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

Cuthbert, AP; Bond, Jacquelyn; Trott, D; Gill, Sukhmani; Broni, Jessica; Marriott, A.; Khoudoli, G; Parkinson, Eric K.; Cooper, CS; Newbold, RF

doi:10.1093/jnci/91.1.37

Cited by 109 publications

(90 citation statements)

References 42 publications

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“…However, so far no cross in which hTERT expression is dominant has been reported. On the other hand there is a number of tumor lines in which hTERT expression behaves like a recessive trait; expression is extinguished in hybrids with telomerase negative cells or by transfer of a single chromosome from a normal cell (Table 1) (Bryan et al, 1995;Cuthbert et al, 1999;Nishimoto et al, 2001). This suggests that hTERT expression in normal cells is repressed by a mechanism which is no longer functional in tumors.…”

Section: Possible Models Of Htert Regulationmentioning

confidence: 99%

“…Upon introduction of a normal chromosome 3, two renal, one breast, and one cervical carcinoma line ceased to express hTERT. Two groups using either a kidney renal carcinoma (Tanaka et al, 1998) or a breast cancer derived line (Cuthbert et al, 1999) as recipients have narrowed the region that confers repression to p14.2 ± 21.1. This region overlaps with a segment of chromosome 3 that undergoes frequent LOH in breast cancer (Maitra et al, 2001).…”

Section: Possible Models Of Htert Regulationmentioning

confidence: 99%

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Regulation of the human telomerase reverse transcriptase gene

Ducrest¹,

Szutorisz²,

Lingner³

et al. 2002

Oncogene

178

145

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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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Section: Possible Models Of Htert Regulationmentioning

confidence: 99%

Section: Possible Models Of Htert Regulationmentioning

confidence: 99%

Regulation of the human telomerase reverse transcriptase gene

Ducrest¹,

Szutorisz²,

Lingner³

et al. 2002

Oncogene

178

145

View full text Add to dashboard Cite

show abstract

“…Recently a number of laboratories have identified a putative telomerase repressor gene mapped to chromosome region 3p14-21 or 3p21-22 (Mehle et al, 1998;Cuthbert et al, 1999;Tanaka et al, 1998;Horikawa et al, 1998). For example, loss of heterozygosity at chromosome 3p correlated with telomerase activity in renal cell carcinoma (Mehle et al, 1998).…”

Section: mentioning

confidence: 99%

“…For example, loss of heterozygosity at chromosome 3p correlated with telomerase activity in renal cell carcinoma (Mehle et al, 1998). Strong repression of telomerase was observed following transfer of chromosome 3 into breast cancer cells (Cuthbert et al, 1999). In nasopharyngeal cancer patients, loss of heterozygosity or homozygous deletion at the chromosome region of 3p14-21 was often found (Huang et al, 1994;.…”

Section: mentioning

confidence: 99%

True

Chang¹,

Liao²,

Jung³

et al. 2000

Br J Cancer

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Telomerase is a specialized ribonucleoprotein polymerase that directs the synthesis of telomere repeats at chromosome ends. Accumulating evidence has indicated that telomerase is stringently repressed in normal human somatic tissues but reactivated in cancers and immortal cells, suggesting that reactivation of telomerase plays an important role in carcinogenesis. In this study, the status of telomerase activity in diseased human nasopharyngeal lesions was determined by the telomeric repeat amplification protocol (TRAP). Fifty-four patients participated including 17 inflammation or hyperplasia, eight with squamous metaplasia, and 29 with different stages of carcinomas. Telomerase activity was detected in 1 of 17 (5.9%) inflammatory or lymphoid hyperplastic tissues, 3 of 8 (37.5%) squamous metaplastic, and 25 of 29 (86.2%) carcinoma tissues. The differences in telomerase expression in these groups is statistically significant ( P < 0.001). Levels of telomerase activity correlated with tumour stage ( P = 0.024). These results suggest that telomerase reactivation plays a role in the carcinogenesis of nasopharyngeal cancer. Since telomerase activity is found in the majority of nasopharyngeal cancers and a subset of metaplasia, this enzyme may be served as a reference to monitoring the status of abnormal nasopharyngeal tissues. © 2000 Cancer Research Campaign

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“…Genetic analysis of the immortal phenotype has revealed several genetic alterations that are important to the process including the dysfunction of p53, INK4A and a gene on chromosome 3p that represses telomerase activity (Loughran et al, 1997;Parkinson et al, 1997). In addition, microcell-mediated monochromosome transfer (MMCT) experiments suggest that other cancer mortality genes may exist (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001;Forsyth et al, 2002). Loss of heterozygosity (LOH) at some of these chromosomal loci supports a role for the dysfunction of these putative mortality genes in the immortality of human SCCs (Loughran et al, 1997;Forsyth et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

et al. 2003

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Normal human keratinocytes possess a finite replicative lifespan. Most advanced squamous cell carcinomas (SCCs), however, are immortal, a phenotype that is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) at several genetic loci, suggestive of the dysfunction of other mortality genes. We show here that human chromosome 6 specifically reduces the proliferation or viability of a human SCC line, BICR31, possessing LOH across the chromosome. This was determined by an 88% reduction in colony yield (Po0.001), following the reintroduction of an intact normal chromosome 6 by monochromosome transfer. Deletion analysis of immortal segregants using polymorphic markers revealed the loss of a 2.9 Mbp interval, centred on marker D6S1045 at 6q14.3-q15, in 6/ 19 segregants. Crucially, allelic losses of this region were not identified in control hybrids constructed between chromosome 6 and the BICR6 SCC cell line that is heterozygous for chromosome 6 and which showed no reduction in colony formation relative to the control chromosome transfers. This indicates that the minimally deleted region at D6S1045 is not the result of fragile sites, a recombination hot spot, or a feature of the monochromosome transfer technique. LOH of D6S1045 was found in 2/9 immortal SCC lines and was part of a minimally deleted region of line BICR19. Furthermore, allelic imbalance, consistent with LOH, was detected in 3/ 17 advanced SCCs of the tongue. These results suggest the existence of a suppressor of SCC immortality and tumour development at chromosome 6q14.3-q15, which is important to a subset of human SCCs.

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

Abstract: 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.

Cited by 109 publications

References 42 publications

Regulation of the human telomerase reverse transcriptase gene

Regulation of the human telomerase reverse transcriptase gene

True

Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

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