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The aim of this study was to investigate telomerase reactivation, to quantitatively measure the human telomerase reverse transcriptase (hTERT) content and telomerase activity level (TA) in routine histological and cytological samples, and to examine the relationship between these values and morphological factors. We analyzed 86 (35 cytological and 51 histological) lesions which were divided into four main groups: renal tumors, soft tissue tumors, bladder-urine and thyroid gland lesions. The relative expression of mRNA of hTERT was examined by real-time polymerase chain reaction (RT-PCR). Almost all of the renal cell carcinomas showed TA. In soft tissue tumors no correlation was seen between TA and histogenesis, aggressiveness and prognosis. Concerning cytological material a very good correlation was seen between TA and the benign or malignant nature of these tumors (92.3% specificity and 60% sensitivity). Our results indicated that TA can be used beside histology also in cytologic samples, for example in the preoperative differential diagnosis of the thyroid gland lesions and urine samples. Telomerase reactivation may not play an important role in tumorigenesis in STT. Useful observations can be made by concentrating not only on one group of diseases or localization but the unselected analysis of routine diagnostic cases can also be of help both in diagnosis and therapy.
Int J Mol Med 2004 Feb
PMID:Measuring telomerase activity in various human tumors in routine histology and cytology. 1471 39

Uterine endometrium displays telomerase activity in a menstrual cycle-dependent manner, despite its somatic origin. This study was performed to elucidate the regulation of telomerase in human endometrium. Telomerase activity and human telomerase reverse transcriptase mRNA expression in proliferative endometrium were significantly stronger than those in secretory endometrium. Their expression was only detected in epithelial cells, although stromal cells also showed proliferation. The growth of epithelial cells decreased day by day in accordance with the decline of telomerase activity. Telomerase activity was significantly stronger in co-cultures of epithelial and stromal cells than in cultures of epithelial cells alone. Moreover, the telomerase activity of co-cultured cells was increased by estradiol or basic fibroblast growth factor, whereas that of epithelial cells cultured alone showed no change. Thus, human endometrium shows reversible telomerase activation during the menstrual cycle, unlike cancer tissues. Also, the telomerase activity of uterine endometrial epithelial cells might be modulated by paracrine effectors released from stromal cells, and not only by the direct action of sex steroids such as estradiol and progesterone.
Int J Mol Med 2004 Mar
PMID:Telomerase activation in endometrial epithelial cells by paracrine effectors from stromal cells in primary cultured human endometrium. 1476 74

The expression of telomerase in human cells is strictly controlled by multiple mechanisms including transcription and alternative splicing of telomerase reverse transcriptase (hTERT). In this study, we demonstrated the possibility of modulating the hTERT splicing pattern in DU145 human prostate carcinoma cells through the use of 2'-O-methyl-RNA phosphorothioate oligonucleotides targeting the splicing site located between intron 5 and exon 6 in the hTERT pre-mRNA. An 18-h oligonucleotide exposure induced a decrease in the full-length hTERT transcript and a concomitant increase in the alternatively spliced transcripts, which resulted in significant inhibition of telomerase catalytic activity. Moreover, exposure to the R7 oligomer (which induced the most pronounced modulation of the hTERT splicing pattern and the greatest telomerase inhibition) caused a marked reduction in DU145 cell growth and the induction of apoptosis starting 2 days after treatment. Such data support the concept that down-regulation of hTERT expression can cause short-term effects on tumour cell growth, which are telomere-shortening independent.
Cell Mol Life Sci 2004 Jul
PMID:Oligomer-mediated modulation of hTERT alternative splicing induces telomerase inhibition and cell growth decline in human prostate cancer cells. 1524 52

TIN2 is a negative regulator of telomere elongation that interacts with telomeric DNA repeat binding factor 1 (TRF1) and affects telomere length by a telomerase-dependent mechanism. Here we show that inactivation of the mouse TRF1-interacting protein 2 (TIN2) gene results in early embryonic lethality. We further observed that the embryonic lethality of TIN2 mutant mice was not affected by inactivation of the telomerase reverse transcriptase gene, indicating that embryonic lethality is not the result of telomerase-dependent changes in telomere length or function. Our findings suggest that TIN2 has a role independent of telomere length regulation that is essential for embryonic development and cell viability.
Mol Cell Biol 2004 Aug
PMID:Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway. 1525 30

Activation of telomerase plays a critical role in unlimited proliferation and immortalization of cells. Telomerase activity has been shown to correlate with tumor progression, indicating that tumors expressing this enzyme possess aggressive clinical behavior and that telomerase activity may be a useful biomarker for early detection of cancer. However, measurements of telomerase activity by current methods such as telomeric repeat amplification protocol (TRAP)/polymerase chain reaction (PCR) or antibody-based radioimmunoassay (RIA) are low-throughput and not robust enough to easily accommodate the required statistical analysis to determine whether telomerase activity is a practical biomarker. As part of the National Cancer Institute Early Detection Research Network of analytical validation, we have developed a robot assisted TRAP assay (RApidTRAP) of telomerase, a potential biomarker for cancer early detection. Measurements of human telomerase reverse transcriptase catalytic subunit (hTERT) mRNA were performed in concert with measurement of telomerase activity. For this purpose we determined hTERT mRNA concentration and telomerase activity in human normal (RPE-28) and cancer (A549) cell lines as well as in human serum (SRM 1951A). Telomerase activity measurements were made using the TRAP/PCR capillary electrophoresis (CE) method on (50 to 1000) cells/reaction isolated from cell extracts. Measurement of hTERT mRNA was made using specific primers and probes on a LightCycler in the range of (10 to 7000) cells/reaction. Comparison of high-throughput telomerase activity measurements using the robot and those performed manually were consistent in sensitivity and reproducibility. Using this combination of telomerase activity and hTERT mRNA measurements, the automated system improved efficiency over traditional TRAP/PCR methods.
J Mol Diagn 2004 Aug
PMID:Analytical validation of telomerase activity for cancer early detection: TRAP/PCR-CE and hTERT mRNA quantification assay for high-throughput screening of tumor cells. 1526 91

