Cited by 211Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenomics and Chromatin Dynamics

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Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms

Horikawa, I., Barrett, J. C.·2003·Carcinogenesis

DOI 10.1093/carcin/bgg085

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Abstract

Malignant transformation from mortal, normal cells to immortal, cancer cells is generally associated with activation of telomerase and subsequent telomere maintenance. A major mechanism to regulate telomerase activity in human cells is transcriptional control of the telomerase catalytic subunit gene, human telomerase reverse transcriptase (hTERT). Several transcription factors, including oncogene products (e.g. c-Myc) and tumor suppressor gene products (e.g. WT1 and p53), are able to control hTERT transcription when over-expressed, although it remains to be determined whether a cancer-associated alteration of these factors is primarily responsible for the hTERT activation during carcinogenic processes. Microcell-mediated chromosome transfer experiments have provided evidence for endogenous factors that function to repress the telomerase activity in normal cells and are inactivated in cancer cells. At least one of those endogenous telomerase repressors, which is encoded by a putative tumor suppressor gene on chromosome 3p, acts through transcriptional repression of the hTERT gene. The hTERT gene is also a target site for viruses frequently associated with human cancers, such as human papillomavirus (HPV) and hepatitis B virus (HBV). HPV E6 protein contributes to keratinocyte immortalization and carcinogenesis through trans-activation of the hTERT gene transcription. In at least some hepatocellular carcinomas, the hTERT gene is a non-random integration site of HBV genome, which activates in cis the hTERT transcription. Thus, a variety of cellular and viral oncogenic mechanisms converge on transcriptional control of the hTERT gene. Regulation of chromatin structure through the modification of nucleosomal histones may mediate the action of these cellular and viral mechanisms. Further elucidation of the hTERT transcriptional regulation, including identification and characterization of the endogenous repressor proteins, should lead to better understanding of the complex regulation of human telomerase in normal and cancer cells and may open up new strategies for anticancer therapy.

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Authors: Horikawa, I., & Barrett, J. C.
Affiliations: National Institutes of Health (US)
Corresponding author: Horikawa, I.
ORCID: Horikawa, I.
Barrett, J. C.
Venue: Carcinogenesis
Publisher: Oxford University Press (OUP)
Published: 2003-05-22
Volume: 24
Issue: 7
Pages: 1167-1176
ISSN: 0143-3334 (ISSN-L)
1460-2180
DOI: 10.1093/carcin/bgg085
OpenAlex: W2170172182
Cited by: 211
References: 125
Citations by year: 2026: 1 · 2025: 4 · 2024: 5 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 4 · 2014: 13 · 2013: 11 · 2012: 8
FWCI: 1.02
Type: journal article
Language: en
Open access: closed
Locations: Carcinogenesis (publishedVersion)
PubMed (publishedVersion)
Funders: Georgetown University
Korea Advanced Institute of Science and Technology
National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: hTERT, telomerase, transcriptional regulation, telomere maintenance, c-Myc, WT1, p53, E6 oncoprotein, hepatitis B virus, viral oncogenesis, chromatin structure, histone modifications, cell immortalization, hepatocellular carcinoma, cancer therapy
MeSH terms: Cell Transformation, Viral, DNA-Binding Proteins, Humans, Transcription, Genetic, Transcriptional Activation, Gene Expression Regulation, Enzymologic, Telomere, Telomerase, DNA Methylation, Papillomaviridae

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Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms

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