Amplification of the <i>telomerase reverse transcriptase</i> (<i>hTERT</i>) gene in cervical carcinomas

Zhang, Anju; Zheng, Chengyun; Hou, Mi; Lindvall, Charlotta; Wallin, Keng-Ling; Ángström, T; Yang, Xiaoyan; Hellström, Ann‐Cathrin; Blennow, Elisabeth; Björkholm, Magnus; Zetterberg, Anders; Gruber, Astrid; Xu, Dawei

doi:10.1002/gcc.10071

Cited by 92 publications

(125 citation statements)

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“…In FISH analysis, about half of the cases demonstrated 3 hTERT gene copies per nucleus. These data are in agreement with previous studies showing that hTERT amplification is a common finding in epithelial and brain tumors, [18][19][20] but the association between this feature and telomerase activity has not been evaluated. In our study of colorectal cancer, no significant association between hTERT gene copy number and hTERT RNA expression or telomerase activity levels could be demonstrated, indicating that this factor is of no or minor importance for the expression of telomerase in colorectal cancer.…”

Section: Discussionsupporting

confidence: 89%

“…17 Interestingly, amplification (or increase in gene copy number) of the hTERT gene at chromosome 5p15.33 has been demonstrated in a significant fraction of established cell lines and malignant tumors of different origin using FISH or differential PCR. [18][19][20] Whether this increased gene dosage also results in an increased hTERT RNA expression followed by upregulation of telomerase activity has not been clarified. In a series of embryonal brain tumors, hTERT gene amplification was associated with increased mRNA expression but telomerase activity was not studied.…”

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confidence: 99%

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hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

Palmqvist

Zhang

et al. 2005

Intl Journal of Cancer

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In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (≥ 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels. © 2005 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

Palmqvist

Zhang

et al. 2005

Intl Journal of Cancer

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“…In the two remaining tumors there was a change compared to normal tissue from the same patient, compatible with ampli®cation of one hTERT allele. Ampli®cation of the hTERT gene was also detected in another study, in 20% of primary tumors and 40% human cancer derived cell lines (Zhang et al, 2000). Ampli®cation may be the result of selection for higher expression of an active hTERT gene.…”

Section: Possible Models Of Htert Regulationmentioning

confidence: 65%

Regulation of the human telomerase reverse transcriptase gene

Ducrest¹,

Szutorisz²,

Lingner³

et al. 2002

Oncogene

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Most somatic human cells lack telomerase activity because they do not express the telomerase reverse transcriptase (hTERT) gene. Conversely, most cancer cells express hTERT and are telomerase positive. For most tumors it is not clear whether hTERT expression is due to their origin from telomerase positive stem cells or to reactivation of the gene during tumorigenesis. Telomerase negative cells lack detectable cytoplasmic and nuclear hTERT transcripts; in telomerase positive cells 0.2 to 6 mRNA molecules/cell can be detected. This suggests that expression is regulated by changes in the rate of hTERT gene transcription. In tumor cell lines hTERT expression behaves like a recessive trait, indicating that lack of expression in normal cells is due to one or several repressors. Studies with monochromosomal hybrids indicate that several chromosomes may code for such repressors. A number of transcription factors, tumor suppressors, cell cycle inhibitors, cell fate determining molecules, hormone receptors and viral proteins have been implicated in the control of hTERT expression; but these studies have not yet provided a clear explanation for the tumor speci®c expression of the hTERT gene, and the cis-acting elements which are the targets of repression in normal cells still have to be identi®ed.

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“…16 Expression of hTERT is usually inactivated in normal cells, although some cells with high rates of self-renewal, such as stem cells and cells in the intestine and ovary, depend on hTERT to maintain telomere length. [17][18][19] Overexpression of hTERT for cell immortalization or telomerase activation occurs in several ways, including increased gene copy number 20,21 and transcriptional modulation. 22,23 At the transcriptional level, the hTERT promoter does not have TATA or CAAT boxes 24 but does have several transcription factor binding sites within 1…”

Section: Introductionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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Amplification of the telomerase reverse transcriptase (hTERT) gene in cervical carcinomas

Cited by 92 publications

References 23 publications

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer

Regulation of the human telomerase reverse transcriptase gene

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

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