Telomerase activity in human intestine

Hiyama, Eiso; Tatsumoto, Nobuhide; Kodama, Takayuki; Hiyama, Keiko; Shay, JW; Yokoyama, T.

doi:10.3892/ijo.9.3.453

Cited by 209 publications

(256 citation statements)

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“…Age-dependent loss of telomeric DNA has been observed in both lymphocytes and neutrophils (Vaziri et al, 1993) as well as in other tissues (Hiyama et al, 1996;Wright and Shay, 2005). The length of telomeres in adult blood leucocytes was reported to be shorter than that in germline cells from the same donor (Cooke and Smith, 1986).…”

Section: Telomeres and Telomerase In Haematopoietic Stem Cellsmentioning

confidence: 99%

Telomere and telomerase in stem cells

2007

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Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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Section: Telomeres and Telomerase In Haematopoietic Stem Cellsmentioning

confidence: 99%

Telomere and telomerase in stem cells

2007

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“…Therefore, some of the tumours we studied may have been removed before any of their cells acquired immortality. In contrast, the telomerase positivity rate of metastatic brain tumours was as high as that of primary cancers (Chadeneau et al, 1995;Hiyama E et al, 1995b;Hiyama K et al, 1995;Tahara et al, 1995;Sommerfeld et al, 1996). This is because metastatic brain tumour cells have already become immortal at their primary lesion stage.…”

Section: Qualitative Telomerase Activitymentioning

confidence: 99%

Telomerase activity in 144 brain tumours

Sano

Asai²,

Mishima³

et al. 1998

Br J Cancer

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Summary Unlimited proliferation in immortalized cells is believed to be highly dependent on the activity of telomerase, a ribonucleoprotein that synthesizes telomeric repeats onto chromosome ends. Using a polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) assay, we analysed telomerase activity in 99 benign and 45 malignant brain tumours. The TRAP assay results were quantitated by normalizing the telomerase activity of each specimen to that of human glioma cell line T98G to obtain the relative telomerase activity. Telomerase activity was also assessed visually from the autoradiograms as being positive or negative. One hundred and sixteen tumours with negative telomerase activity had null relative telomerase activity, whereas 28 tumours with positive telomerase activity had relative telomerase activities of 12-84.3% (mean 0% vs 36.1 ± 19.3%, P < 0.0001). Thus, quantification of telomerase activity confirmed the results of the visual evaluation of telomerase activity on autoradiograms. Based on the assessment, malignant brain tumours had a higher positive rate of telomerase activity than benign tumours (57.8% vs 2.0%, P < 0.001). These data indicate that positive telomerase activity is strongly associated with malignant brain tumours and is rather rare in benign tumours, such as neurinomas or meningiomas.

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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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Telomerase activity in human intestine

Cited by 209 publications

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Telomere and telomerase in stem cells

Telomere and telomerase in stem cells

Telomerase activity in 144 brain tumours

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

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