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Telomerase modulates Wnt signalling by association with target gene chromatin
Open accessAbstract
Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/beta-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/beta-catenin signalling by serving as a cofactor in a beta-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior-posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert(-/-) mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/beta-catenin signalling pathway.
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“As expected, AAV9-mTERT-DN treatment increased CyclinD1 expression in a number of tissues (Fig 5A and B), in accordance with previous findings (Park et al, 2009).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Park et al, 2009
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“These results are consistent with previous findings that TERT can act as a transcriptional modulator not only in highly proliferating cells but also in terminally differentiated cells.16,27”
From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [27]
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“in agreement with the proposed role of TERT as activator of genes of the Wnt pathway (Park et al, 2009), tissues with increased TERT expression also showed increased expression of active β-catenin, as well as of its target gene cyclinD1, which in turn may mediate some of the known effects of TERT improving stem cell mobilization (Flores et al, 2005; Reya & Clevers, 2005; Sarin et al, 2005).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Park et al, 2009
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“Stable overexpression of TERT in mouse skin enhanced the ability of bulge stem cells to enter cell cycle when stimulated with phorbol esters (147).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [147]
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InfluentialMouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells
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Telomerase directly regulates NF-κB-dependent transcription
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“It is very relevant that hTERT transcriptionally activates cellular gene sets that are very similar to those induced by the Wnt pathway (47) and might reflect its ability to convert primary keratinocytes into a stem-like state (mentioned above).”
Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment
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“Higher level of β‐catenin in the nucleus also causes the expression of telomerase reverse transcriptase that identified as a characteristic of CCSC (Park et al., 2009).”
BackgroundWnt/β-catenin Signaling in Embryonic Stem Cell Self-renewal and Somatic Cell Reprogramming
Miki, T., Yasuda, S.-Y., & Kahn, M. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9275-1 · Cited by 149
“Park et al reported that telomerase directly interacts with BRG1 and serves as a cofactor in a β-catenin transcriptional complex [87].”
BackgroundPovedano, J. M., Martinez, P., Serrano, R., Tejera, Á., Gómez-López, G., Bobadilla, M., Flores, J. M., Bosch, F., & Blasco, M. A. (2018) · eLife · doi:10.7554/elife.31299 · Cited by 139
Tejera, Á. M., d’Alcontres, M. S., Thanasoula, M., Marión, R. M., Martínez, P., Liao, C., Flores, J. M., Tarsounas, M., & Blasco, M. A. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.03.011 · Cited by 157
“…morphogenesis defects in Tpp1 null skin are not associated with a defective Wnt/β-catenin pathway, a known regulator of hair follicle development in mice ( Huelsken et al., 2001, Paus et al., 1999 and Zhang et al., 2008), recently described to be regulated by TERT levels (Park et al., 2009).”
BackgroundTelomere structure and telomerase in health and disease
Gomez, D. E., Armando, R. G., Fariña, H. G., Menna, P. L., Cerrudo, C. S., Ghiringhelli, P. D., & Alonso, D. F. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1611 · Cited by 155
“Indeed, TERT can function as a transcriptional modulator of the Wnt-β-catenin signaling pathway (90).”
BackgroundJoseph, I., Tressler, R., Bassett, E., Harley, C. B., Buseman, C. M., Pattamatta, P., Wright, W. E., Shay, J. W., & Go, N. F. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0233 · Cited by 147
CST Meets Shelterin to Keep Telomeres in Check
Giraud-Panis, M.-J. E., Teixeira, M. T., Géli, V., & Gilson, É. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.08.024 · Cited by 157
Bojesen, S. E. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12083 · Cited by 143
Therapeutic Targeting of Telomerase
Jäger, K., & Walter, M. (2016) · Genes · doi:10.3390/genes7070039 · Cited by 144
“, as a cofactor in a β-catenin transcriptional complex [12], which plays a role in embryogenesis and development [13].”
BackgroundTelomere Length as Cardiovascular Aging Biomarker
De Meyer, T., Nawrot, T., Bekaert, S., De Buyzere, M. L., Rietzschel, E. R., & Andrés, V. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.06.014 · Cited by 139
Transcriptional outcome of telomere signalling
Ye, J., Renault, V. M., Jamet, K., & Gilson, É. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3743 · Cited by 152
Strong, M. A., Vidal-Cardenas, S. L., Karim, B. O., Yu, H. M., Guo, N., & Greider, C. W. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05312-11 · Cited by 136
“A previous publication (60) suggested that some mTERT / mice have missing ribs, which was interpreted as a Wnt pathway developmental defect.”