Reversible histone acetylation, governed dynamically by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a pivotal role in regulation of gene expression through remodeling chromatin structure. Manipulation of the equilibrium between acetylation and deacetylation of histones by specific HDAC inhibitors is thus a useful tool to study functional role(s) for histone hyper-/hypoacetylation in controlling gene transcription and many other cellular activities. By using the trans-activating effect of trichostatin A (TSA), a widely used HDAC inhibitor, on the telomerase reverse transcriptase (hTERT) gene as an example, we summarize various aspects of HDAC inhibitors and provide a general strategy for their in vitro application in studies of gene regulation.
Methods Mol Biol 2004
PMID:Inhibition of histone deacetylases. 1527 6

Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT(+/-) heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR(+/-) heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.
Mol Cell Biol 2004 Aug
PMID:Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo. 1528 3

A number of recent studies indicate that programmed + 1 ribosomal frameshifting is frequently required for the expression of genes in species of the genus Euplotes. In E. crassus, three genes encoding the telomerase reverse transcriptase (TERT) subunit have been previously found to possess one or two + 1 frameshift sites. To examine the origin of frameshift sites within the Euplotes group, we have isolated segments of the TERT gene from five Euplotes species. Coupled with phylogenetic analysis, the results indicate that one frameshift site in the TERT gene arose late in the evolution of the group. In addition, a novel frameshift site was identified in the TERT gene of E. minuta, a species where frameshifting has not been previously reported. Coupled with other studies, the results indicate that frameshift sites have arisen during the diversification of the euplotids. The results also are discussed in regard to the mutations necessary to generate frameshift sites, and the specialization of TERT protein function that has apparently occurred in E. crassus.
J Mol Evol 2004 Jun
PMID:Evolution of programmed ribosomal frameshifting in the TERT genes of Euplotes. 1546 27

Defining the key players in normal breast differentiation is instrumental to understanding how morphogenesis becomes defective during breast cancer progression. During the past 2 decades much effort has been devoted to the development of technologies for purification and expansion of primary human breast cells in culture and optimizing a relevant microenvironment, which may help to define the niche that regulates breast differentiation and morphogenesis. In contrast to the general property of cancer, normal human cells have a finite lifespan. After a defined number of population doublings, normal cells enter an irreversible proliferation-arrested state referred to as replicative senescence. To overcome this obstacle for continuous long-term studies, replicative senescence can be bypassed by treatment of cells with chemical agents such as benzopyrene, by radiation or by transfection with viral oncogenes or the gene for human telomerase (human telomerase reverse transcriptase, hTERT). A drawback of some of these protocols is a concurrent introduction of chromosomal changes, which sometimes leads to a transformed phenotype and selection of a subpopulation, which may not be representative of the tissue of origin. In recent years, we have sought to establish immortalized primary breast cells, which retain crucial characteristics of their original in situ tissue pattern. This review discusses various approaches to immortalization of breast-derived epithelial and stromal cells and the application of such cell lines for studies on human breast morphogenesis.
Cell Mol Life Sci 2004 Oct
PMID:Immortalization protocols used in cell culture models of human breast morphogenesis. 1552 59

Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) are expected to serve as an excellent alternative to bone marrow-derived human mesenchymal stem cells. However, it is difficult to study them because of their limited life span. To overcome this problem, we attempted to produce a strain of UCBMSCs with a long life span and to investigate whether the strain could maintain phenotypes in vitro. UCBMSCs were infected with retrovirus carrying the human telomerase reverse transcriptase (hTERT) to prolong their life span. The UCBMSCs underwent 30 population doublings (PDs) and stopped dividing at PD 37. The UCBMSCs newly established with hTERT (UCBTERTs) proliferated for >120 PDs. The p16INK4a/RB braking pathway leading to senescence can be inhibited by introduction of Bmi-1, a polycomb-group gene, and human papillomavirus type 16 E7, but the extension of the life span of the UCBMSCs with hTERT did not require inhibition of the p16INK4a/RB pathway. The characteristics of the UCBTERTs remained unchanged during the prolongation of life span. UCBTERTs provide a powerful model for further study of cellular senescence and for future application to cell-based therapy by using umbilical cord blood cells.
Mol Biol Cell 2005 Mar
PMID:Immortalization of human fetal cells: the life span of umbilical cord blood-derived cells can be prolonged without manipulating p16INK4a/RB braking pathway. 1564 78


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