Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hallmark of cancer cells is the ability to proliferate indefinitely. This acquisition of an immortal lifespan usually requires the activation of telomerase, the enzyme that elongates telomeres. Human telomerase is minimally composed of the reverse transcriptase subunit hTERT, and the RNA subunit hTR. While hTR is ubiquitously expressed in human cells, the hTERT subunit is generally transcriptionally repressed in most normal somatic cells, but is illegitimately activated to restore telomerase activity in cancer cells. Indeed, in the thousands of different human tumours assayed, 85% were scored positive for telomerase activity. However, the levels of telomerase activity detected in tumour samples can vary substantially and even some normal somatic cells have been found to have low levels of enzyme activity. As the functional significance of low levels of telomerase activity is unclear, we investigated whether there is a minimum level of telomerase activity required for tumourigenesis. Using mutants of hTERT that induce varying levels of telomerase activity, we show that there does indeed exist a threshold of activity required for the processes of immortalization, transformation and tumourigenesis. Thus, low levels of activity detected in certain somatic cells would not be expected to contribute to tumourigenesis, nor does the mere detection of telomerase in cancer cells necessarily signify an immortal lifespan.
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PMID:Mutational analysis defines a minimum level of telomerase activity required for tumourigenic growth of human cells. 1237 Aug 34

Telomerase is a specialized reverse transcriptase responsible for maintaining the termini of linear chromosomes. The human enzyme is a ribonucleoprotein complex minimally comprising a catalytic protein moiety (hTERT) and an RNA subunit (hTR) which acts as the template for the reverse transcriptase reaction. Here we report expression of recombinant hTERT protein in insect cells utilizing a baculovirus expression system. The recombinant hTERT protein reconstitutes telomerase activity in the presence of hTR, either when co-expressed in insect cells or when added in vitro. Reconstitution of telomerase activity using this system will facilitate further analysis of the biochemical and biophysical properties of this enzyme.
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PMID:Reconstitution of telomerase activity utilizing human catalytic subunit expressed in insect cells. 1237 32

Expression of TERT, the reverse transcriptase component of telomerase, is necessary to convert normal human cells to cancer cells. Despite this, "telomerization" by hTERT does not appear to alter the normal properties of cells. In a cell transplantation model in which bovine adrenocortical cells form vascularized tissue structures beneath the kidney capsule in scid mice, telomerization does not perturb the functional tissue-forming capacity of the cells. This cell transplantation model was used to study the cooperation of hTERT with SV40 T antigen (SV40 TAg) and oncogenic Ras in tumorigenesis. Only cells expressing all three genes were tumorigenic; this required large T, but not small t, antigen. These cells produced a continuously expanding tissue mass; they were invasive with respect to adjacent organs and eventually destroyed the kidney. Cells expressing only hTERT or only Ras produced minimally altered tissues. In contrast, SV40 TAg alone produced noninvasive nodules beneath the kidney capsule that had high proliferation rates balanced by high rates of apoptosis. The use of cell transplantation techniques in a cell type that is able to form tissue structures with or without full neoplastic conversion allows the phenotypes produced by individual cooperating oncogenes to be observed.
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PMID:Cooperation of hTERT, SV40 T antigen and oncogenic Ras in tumorigenesis: a cell transplantation model using bovine adrenocortical cells. 1240 43

In previous work we demonstrated that various types of cultured cells with a limited life span could not reactivate DNA synthesis in the nuclei of mouse peritoneal macrophages in heterokaryons. We now investigate the role of telomerase in the process of the macrophage nucleus reactivation in heterokaryons with immortal telomerase-positive 3T3 Swiss mouse fibroblasts and human fibroblasts with introduced hTERT gene. We report that introduction of the hTERT gene into human diploid fibroblasts results in emergence of telomerase activity in these cells and the ability to induce the reactivation of DNA synthesis in the macrophage nuclei in heterokaryons. Inhibition of telomerase activity in heterokaryons by reverse transcriptase inhibitors (azidothymidine and guanosine polyphosphonate analogues) and by a 2'-O-methyl-RNA oligonucleotide anti-sense to the template region of telomerase RNA, block reactivation of DNA synthesis in macrophage nuclei without inhibiting DNA synthesis in the nuclei of fibroblasts. Our results suggest alterations (shortening or damage) in the macrophage telomere structure. As far as we know, heterokaryons with macrophages are the first cellular model for rapid investigation of the effects of telomerase inhibitors.
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PMID:Telomerase-dependent reactivation of DNA synthesis in macrophages implies alteration of telomeres. 1246 77

