An Investigation of the Effects of the Core Protein Telomerase Reverse Transcriptase on Wnt Signaling in Breast Cancer Cells

Listerman, Imke; Gazzaniga, Francesca S.; Blackburn, Elizabeth H.

doi:10.1128/mcb.00844-13

Cited by 49 publications

(45 citation statements)

References 44 publications

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“…In contrast to the previously described results, one study failed to find evidence for physical association of TERT with BRG1 or B-Catenin in human breast cancer lines and HeLa cells (Listerman et al 2014). Instead, these authors suggest that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of TERT with B-Catenin (Park et al 2009).…”

Section: R133 Review a Pestana And Others Tert Biology And Function Icontrasting

confidence: 55%

“…Instead, these authors suggest that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of TERT with B-Catenin (Park et al 2009). Furthermore, altering TERT levels in four different breast cancer cell lines caused minimal and discordant effects on Wnt target and Wnt pathway gene expression (Listerman et al 2014).…”

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 99%

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TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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Section: R133 Review a Pestana And Others Tert Biology And Function Icontrasting

confidence: 55%

Section: R133 Review a Pestana And Others Tert Biology And Function Imentioning

confidence: 99%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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“…22 The following lentiviruses were generated from those previously described by Li et al, 22 but the cytomegalovirus (CMV) promoter was replaced with the elongation factor 1-a promoter driving either puromycin resistance or green fluorescent protein (GFP): empty vector, scrambled-sequence shRNA (shScramble), and shTR1. shTERT was generated in the same lentiviruses based on the target sequence from Listerman et al 23 shTR2 was generated based on a previously published target sequence. 24 shBIM was generated based on the previously published target sequence.…”

Section: Plasmids and Lentivirusmentioning

confidence: 99%

An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity

Gazzaniga

Blackburn

2014

Blood

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• Telomerase RNA component hTR, but not the core enzymatic protein component hTERT, protects T cells from apoptosis.• hTR prevents dexamethasone-induced apoptosis specifically when in a telomerase enzymatically inactive state.Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long-term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasoneinduced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease. (Blood. 2014;124(25):3675-3684)

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“…However, the proposed noncanonical role of TERT in the Wnt/β-catenin signaling cascade has been controversial. Several studies have reported a lack of physical association of TERT with BRG1 or β-catenin (Listerman et al, 2014), as well as no apparent effect of TERT deficiency on phenotypes associated with Wnt signaling in TERT-knockout mice (Strong et al, 2011). Although TERT appears to regulate the expression of growth-promoting genes, this event might not be solely promoted by Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Telomerase activates transcription of cyclin D1 gene through an interaction with NOL1

Hong¹,

Lee²,

Chung³

2016

Development

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Telomerase is a ribonucleoprotein enzyme that is required for the maintenance of telomere repeats. Although overexpression of telomerase in normal human somatic cells is sufficient to overcome replicative senescence, the ability of telomerase to promote tumorigenesis requires additional activities that are independent of its role in telomere extension. Here, we identify proliferationassociated nucleolar antigen 120 (NOL1, also known as NOP2) as a telomerase RNA component (TERC)-binding protein that is found in association with catalytically active telomerase. Although NOL1 is highly expressed in the majority of human tumor cells, the molecular mechanism by which NOL1 contributes to tumorigenesis remained unclear. We show that NOL1 binds to the T-cell factor (TCF)-binding element of the cyclin D1 promoter and activates its transcription. Interestingly, telomerase is also recruited to the cyclin D1 promoter in a TERC-dependent manner through the interaction with NOL1, further enhancing transcription of the cyclin D1 gene. Depletion of NOL1 suppresses cyclin D1 promoter activity, thereby leading to induction of growth arrest and altered cell cycle distributions. Collectively, our findings suggest that NOL1 represents a new route by which telomerase activates transcription of cyclin D1 gene, thus maintaining cell proliferation capacity.

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An Investigation of the Effects of the Core Protein Telomerase Reverse Transcriptase on Wnt Signaling in Breast Cancer Cells

Cited by 49 publications

References 44 publications

TERT biology and function in cancer: beyond immortalisation

TERT biology and function in cancer: beyond immortalisation

An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity

Telomerase activates transcription of cyclin D1 gene through an interaction with NOL1

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