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)

Telomerase is a specialized type of reverse transcriptase which catalyzes the synthesis of telomeric DNA using intrinsic RNA as a template. The enzyme was originally found in a ciliate Tetrahymena, and has been extensively investigated using ciliates or budding yeast. In mammals, the enzyme is highly active in most cancer cells and germ cells, but is inactive in most somatic cells, suggesting the activation of telomerase may be important for the continued cell growth or progression of cancer cells. Recently, two protein components of the mammalian telomerase have been identified using homology to the sequencing data from unicellular eukaryotes. Interestingly, telomerase activity was induced by the expression of catalytic subunit, hTERT, in telomerase-negative normal fibroblast cells, indicating that it plays a key role in the activation of telomerase in cancer cells.
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PMID:[Structure and regulation mechanisms of telomerase]. 961 4

Telomere shortening in human somatic cells and telomere maintenance in most human immortal cell lines and tumours correlate respectively with the absence and presence of telomerase, the enzyme that synthesizes telomeric DNA de novo . However, approximately 30% of in vitro immortalized human cell lines do not express this enzyme and maintain telomeres by an alternative pathway (ALT) that may also operate in some tumours. Human telomerase is a reverse transcriptase comprising minimally an RNA subunit (hTER) and a catalytic protein moiety (hTERT). Normal somatic cells retain expression of hTER but not of hTERT, and can be converted to a telomerase-positive phenotype by ectopic expression of the catalytic protein. We similarly have restored enzymatic activity to those ALT cell lines that retain hTER expression. We also report that in those ALT cells that are hTER negative, reintroduction of both hTER and hTERT is necessary and sufficient for conversion to telomerase positivity. Moreover, transfection of these cells with hTERT in conjunction with hTERs with a mutated template results in the expression of an enzyme with altered specificity. Reconstitution of telomerase activity in ALT cells, particularly an activity capable of synthesizing mutant telomeric DNA, may be exploited for the study of the ALT mechanism and its interaction with the telomerase-dependent pathway, and for assessing the effects of mutant telomeres on cell viability.
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PMID:Reconstitution of wild-type or mutant telomerase activity in telomerase-negative immortal human cells. 961 72

Activity of telomerase, the enzyme that synthesizes the telomere ends of linear eukaryotic chromosomes, is repressed in most normal human somatic cells but induced in most human cancers. Normal human cells that lack telomerase activity progressively lose telomere sequences. In contrast, most immortalized cell lines and malignant human tumors appear to maintain constant telomere length via telomerase activity. Telomerase is composed of at least two subunits, an RNA subunit that templates telomere synthesis, and a catalytic protein subunit. The gene encoding the catalytic protein subunit of telomerase has recently been identified, first in yeast and ciliates and then in humans. This catalytic subunit belongs to the reverse transcriptase family. Studies of telomerase subunits further define a role for telomerase in the control of mammalian cell lifespan. The expression of the human telomerase catalytic subunit gene, hTERT, is induced in immortalized cells and primary tumors. When hTERT is ectopically expressed in hitherto telomerase-negative cells, telomerase enzyme activity appears, and an extended lifespan has been observed in some cells. In contrast, disruption of the mouse telomerase RNA subunit gene, mTERC, results in a delayed failure of cell proliferation. Telomerase activity therefore appears to be necessary for the prolonged survival of mammalian cells.
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PMID:Telomerase enzyme activation and human cell immortalization. 1002 30

Human fibroblasts whose lifespan in culture has been extended by expression of a viral oncogene eventually undergo a growth crisis marked by failure to proliferate. It has been proposed that telomere shortening in these cells is the property that limits their proliferation. Here we report that ectopic expression of the wild-type reverse transcriptase protein (hTERT) of human telomerase averts crisis, at the same time reducing the frequency of dicentric and abnormal chromosomes. Surprisingly, as the resulting immortalized cells containing active telomerase continue to proliferate, their telomeres continue to shorten to mean lengths below those in control cells that enter crisis. These results provide evidence for a protective function of human telomerase that allows cell proliferation without requiring net lengthening of telomeres.
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PMID:Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening. 1009 39

