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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Telomerase maintains the simple sequence repeats at chromosome ends, protecting cells from genomic rearrangement, proliferative senescence and death. The telomerase reverse transcriptase (TERT) and telomerase RNA (TER) alone can assemble into active enzyme in a heterologous cell extract, but the physiological process of telomerase biogenesis is more complex. The endogenous accumulation of Tetrahymena thermophila TERT and TER requires an additional telomerase holoenzyme protein, p65. Here, we reconstitute this cellular pathway for telomerase ribonucleoprotein biogenesis in vitro. We demonstrate that tandem RNA interaction domains in p65 recognize the sequence of the TER 3' stem. Notably, the p65-TER complex recruits TERT much more efficiently than does TER alone. Using bacterially expressed p65 and TERT polypeptides, we show that p65 enhances TERT-TER interaction by a mechanism involving a conserved bulge in the protein-bridging TER molecule. These findings reveal a pathway for telomerase holoenzyme biogenesis that preassembles TER for TERT recruitment.
Nat Struct Mol Biol 2005 Mar
PMID:A telomerase holoenzyme protein enhances telomerase RNA assembly with telomerase reverse transcriptase. 1569 74

Normal human liver cells have a limited capacity for proliferation due to telomere shortening, whereas immortalized cells prevent shortening of the 3' single strand telomeric repeat by expressing telomerases, including human telomerase reverse transcriptase (hTERT). The hTERT transcript contains three deletion sites that give rise to alternatively spliced variants (ASVs). Recently, hTERT expression was observed in cycling primary presenescent human fibroblasts, which were believed to lack hTERT expression and telomerase activity. hTERT mRNA was expressed in the synthesis (S) phase of the cell cycle. Although hTERT mRNA has eight isoforms, it is not known which of the hTERT ASVs are expressed in S phase. In order to determine the possible relationships between the cell cycle and ASV expressions, we measured the full-length isoform and ASVs of hTERT mRNA in a mortal liver cell line and immortal cell lines that were synchronized in S phase of the cell cycle. Using RT nested-PCR analysis, the full-length isoform and alpha-deletion ASV of hTERT were detected in the LI90 mortal liver cell line at points when cells in S phase represented >48% of the cell population without detectable telomerase activity. hTERT was always expressed in the HLE and Huh-7 hepatocellular carcinoma cell lines, regardless of the cell cycle. Our results suggest the possibility that telomerase is regulated in a cell cycle-dependent manner in normal liver cells.
Int J Mol Med 2005 Apr
PMID:Expression of hTERT mRNA in a mortal liver cell line during S phase without detectable telomerase activity. 1575 32

Telomerase-mediated telomeric DNA synthesis is important for eukaryotic cell immortality. Telomerase adds tracts of short telomeric repeats to DNA substrates using a unique repeat addition form of processivity. It has been proposed that repeat addition processivity is partly regulated by a telomerase reverse transcriptase (TERT)-dependent anchor site; however, anchor site-mediating residues have not been identified in any TERT. We report the characterization of an N-terminal human TERT (hTERT) RNA interaction domain 1 (RID1) mutation that caused telomerase activity defects consistent with disruption of a template-proximal anchor site, including reduced processivity on short telomeric primers and reduced activity on substrates with nontelomeric 5' sequences, but not on primers with nontelomeric G-rich 5' sequences. This mutation was located within a subregion of RID1 previously implicated in biological telomerase functions unrelated to catalytic activity (N-DAT domain). Other N-DAT and C-terminal DAT (C-DAT) mutants and a C-terminally tagged hTERT-HA variant were defective in elongating short telomeric primers, and catalytic phenotypes of DAT variants were partially or completely rescued by increasing concentrations of DNA primers. These observations imply that RID1 and the hTERT C terminus contribute to telomerase's affinity for its substrate, and that RID1 may form part of the human telomerase anchor site.
Mol Biol Cell 2005 Jul
PMID:An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization. 1585 55

