Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization
Open accessAbstract
The immortalization of human cells is a critical step during tumorigenesis. In vitro , normal human somatic cells must overcome two proliferative blockades, senescence and crisis, to become immortal. Transformation with viral oncogenes extends the life span of human cells beyond senescence. Such transformed cells eventually succumb to crisis, a period of widespread cellular death that has been proposed to be the result of telomeric shortening. We now show that ectopic expression of the telomerase catalytic subunit (human telomerase reverse transcriptase or hTERT) and subsequent activation of telomerase can allow postsenescent cells to proliferate beyond crisis, the last known proliferative blockade to cellular immortality. Moreover, we demonstrate that alteration of the carboxyl terminus of human telomerase reverse transcriptase does not affect telomerase enzymatic activity but impedes the ability of this enzyme to maintain telomeres. Telomerase-positive cells expressing this mutant enzyme fail to undergo immortalization, further tightening the connection between telomere maintenance and immortalization.
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Ectopically expressed hTERT maintains telomere length and allows unlimited growth.
“Ectopically expressed hTERT maintains telomere length and allows unlimited growth (Bodnar et al. 1998; Counter et al. 1998; Vaziri and Benchimol 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Counter et al. 1998
Telomere shortening in the absence of telomerase plays a critical role in signaling entry into senescence.
“Thus, telomere shortening in the absence of telomerase plays a critical role in signaling entry into senescence”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Counter et al. 1998
Overexpression of TERT prevents senescence and crisis in these fibroblasts.
“Senescence and crisis in these fibroblasts are effectively averted by overexpresssion of telomerase reverse transcriptase (TERT), the catalytic protein subunit of telomerase, an enzyme complex that synthesizes telomere repeats (28,29).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [29]
Transfection of cells with hTERT and subsequent expression of active telomerase extend the life spans of normal human fibroblasts and epithelial cells.
“transfection of cells with the gene encoding the human telomerase reverse transcriptase component (hTERT) and subsequent expression of active telomerase have been shown to extend the life spans of normal human fibroblasts and epithelial cells (25–27).”
From Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death (1999) · cites this paper as [27]
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- Authors
- Counter, C. M., Hahn, W. C., Wei, W., Caddle, S. D., Beijersbergen, R. L., Lansdorp, P. M., Sedivy, J. M., & Weinberg, R. A.
- Affiliations
- Brown University (US)
- The Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; and Terry Fox Laboratory, British Columbia Cancer Research Centre, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3 Canada
- Duke University (US)
- Corresponding author
- Wei, Wenyi
- Weinberg, Robert A.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-12-08
- Volume
- 95
- Issue
- 25
- Pages
- 14723-14728
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24516
- OpenAlex
- W2075808770
- Cited by
- 649
- References
- 34
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 16 · 2023: 15 · 2022: 10 · 2021: 15 · 2020: 13 · 2019: 16 · 2018: 15 · 2017: 18 · 2016: 20 · 2015: 25 · 2014: 18 · 2013: 21 · 2012: 23
- FWCI
- 24.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Massachusetts Institute of Technology
- Ludwig Institute for Cancer Research
- National Institutes of Health (5r35ca039826-10)
- National Cancer Institute (CA 39826)
- National Institute of General Medical Sciences (GM-RO1-41690)
- National Institute of Allergy and Infectious Diseases (AI 29524, R21AI029524, R01AI029524)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Organoselenium and organotellurium chemistry
- Keywords
- telomerase, hTERT, telomere maintenance, cell immortalization, replicative senescence, crisis, telomere shortening, viral oncogenes, carboxyl terminus, telomerase catalytic subunit, carcinogenesis
- MeSH terms
- Cell Division, Cell Transformation, Neoplastic, Cell Transformation, Viral, DNA-Binding Proteins, Gene Expression Regulation, Humans, Proteins, RNA, Telomere, Telomerase
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