BackgroundInfluentialLiu, Y., Yang, M., Luo, J., & Zhou, H. (2020) · International Journal of Oral Science · doi:10.1038/s41368-020-00087-0 · Cited by 139
“In addition, the high expression of telomerase in CSCs helped maintain their self-renewal ability by playing a role in preventing DNA telomere shortening during cell division, thus allowing cells to proliferate indefinitely,(91) and promoting EMT of CSCs while still maintaining their stemness.(92,93) Therefore, the al…”
BackgroundHu, C.-J., Ni, Z., Li, B., Yong, X., Yang, X., Zhang, J.-W., Zhang, D., Qin, Y., Jie, M., Dong, H. F., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309322 · Cited by 128
Epigenetic regulation of aging stem cells
Pollina, E. A., & Brunet, A. (2011) · Oncogene · doi:10.1038/onc.2011.45 · Cited by 111
“Consistent with its prominent role in stem cell proliferation independent of its reverse transcriptase activity, TERT is a pivotal component of the transcriptional complex downstream of WNT signaling (Choi et al., 2008; Park et al., 2009).”
BackgroundDing, D., Peng, X., Zhou, J., Wang, M., & Cong, Y. (2013) · The FASEB Journal · doi:10.1096/fj.13-230904 · Cited by 132
“Recent findings suggest that telomerase acts as a transcriptional modulator of the Wnt- catenin signaling pathway and as an RNA-dependent RNA polymerase (10, 18).”
BackgroundShkreli, M., Sarin, K. Y., Pech, M. F., Papeta, N., Chang, W., Brockman, S. A., Cheung, P., Lee, E. Y., Kuhnert, F., Olson, J. L., et al. (2011) · Nature Medicine · doi:10.1038/nm.2550 · Cited by 129
“Based on our previous studies linking telomerase to the Wnt program 22–24 , we hypothesized that activation of Wnt signaling may underlie podocyte activation in i-TERT mice.”
Self-citationHrdličková, R., Nehyba, J., & Bose, H. R. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00550-12 · Cited by 133
“The activation of the Wnt pathway has been correlated with the ability of the human TERT protein to stimulate cell proliferation (49).”
BackgroundInfluentialTelomeres and telomerase in prostate cancer development and therapy
Graham, M. K., & Meeker, A. K. (2017) · Nature Reviews Urology · doi:10.1038/nrurol.2017.104 · Cited by 125
Rheumatoid Arthritis: A Role for Immunosenescence?
Lindström, T. M., & Robinson, W. H. (2010) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2010.02965.x · Cited by 124
New prospects for targeting telomerase beyond the telomere
Arndt, G. M., & MacKenzie, K. L. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.55 · Cited by 120
LIG4 mediates Wnt signalling-induced radioresistance
Jun, S., Jung, Y., Suh, H. N., Wang, W., Kim, M. J., Oh, Y. S., Lien, E. M., Shen, X. H., Matsumoto, Y., McCrea, P. D., et al. (2016) · Nature Communications · doi:10.1038/ncomms10994 · Cited by 117
Self-citationRejuvenating the immune system in rheumatoid arthritis.
Weyand, C. M., Fujii, H., Shao, L., & Goronzy, J. J. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.180 · Cited by 112
The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels
Griffin, C. T., Curtis, C. D., Davis, R. B., Muthukumar, V., & Magnuson, T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013751108 · Cited by 109
“Previous studies have shown that BRG1 and β-catenin coregulateWnt signaling in nonvascular cells by mediating chromatin remodeling and transcriptional activation of Wnt target genes (32, 33).”
BackgroundLiu, N., Ding, D., Hao, W., Yang, F., Wu, X., Wang, M., Xu, X., Ju, Z., Liu, J., Song, Z., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw549 · Cited by 112
“It is therefore possible that hTERT recruits different proteins (Sp1, p65, Brg1 or -catenin) (34,40) and forms different protein complexes to regulate specific gene expression dependent on the target gene promoters and the cellular context.”