Telomerase is a reverse transcriptase that maintains chromosome ends, compensating for the progressive loss of DNA that occurs during replication. High telomerase enzyme activity is an unfavorable prognostic feature for several types of cancers. We investigated whether telomerase level predicts outcome for patients with the pediatric renal malignancy Wilms' tumor. In a case-cohort study of 78 patients with favorable histology Wilms' tumor, we compared tumor telomerase levels in patients with and without eventual recurrence. Three measures of telomerase were used: (a) telomerase enzyme activity; (b) expression of hTR, the RNA component of telomerase; and (c) mRNA expression of hTERT, the gene that encodes the catalytic component of the enzyme. Of the evaluable samples, 81% had detectable telomerase activity, 97% had detectable hTERT transcript, and 100% had detectable hTR. Weak correlations were observed between telomerase activity and hTR level (r = 0.34, P = 0.02) and between telomerase activity and hTERT mRNA level (r = 0.32, P = 0.04). Of the variables assessed, only hTERT mRNA expression correlated with outcome. The median hTERT mRNA level in tumors with recurrence was higher than that in tumors without recurrence (1.42 versus 0.97 units, P = 0.023, Wilcoxon). Univariate analysis of hTERT mRNA level as a continuous variable suggested that each unit increase in hTERT mRNA level increased the risk of recurrence (RR) by a factor of 1.66 [95% confidence interval (CI), 1.2-2.3; P < 0.005]. Compared with tumors with hTERT mRNA levels of 0-1 units, tumors with hTERT mRNA levels of 1-2 units had a RR of 2.72 (95% CI, 0.91-8.13; P = 0.074), and tumors with hTERT mRNA levels >2 units had a RR of 6.40 (95% CI, 1.49-27.67, P = 0.013). Multivariate analysis of hTERT mRNA level as a predictor of recurrence, adjusted for tumor stage and age at diagnosis, revealed a RR of 1.48 (95% CI, 0.9-2.6; P = 0.16). Measurement of hTERT mRNA level may, therefore, enable clinicians to identify a population of patients at high risk for recurrence and to adjust their therapy accordingly. A larger study will be necessary to determine whether hTERT expression is an independent prognostic indicator. Further biological investigation is warranted to discern whether the link between high hTERT expression and unfavorable prognosis is causative or correlative.
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PMID:High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms' tumor. 1048 76

The aim of this study is to investigate the effect of the p21 gene transfection on the growth of cultured human glioma cell lines, and analyze the telomerase activity, and detection of telomerase components in p21 transfectant. The p21 gene was transfected into human glioma cell lines, U251MG and T98G with our novel liposome. The cell growth was assessed by counting the number of trypan blue-excluding cells in a hemocytometer and flow cytometry analysis. The expression of P21 protein and its mRNA were examined by Western and Northern blot analysis. The telomerase activity was assayed by TRAP (telomerase repeat amplification protocol)/TRAP-HPA (hybridization protection assay) method qualitatively and quantitatively. The length of telomere was measured by Southern blot analysis. The expression of telomerase components (hTERT, hTERC and TEP1) were examined by RT-PCR (reverse transcriptase-polymerase chain reaction). The p21 transfectant demonstrated the expression of P21 protein and its mRNA. The p21 transfection of human glioma cells results in growth inhibition and G0/G1 arrest. The p21 transfectant revealed a decrease of telomerase activity and hTERT expression as compared with control cells. These results suggest that p21 transfection induces G0/G1 arrest in human glioma cells which associates with the reduction in the telomerase activity and hTERT expression.
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PMID:Growth inhibition of human glioma cells by transfection-induced P21 and its effects on telomerase activity. 1093 98

Telomerase, the enzyme that maintains the ends of chromosomes, is absent from the majority of somatic cells but is present and active in most tumours. The gene for the reverse transcriptase component of telomerase (hTERT) has recently been identified. A cDNA clone of this gene was used as a probe to identify three genomic bacterial artificial chromosome (BAC) clones, one of which was used as a probe to map hTERT by fluorescence in situ hybridization (FISH) to chromosome 5p15.33. This BAC probe was further used to look at copy number of the hTERT region in immortal cell lines. We found that 10/15 immortal cell lines had a modal copy number of 3 or more per cell, with one cell line (CaSki) having a modal copy number of 11. This suggests that increases in copy number of the hTERT gene region do occur, and may well be one route to upregulating telomerase levels in tumour cells. 5p15 gains and amplifications have been documented for various tumour types, including non-small cell lung carcinoma, squamous cell carcinoma of head and neck, and uterine cervix cancer, making hTERT a potential target.
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PMID:Mapping of the gene for the human telomerase reverse transcriptase, hTERT, to chromosome 5p15.33 by fluorescence in situ hybridization. 1093 4

