Telomerase Repressor Sequences on Chromosome 3 and Induction of Permanent Growth Arrest in Human Breast Cancer Cells

Cuthbert, A. P.; Bond, J.; Trott, D. A.; Gill, S.; Broni, J.; Marriott, A.; Khoudoli, G.; Parkinson, E. K.; Cooper, C. S.; Newbold, R. F.

doi:10.1093/jnci/91.1.37

Cited by 114Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenetics, Aging, and Longevity in Model Organisms

Telomerase Repressor Sequences on Chromosome 3 and Induction of Permanent Growth Arrest in Human Breast Cancer Cells

Cuthbert, A. P., Bond, J., Trott, D. A., Gill, S., Broni, J., Marriott, A., Khoudoli, G., Parkinson, E. K. +2 more·1999·JNCI Journal of the National Cancer Institute

DOI 10.1093/jnci/91.1.37

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Abstract

BACKGROUND: Activation of the enzyme telomerase, which has been associated with cellular immortality, may constitute a key step in the development of human cancer. Telomerase is repressed in most normal human somatic cells. This study was conducted, using a genetic complementation approach, with the aim of identifying and mapping the genes responsible for repressing telomerase and, simultaneously, to establish the effect of experimentally induced telomerase repression on human tumor cell growth. METHODS: Individual human chromosomes isolated from normal diploid cells and tagged with bacterial antibiotic resistance genes (for later selection) were introduced into cells of the human breast carcinoma cell line 21NT by means of microcell transfer. Selected hybrid clones were screened for telomerase activity by use of the polymerase chain reaction-based telomere repeat amplification protocol (TRAP) assay, and the proliferative fate of the hybrid clones was determined. Regions of the introduced chromosomes associated with telomerase repression were mapped using segregant hybrids and a deletion analysis that employed microsatellite DNA markers. RESULTS: Strong repression of telomerase was observed following transfer of human chromosome 3 into 21NT cells but not after transfer of chromosomes 8, 12, or 20. The vast majority of hybrid clones with repressed telomerase entered permanent growth arrest after 10-18 population doublings. Deletion analysis of nonrepressed segregant monochromosome 3 hybrids indicated two regions on the short arm of chromosome 3 (3p21.3-p22 and 3p12-21.1) where telomerase regulator genes may be located. CONCLUSIONS: Telomerase in human breast cancer cells is efficiently repressed by a gene or genes on normal human chromosome 3p, and this repression is associated with permanent growth arrest of the tumor cells.

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Normal human chromosomes 3, 4, 6, 7, 10, and 17 repress telomerase activity in some but not all cancer cells.
“Several normal human chromosomes, including chromosomes 3, 4, 6, 7, 10, and 17, have been shown to repress telomerase activity in some but not all cancer cells.(77)(78)(79)(80)(81)(82)(83)(84)(85)”
From Understanding and exploiting <i>hTERT</i> promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [79]

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ARTICLES Telomerase Repressor Sequences on Chromosome 3 and Induction of Permanent Growth Arrest in Human Breast Cancer Cells
Cuthbert, A. P., Bond, J., Trott, D. A., Gill, R., Broni, J., Marriott, A., Khoudoli, G. A., Parkinson, E. K., Cooper, C. S., & Newbold, R. F. (2015)
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Human chromosome 5 carries a putative telomerase repressor gene
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A chromosome 3-encoded repressor of the human telomerase reverse transcriptase (hTERT) gene controls the state of hTERT chromatin.
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Functional identification and mapping of a gene that represses telomerase hTERT transcription in prostate cancer cells
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Authors: Cuthbert, A. P., Bond, J., Trott, D. A., Gill, S., Broni, J., Marriott, A., Khoudoli, G., Parkinson, E. K., Cooper, C. S., & Newbold, R. F.
Affiliations: Brunel University of London (GB)
Corresponding author: Cuthbert, A. P.
ORCID: Parkinson, E. K.
Cooper, C. S.
Venue: JNCI Journal of the National Cancer Institute
Publisher: Oxford University Press (OUP)
Published: 1999-01-06
Volume: 91
Issue: 1
Pages: 37-45
ISSN: 0027-8874 (ISSN-L)
1460-2105
DOI: 10.1093/jnci/91.1.37
OpenAlex: W2102936230
Cited by: 114
References: 59
Citations by year: 2024: 1 · 2021: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1
FWCI: 13.40
Type: journal article
Language: en
Open access: closed
Locations: JNCI Journal of the National Cancer Institute (publishedVersion)
PubMed (publishedVersion)
Brunel University Research Archive (BURA) (Brunel University London) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
UEA Digital Repository (University of East Anglia) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: telomerase, chromosome 3, breast cancer, growth arrest, gene complementation, chromosome 3p, telomere repeat amplification protocol
MeSH terms: Adult, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Cell Division, Cell Fusion, Chromosomes, Chromosomes, Human, Pair 3, Female, Growth Inhibitors, Humans, Hybrid Cells, Neoplasm Proteins, Repressor Proteins, Tumor Cells, Cultured, Gene Expression Regulation, Enzymologic, Polymerase Chain Reaction, Telomere, In Situ Hybridization, Fluorescence, Gene Transfer Techniques, Telomerase

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Telomerase Repressor Sequences on Chromosome 3 and Induction of Permanent Growth Arrest in Human Breast Cancer Cells

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Integrity signals

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