Four different approaches have been reviewed herein: i) nucleoside analogs as mock agents of the reverse transcriptase (hTERT) catalytic site; ii) miscellaneous molecules with unknown mechanism(s) of action; iii) inhibitors of upstream processes of regulation of the hTERT subunit; iiii) immunotherapy against immunogenic hTERT-derived peptides.
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PMID:Alternative approaches to the discovery and development of telomerase-targeted anticancer drugs. 1257 Aug 53

Telomerase activity (TA) is the most recently recognized prognostic factor in neuroblastoma, and its outstanding predictive power was documented by several studies. However, TA measurements require fresh tumor tissue that is not always available in daily clinical practice. We previously described a reverse transcriptase-polymerase chain reaction assay that we used to investigate the possible prognostic relevance of the telomerase catalytic subunit, hTERT, at the mRNA level. Because hTERT mRNA undergoes alternative splicing as a regulatory mechanism of TA, we discriminated between truncated and full-length hTERT transcripts. In a retrospective study on 124 neuroblastomas, 56 (45.2%) tumors showed spliced hTERT transcripts, whereas 30 (24.2%) contained full-length hTERT transcripts. The presence of both spliced and full-length hTERT transcripts was significantly associated with MYCN amplification. hTERT in general showed no correlation to other prognostic factors, ie, International Neuroblastoma Staging System stage, International Neuroblastoma Pathology classification grade, or age at diagnosis, whereas the presence of full-length transcripts was significantly associated with higher stages. The presence of any hTERT transcripts carried no significant prognostic information, yet full-length hTERT transcripts were highly predictive of poor outcome (P < 0.0001). In a multivariate analysis, full-length hTERT transcripts and International Neuroblastoma Pathology classification grade emerged as the sole independent predictors of event-free survival, with relative risks of 10.0 and 3.9, respectively. The strong statistical correlation of full-length hTERT transcripts with clinical outcome in neuroblastoma suggests that the reverse transcriptase-polymerase chain reaction analysis of hTERT transcripts may be equatable to TA measurements. Because this assay is well suited for archival material, it could become a useful adjunct in evaluating the prognosis of individual neuroblastoma cases.
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PMID:Full-length telomerase reverse transcriptase messenger RNA is an independent prognostic factor in neuroblastoma. 1259 34

Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) gene is the rate-limiting determinant of telomerase reactivation. The present study aims to quantitatively measure the expression of hTERT mRNA in human breast cancer, adjacent non-cancerous tissue (ANCT) and benign breast lesions, examine the association between hTERT and the clinicopathological characteristics of the cancer specimens and to explore the relationship between c-Myc and hTERT expressions. RNA was extracted from 49 breast carcinomas, 46 matched ANCT, and eight fibroadenomas. hTERT and c-Myc mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology. hTERT mRNA was present in all of the cancerous and most of ANCT specimens with levels being much higher in the cancerous tissue than in ANCT. The ratio of hTERT mRNA in tumour to that in ANCT was 2011 (95% confidence interval 373-10,853, P < 0.0001). There was no significant association between tumour hTERT expression and patient's age, tumour size, grade, nodal metastasis, estrogen receptor (ER) positivity, lymphovascular (LVI) or c-Myc expression. However, there was a weak but significant negative correlation between hTERT expression and progesterone receptor (PR) status (p = 0.04) in tumours. hTERT mRNA expression was also significantly higher in carcinomas (median = 2.61 x 10(6)) than in fibroadenomas (median = 424).We conclude that hTERT mRNA expression is significantly higher in human breast cancer than in non-cancerous breast tissue suggesting that hTERT has a potential role in breast cancer diagnosis. The hTERT mRNA levels in tumour do not seem to be associated with the patient's age or advanced tumour stage. Furthermore, hTERT mRNA expression does not correlate with c-Myc mRNA expression in breast cancer.
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PMID:hTERT expression in human breast cancer and non-cancerous breast tissue: correlation with tumour stage and c-Myc expression. 1260 27

