A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita

Fernández, Rafael; Johnson, F. Brad

doi:10.1111/nyas.13692

Cited by 11 publications

(9 citation statements)

References 103 publications

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“…Given that telomerase expression is also positively regulated by Wnt in the context of stem cells and cancer (Hoffmeyer et al, 2012), the results indicate that the Wnt signaling pathway, telomerase expression, and telomere capping by shelterin proteins mutually reinforce themselves through a positive feedback loop (Yang et al, 2017). In the light of these results, the same team proposed that the developmental transformations in the axial skeleton that were observed in G1 mTERT −/− could be due to the presence of one or a few numbers of single aberrantly shortened telomere in the germline of the parents TERT +/− that were used to create the G1 TERT −/− mice (Fernandez and Johnson, 2018). Whether one or a few uncapped telomeres could downregulate the canonical WNT signaling pathway remains an open question.…”

Section: Tert and The Wnt/β-catenin Pathway: Autopsy Of A Controversymentioning

confidence: 99%

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

Ségal-Bendirdjian

Géli

2019

Front. Cell Dev. Biol.

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Telomerase plays a critical role in stem cell function and tissue regeneration that depends on its ability to elongate telomeres. For nearly two decades, it turned out that TERT regulates a broad spectrum of functions including signal transduction, gene expression regulation, and protection against oxidative damage that are independent of its telomere elongation activity. These conclusions that were mainly obtained in cell lines overexpressing telomerase were further strengthened by in vivo models of ectopic expression of telomerase or models of G1 TERT knockout mice without detectable telomere dysfunction. However, the later models were questioned due to the presence of aberrantly shortened telomere in the germline of the parents TERT +/− that were used to create the G1 TERT −/− mice. The physiological relevance of the functions associated with overexpressed telomerase raised also some concerns due to artifactual situations and localizations and complications to quantify the level of TERT. Another concern with non-canonical functions of TERT was the difficulty to separate a direct TERT-related function from secondary effects. Despite these concerns, more and more evidence accumulates for non-canonical roles of telomerase that are non-obligatory extra-telomeric. Here, we review these non-canonical roles of the TERT subunit of telomerase. Also, we emphasize recent results that link TERT to mitochondria and protection to reactive oxygen species suggesting a protective role of TERT in neurons. Throughout this review, we dissect some controversies regarding the non-canonical functions of telomerase and provide some insights to explain these discrepancies. Finally, we discuss the importance of understanding these alternative functions of telomerase for the development of anticancer strategies.

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Section: Tert and The Wnt/β-catenin Pathway: Autopsy Of A Controversymentioning

confidence: 99%

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

Ségal-Bendirdjian

Géli

2019

Front. Cell Dev. Biol.

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“…Our previous work uncovered a positive feedback loop between Wnt signaling and telomeres in the intestine (Woo et al, 2016;Yang et al, 2017). Here we show that aspects of the Wnt-telomere feedback loop appear to be at play in AT2 cells (Fernandez and Johnson, 2018), arguing that this connection between Wnt and telomeres is present not just in proliferative tissues such as the intestine, but also in lung cells, cells from a tissue that are normally quiescent but proliferate in response to injury. Previous work highlighted the importance of telomerase during alveolar regeneration (Driscoll et al, 2000;Lee et al, 2009).…”

Section: Discussionmentioning

confidence: 67%

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Fernández

Gardner

Slovik

et al. 2020

Preprint

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Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC related pathologies.

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“…WNT and TERT are also linked by their relationship to telomere capping [97,98]. Late generation Terc −/− mice show telomere shortening leading to uncapping.…”

Section: Interactions Between Tert and β-Catenin In Cultured Cells And Animal Modelsmentioning

confidence: 99%

“…Late generation Terc −/− mice show telomere shortening leading to uncapping. These capping defects can downregulate WNT/β-catenin signaling in high turnover cells, and WNT agonists can rescue the effects [98]. This rescue is not mediated by telomere lengthening but by increased expression of Shelterin complex proteins (Trf2 and Pot1a) [98].…”

Section: Interactions Between Tert and β-Catenin In Cultured Cells And Animal Modelsmentioning

confidence: 99%

“…These capping defects can downregulate WNT/β-catenin signaling in high turnover cells, and WNT agonists can rescue the effects [98]. This rescue is not mediated by telomere lengthening but by increased expression of Shelterin complex proteins (Trf2 and Pot1a) [98]. This group proposed that the phenotype observed by Park et al may be due to the presence of a shortened telomere in the Tert +/− parent that led to the downregulation of WNT/β-catenin signaling at some critical phase of development of the G1 Tert −/− offspring [98].…”

Section: Interactions Between Tert and β-Catenin In Cultured Cells And Animal Modelsmentioning

confidence: 99%

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Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma

Kotiyal

Evason

2021

Cancers

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Hepatocellular carcinoma (HCC) is one of the deadliest human cancers. Activating mutations in the telomerase reverse transcriptase (TERT) promoter (TERTp) and CTNNB1 gene encoding β-catenin are widespread in HCC (~50% and ~30%, respectively). TERTp mutations are predicted to increase TERT transcription and telomerase activity. This review focuses on exploring the role of TERT and β-catenin in HCC and the current findings regarding their interplay. TERT can have contradictory effects on tumorigenesis via both its canonical and non-canonical functions. As a critical regulator of proliferation and differentiation in progenitor and stem cells, activated β-catenin drives HCC; however, inhibiting endogenous β-catenin can also have pro-tumor effects. Clinical studies revealed a significant concordance between TERTp and CTNNB1 mutations in HCC. In stem cells, TERT acts as a co-factor in β-catenin transcriptional complexes driving the expression of WNT/β-catenin target genes, and β-catenin can bind to the TERTp to drive its transcription. A few studies have examined potential interactions between TERT and β-catenin in HCC in vivo, and their results suggest that the coexpression of these two genes promotes hepatocarcinogenesis. Further studies are required with vertebrate models to better understand how TERT and β-catenin influence hepatocarcinogenesis.

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A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita

Cited by 11 publications

References 103 publications

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma

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