BackgroundTCFs and Wnt/β-catenin Signaling
Cadigan, K. M. (2012) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-386499-4.00001-x · Cited by 108
Maintenance of tumor initiating cells of defined genetic composition by nucleostemin
Okamoto, N., Yasukawa, M., Nguyen, C. L., Kasim, V., Maida, Y., Possemato, R., Shibata, T., Ligon, K. L., Fukami, K., Hahn, W. C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015171108 · Cited by 107
“Recent work indicates that TERT regulates stem cell homeostasis independent of its function at telomeres (32) and that TERT, together with BRG1, modulates stem cell homeostasis by modulating the WNT/β-catenin signaling pathway (35).”
BackgroundTreating Cancer by Targeting Telomeres and Telomerase
Ivancich, M., Schrank, Z., Wojdyla, L. M., Leviskas, B., Kuckovic, A., Sanjali, A., & Puri, N. (2017) · Antioxidants · doi:10.3390/antiox6010015 · Cited by 109
Role of CDKN2A/p16 expression in the prognostication of oral squamous cell carcinoma
Padhi, S. S., Roy, S., Kar, M., Saha, A., Roy, S., Adhya, A. K., Baisakh, M. R., & Banerjee, B. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.07.030 · Cited by 109
HiChIRP reveals RNA-associated chromosome conformation
Mumbach, M. R., Granja, J. M., Flynn, R. A., Roake, C. M., Satpathy, A. T., Rubin, A. J., Qi, Y., Jiang, Z., Shams, S., Louie, B. H., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0407-x · Cited by 102
Self-citationCHUNG, S. S., Aroh, C., & Vadgama, J. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083971 · Cited by 107
TERT activation targets DNA methylation and multiple aging hallmarks
Shim, H. S., Iaconelli, J., Shang, X., Li, J., Lan, Z. D., Jiang, S., Nutsch, K., Beyer, B. A., Lairson, L. L., Boutin, A. T., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.048 · Cited by 104
Acetylsalicylic Acid Treatment Improves Differentiation and Immunomodulation of SHED
Liu, Y., Chen, C., Liu, S., Liu, D., Xu, X., Chen, X., & Shi, S. (2014) · Journal of Dental Research · doi:10.1177/0022034514557672 · Cited by 102
“Recently, evidence has suggested that TERT can regulate the Wnt/β-catenin pathway (Choi et al. 2008; Park et al. 2009).”
BackgroundNon-canonical Roles of Telomerase: Unraveling the Imbroglio
Ségal-Bendirdjian, E., & Géli, V. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00332 · Cited by 106
Separation of telomerase functions by reverse genetics
Mukherjee, S., Firpo, E. J., Wang, Y., & Roberts, J. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112414108 · Cited by 104
“Recent studies have shown that mTERT interacts with Brg-1, which binds β-catenin, and is thereby recruited to Wnt target genes, activating their transcription (16, 17).”
BackgroundInfluential
Metadata
- Authors
- Park, J.-I., Venteicher, A. S., Hong, J. Y., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., McLaughlin, M., Veenstra, T. D., Nusse, R., McCrea, P. D., & Artandi, S. E.
- Affiliations
- Stanford Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- National Cancer Institute (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Artandi, Steven E.
- ORCID
- Venue
- Nature
- Published
- 2009-07
- Volume
- 460
- Issue
- 7251
- Pages
- 66-72
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4349391
- OpenAlex
- W2086316954
- Cited by
- 707
- References
- 51
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 23 · 2023: 41 · 2022: 32 · 2021: 48 · 2020: 48 · 2019: 34 · 2018: 38 · 2017: 29 · 2016: 43 · 2015: 48 · 2014: 58 · 2013: 58 · 2012: 60
- FWCI
- 21.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (CA111691, R01CA125453, CA125453, R01CA111691, P30CA124435)
- National Institute of General Medical Sciences (R01GM052112)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- telomerase, telomerase reverse transcriptase, Wnt/β-catenin signaling, SMARCA4, chromatin remodeling, transcriptional regulation, epidermal stem cells, stem cell self-renewal, carcinogenesis, anterior-posterior axis, homeotic transformation, promoter, SWI/SNF complex
- MeSH terms
- Animals, Cell Line, Choristoma, Chromatin, DNA Helicases, HeLa Cells, Humans, Intestine, Small, Nuclear Proteins, Oocytes, Plasmids, Promoter Regions, Genetic, Transcription Factors, Xenopus laevis, Signal Transduction, Genes, Reporter, Telomerase, Somites, Wnt Proteins, beta Catenin, Mice, Wnt3 Protein
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