Telomerase modulates expression of growth-controlling genes and enhances cell proliferation
Abstract
Most somatic cells do not express sufficient amounts of telomerase to maintain a constant telomere length during cycles of chromosome replication. Consequently, there is a limit to the number of doublings somatic cells can undergo before telomere shortening triggers an irreversible state of cellular senescence. Ectopic expression of telomerase overcomes this limitation, and in conjunction with specific oncogenes can transform cells to a tumorigenic phenotype. However, recent studies have questioned whether the stabilization of chromosome ends entirely explains the ability of telomerase to promote tumorigenesis and have resulted in the hypothesis that telomerase has a second function that also supports cell division. Here we show that ectopic expression of telomerase in human mammary epithelial cells (HMECs) results in a diminished requirement for exogenous mitogens and that this correlates with telomerase-dependent induction of genes that promote cell growth. Furthermore, we show that inhibiting expression of one of these genes, the epidermal growth factor receptor (EGFR), reverses the enhanced proliferation caused by telomerase. We conclude that telomerase may affect proliferation of epithelial cells not only by stabilizing telomeres, but also by affecting the expression of growth-promoting genes.
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Apart from initiating replicative immortality, telomerase seems to play a crucial role in almost all the hallmarks of cancer, including cell growth and proliferation through activation of EGFR signaling, resistance to apoptosis through activation of NF-kB, promotion of invasion and metastasis through induction of epithelial-mesenchymal transition via the Wnt/b-catenin pathway that upregulates Snai
“It has to be noted though that apart from initiating replicative immortality, telomerase seems to play a crucial role in almost all the hallmarks of cancer, ranging from cell growth and proliferation through to the activation of EGFR signaling [182], resistance to apoptosis through activation of NF-kB [183], and the promotion of invasion and metastasis through induction of the epithelial–mesenchym”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [182]
Overexpression experiments in transgenic mice and human cells have shown TERT has activities in cellular transformation, proliferation, stem cell biology, cell survival and chromatin regulation.
“Overexpression experiments in transgenic mice and in human cells have shown that TERT exhibits activities in cellular transformation (136-138), proliferation (139), stem cell biology (140-142), cell survival (143,144) and chromatin regulation (145).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [137]
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- Authors
- Smith, L. L., Coller, H. A., & Roberts, J. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Roberts, James M.
- Venue
- Nature Cell Biology
- Published
- 2003-04-22
- Volume
- 5
- Issue
- 5
- Pages
- 474-479
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2017752436
- Cited by
- 438
- References
- 31
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 8 · 2019: 12 · 2018: 17 · 2017: 19 · 2016: 29 · 2015: 20 · 2014: 14 · 2013: 22 · 2012: 30
- FWCI
- 19.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f32ca083311-01)
- National Cancer Institute (1 F32 CA83311-01)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- telomerase, cell proliferation, telomere shortening, cellular senescence, epidermal growth factor receptor, human mammary epithelial cells, carcinogenesis, telomere stabilization, oncogenic transformation
- MeSH terms
- Breast, Cell Division, Cell Transformation, Neoplastic, Cells, Cultured, DNA Replication, Epithelial Cells, Growth Substances, Humans, Mitogens, Molecular Sequence Data, Neoplasms, Repressor Proteins, RNA, Up-Regulation, Gene Expression Regulation, Neoplastic, Cellular Senescence, Telomerase, ErbB Receptors
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