In this study, we utilized the reverse transcriptase component of telomerase, hTERT, and human papillomavirus type 16 (HPV-16) E6 and E7 genes to transform normal and cystic fibrosis (CF) human airway epithelial (HAE) cells. One cell line, designated NuLi-1 (normal lung, University of Iowa), was derived from HAE of normal genotype; three cell lines, designated CuFi (cystic fibrosis, University of Iowa)-1, CuFi-3, and CuFi-4, were derived from HAE of various CF genotypes. When grown at the air-liquid interface, the cell lines were capable of forming polarized differentiated epithelia that exhibited transepithelial resistance and maintained the ion channel physiology expected for the genotypes. The CF transmembrane conductance regulator defect in the CuFi cell lines could be corrected by infecting from the basolateral surface using adenoviral vectors. Using nuclear factor-kappaB promoter reporter constructs, we also demonstrated that the NuLi and CuFi cell lines retained nuclear factor-kappaB responses to lipopolysaccharide. These cell lines should therefore be useful as models for studying ion physiology, therapeutic intervention for CF, and innate immunity.
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PMID:Development of cystic fibrosis and noncystic fibrosis airway cell lines. 1267 69

Telomerase, a ribonucleoprotein, is capable of adding telomeric sequences (TTAGGG hexameric repeats) to the ends of chromosomes and, thereby, halting the erosion of chromosome at each cell division. Whereas most normal somatic cells contain minimal or no detectable telomerase activity, most immortal and tumour cells exhibit significant levels of telomerase activity and show no net loss of telomere length during proliferation. The evaluation of telomerase has been proposed for diagnostic and therapeutic purposes in human cancer. Skin cancer is the most common cancer in humans; the precise molecular events in skin carcinogenesis are numerous and complicated and not yet completely clarified. In this study, we evaluated telomerase in 35 basal cell carcinomas and in 14 squamous cell carcinomas in order to determine if activation of the telomerase enzyme was a pivotal step in the development of skin cancer and whether telomerase activity levels were different between the two histotypes. A higher enzymatic level was shown to be associated with squamous cell carcinomas, while low levels were mainly detected in the basal cell histotype (chi2 test; p=0.02). Telomerase complex activity is dependent on its catalytic subunit, telomerase reverse transcriptase hTERT. By reverse transcription-PCR, using primers within the reverse transcriptase domain of hTERT, we observed a significant correlation between hTERT expression and telomerase activity in our skin tumour samples (p=0.0003). We detected the presence of multiple, alternately spliced transcripts, corresponding to full-length messages as well as spliced messages with critical reverse transcriptase motifs deleted. A higher telomerase messenger level was shown to be associated with squamous cell carcinomas (chi2 test; p<0.0001), as for telomerase activity. Our results provide arguments supporting the role of telomerase in skin cancer and suggest RT-PCR of telomerase RNA as a tool easier and faster than TRAP assay to identify more aggressive malignancies among non-melanoma skin specimens.
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PMID:Evaluation of telomerase in non-melanoma skin cancer. 1268 97

Telomeres are specialized structures at the end of eukaryotic chromosomes that in vertebrates constain hundreds to thousands of tandem repeats of the sequence TTAGGG. In most human somatic cells, telomeres shorten with each cell division, eventually triggering an irreversible arrest of proliferation called cellular senescence. These observations have led to a model in which telomere length reflects the mitotic history of somatic cells. Further support for this hypothesis has come from the discovery of telomerase, a unique reverse transcriptase ribonucleoprotein that has the ability to extend 3' end of telomeres. In fibroblasts, senescence is induced by telomere attrition and depends on p53 and pRb pathways triggered by one or a few critically short telomeres. Previous studies have shown that the replicative life span of various primary human cells can be prolonged by transduction of the telomerase reverse transcriptase (hTERT) gene. The hTERT expressing cells proliferate indefinitely, without undergoing any changes associated with transformation to malignancy. Rapid progress has been made towards the goal of using tumor-specific cytolytic CD8+ T lymphocytes for the immunotherapy of cancer. These cells can be expanded in vitro and, in principle, could be used for adoptive immunotherapy. One of the major problems that remains to be solved is the finite life span of normal human T lymphocytes. In an attempt to overcome this barrier three groups have introduced hTERT cDNA into human T lymphocytes and monitored its effect on their life span. In two of these studies, hTERT significantly extended the replicative life span of CD8+ T clones, whereas this was not the case in the third study using bulk T lymphocytes. Possible explanations for these discordant results are that better growth conditions avoided culture-induced stress in the study with clones, or that clones had undergone alterations leading, for example, to the inactivation of the pRb pathway during their derivation.
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PMID:[Telomerase, elixir of life for human cells?]. 1283 17


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