In the past decade, a great deal has been learnt about the maintenance of telomeres in mammalian cells by the specialized reverse transcriptase, telomerase, and its associated proteins. The catalytic component of telomerase, hTERT, appears to be selectively activated in the vast majority of tumors relative to most somatic cells suggesting that its inhibition may result in antitumor effects. Although beset with some unusual issues as a drug target, recent 'target validation' studies using hTERT dominant-negative and antisense approaches strongly support the view that potent and selective telomerase inhibitors will induce inhibitory effects on tumors, especially in those possessing relatively short telomeres. Inhibitory strategies have focused on three main areas: antisense molecules (oligonucleotides, RNA molecules, ribozymes and peptide nucleic acids) directed against the hTR RNA component of telomerase, small molecule reverse transcriptase inhibitors (e.g. azidothymidine), and, probably most advanced, small molecules capable of interacting with and stabilizing four-stranded (G-quadruplex) structures formed by telomeres. G-quadruplex interactive agents that inhibit telomerase at sub-micromolar concentrations in cell-free assays have been described. Lead optimization and preclinical whole-cell and animal antitumor and pharmacology studies are now progressing which should result in the first generation of telomerase inhibitors being evaluated in the clinic within the next few years.
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PMID:Telomerase inhibitors: targeting the vulnerable end of cancer? 1103 53

Activation of telomerase may allow unlimited cell proliferation and immortalization. One of the telomerase protein subunits has a reverse transcriptase (hTERT) activity that is essential for telomerase function and regulation. In human gliomas, telomerase is frequently associated with malignant tumor progression. In our study, we investigated the expression of hTERT at the cellular level in 34 primary de novo glioblastoma multiforme (GBM) by in situ hybridization (ISH). The expression of hTERT in tumor tissue was also assessed by RT-PCR. In addition, telomerase activity measured by telomeric repeat amplification protocol (TRAP) and telomere length polymorphism assayed by telomere restriction fragment (TRF) Southern blot were investigated. We found that all GBM, including those with negative TRAP reaction, contained abundant amounts of cytoplasmic hTERT mRNA. Interestingly, the ISH analysis revealed that the hTERT mRNA was homogeneously expressed by the whole tumor cell population in about 60% of the GBM. In the remaining cases, hTERT was absent in subsets of tumor cells. TRF analysis, which shows that both TRAP-positive and TRAP-negative de novo GBM have elongated telomeres, further supports that telomerase activity is present in all de novo GBM. Correlations with tumor size and extent of necrosis suggest that hTERT reactivation is an early event in GBM development and that telomerase activity may be lost in subpopulations of neoplastic cells during tumor progression. Finally, ISH analysis of hTERT mRNA seems to provide a prognostic parameter for primary de novo GBM.
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PMID:In situ detection of telomerase catalytic subunit mRNA in glioblastoma multiforme. 1109 11

Telomerase, a cellular reverse transcriptase, adds telomeric repeats to chromosome ends. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to proliferative senescence. Introduction of the telomerase (hTERT) cDNA is sufficient to produce telomerase activity and immortalize normal human cells, suggesting that the repression of telomerase activity is transcriptional. The telomerase transcript has been shown to have at least six alternate splicing sites (four insertion sites and two deletion sites), and variants containing both or either of the deletion sites are present during development and in a panel of cancer cell lines we surveyed. One deletion (beta site) and all four insertions cause premature translation terminations, whereas the other deletion (alpha site) is 36 bp and lies within reverse transcriptase (RT) motif A, suggesting that this deletion variant may be a candidate as a dominant-negative inhibitor of telomerase. We have cloned three alternately spliced hTERT variants that contain the alpha, beta or both alpha and beta deletion sites. These alternate splicing variants along with empty vector and wild-type hTERT were introduced into normal human fibroblasts and several telomerase-positive immortal and tumor cell lines. Expression of the alpha site deletion variant (hTERT alpha-) construct was confirmed by Western blotting. We found that none of the three alternate splicing variants reconstitutes telomerase activity in fibroblasts. However, hTERT alpha- inhibits telomerase activities in telomerase-positive cells, causes telomere shortening and eventually cell death. This alternately spliced dominant-negative variant may be important in understanding telomerase regulation during development, differentiation and in cancer progression.
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PMID:An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. 1119 Nov 10


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