microdissection–Purified Barrett's Adenocarcinoma Cells and Effect of Telomerase Inhibition In vivo

Shammas

Qazi

Batchu

et al. 2008

Clinical Cancer Research

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Purpose: The aims of this study were to investigate telomere function in normal and Barrett's esophageal adenocarcinoma (BEAC) cells purified by laser capture microdissection and to evaluate the effect of telomerase inhibition in cancer cells in vitro and in vivo. Experimental Design: Epithelial cells were purified from surgically resected esophagi. Telomerase activity was measured by modified telomeric repeat amplification protocol and telomere length was determined by real-time PCR assay. To evaluate the effect of telomerase inhibition, adenocarcinoma cell lines were continuously treated with a specific telomerase inhibitor (GRN163L) and live cell number was determined weekly. Apoptosis was evaluated by Annexin labeling and senescence by h-galactosidase staining. For in vivo studies, severe combined immunodeficient mice were s.c. inoculated with adenocarcinoma cells and following appearance of palpable tumors, injected i.p. with saline or GRN163L. Results: Telomerase activity was significantly elevated whereas telomeres were shorter in BEAC cells relative to normal esophageal epithelial cells. The treatment of adenocarcinoma cells with telomerase inhibitor, GRN163L, led to loss of telomerase activity, reduction in telomere length, and growth arrest through induction of both the senescence and apoptosis. GRN163L-induced cell death could also be expedited by addition of the chemotherapeutic agents doxorubicin and ritonavir. Finally, the treatment with GRN163L led to a significant reduction in tumor volume in a subcutaneous tumor model. Conclusions: We show that telomerase activity is significantly elevated whereas telomeres are shorter in BEAC and suppression of telomerase inhibits proliferation of adenocarcinoma cells both in vitro and in vivo.

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Telomerase activity level, but not hTERT mRNA and hTR level, regulates telomere length in telomerase-reconstituted primary fibroblasts

Cited by 16 publications

References 35 publications

Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes

Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes

Acute Exercise Leads to Regulation of Telomere-Associated Genes and MicroRNA Expression in Immune Cells

Telomere Maintenance in Laser Capture Microdissection–Purified Barrett's Adenocarcinoma Cells and Effect of Telomerase Inhibition In vivo

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