Telomerase reverse transcriptase (TERT), a catalytic subunit of telomerase, has been demonstrated to exert a reverse transcriptase function when combined with telomerase RNA component (TERC), the complex of which ensures the maintenance of telomere length in all eukaryotes. Telomerase also prevents cell death, and promotes survival in many types of cells, from various tissues or organs including neurons, muscle, and immune cells, as well as a variety of tumor cells. Recently, a new aspect of telomerase activity, independent of telomere lengthening, has emerged to explain its protective effects on cell survival. Consistent with this, TERT was found to enhance tumorigenesis, and to regulate the expression of genes that control cell growth, which cannot be explained by telomere stabilization per se. Furthermore, the observation that TERT resides not only in the nucleus, but also in the cytosol, reinforces the notion of possible telomere-independent functions. In this review, recent studies regarding the extratelomeric functions of TERT have been comprehensively summarized, and their implications discussed.
Curr Mol Med 2005 Mar
PMID:Extratelomeric functions of telomerase. 1597 78

The promoter for human telomerase reverse transcriptase (hTERTp) is preferentially active in malignant cells. It was recently used to control the expression of the adenoviral E1A gene for the development of oncolytic adenoviruses. To ensure maximal repression in normal cells, the inclusion of additional E-boxes in the proximal region of the core promoter was described. We found that the transcriptional activity of this artificial sequence (T-255-4DEB) is minimal in normal cells, but it is also reduced in all the cancer cell lines tested. The cancer specificity of a new oncolytic adenovirus based in this promoter (AdTE1) was evaluated by direct comparison with wild-type adenovirus type 5 (AdWT) in vitro and in vivo. In all the parameters tested, AdTE1 was attenuated in normal cells, but the efficacy in cancer cells showed a parallel reduction, suggesting a lack of specificity. However, the cytotoxicity of AdTE1 was repressed in senescent cells compared to AdWT. Therefore, we conclude that AdTE1 is preferentially attenuated only in cells that are permanently devoid of telomerase expression such as senescent cells. Further modifications in the telomerase-based promoters should be introduced in order to combine maximal attenuation of oncolytic adenoviruses in normal tissues and enhanced activity in tumors.
J Mol Med (Berl) 2005 Sep
PMID:An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells. 1597 17

Bisphosphonates are important in the management of tumours with secondary bone involvement. Recent findings have suggested that these drugs also have an effect on primary tumour burden. Telomerase is a cellular ribonucleoprotein reverse transcriptase responsible for elongation of the telomere. Telomerase expression is increased in many cancers. We studied the direct effects of clodronate, alendronate, and pamidronate (from 10(-6) to 10(-4) M) on MCF-7 human breast cancer cell line. In particular, we investigated their effect on viability, proliferation, apoptosis, human telomerase reverse transcriptase expression (h-TERT) by RT-PCR and telomerase activity. Alendronate and pamidronate showed an inhibition of viability (-63 and -35%, respectively; p < 0.0001) and proliferation of cancer cells, while no effect was observed with clodronate. Amino-bisphosphonates induced a significant increase of apoptosis in MCF-7. In addition, they showed a significant decrease in telomerase expression and activity with respect to control and to clodronate.
Mol Cell Endocrinol 2005 Aug 30
PMID:Bisphosphonates decrease telomerase activity and hTERT expression in MCF-7 breast cancer cells. 1597 18

The end of eukaryotic genomic DNA is capped by a specialized structure called as "telomere", which consists of the repetitive array of nucleotide sequence, TTAGGG, in humans and mice, and a variety of binding proteins. Telomerase is a ribonucleoprotein (RNP) complex responsible for the elongation of telomeres to maintain the genomic integrity, and is composed of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and their associated factors regulating the catalytic activity of telomerase. Although it is now apparent that telomerase protects cells from apoptosis via the maintenance of genomic integrity by stabilizing telomeres, our understanding for the physiological role of telomerase is yet far from completion, and emerging evidence suggests that telomerase has additional extratelomeric roles in mediating cell survival and anti-apoptotic functions against various cytotoxic stresses. Here we summarize and discuss how telomerase and telomeres are involved in mediating cellular protection against apoptosis.
Mol Cells 2005 Jun 30
PMID:The pleiotropy of telomerase against cell death. 1599 45

Telomerase is a specialised reverse transcriptase that synthesises and preserves telomeres (the ends of chromosomes), thereby playing a key role in regulating the lifespan of cell proliferation. Telomerase activity is critically involved in cell development, ageing and tumourigenesis. Activation of telomerase to maintain telomeres is required for self renewal and proliferative expansion of a number of cell types, including stem cells, activated lymphocytes and cancerous cells. However, recent studies show that the safeguard mechanisms and the modes of regulation of telomerase are more revealing than thought under various physiological and pathological conditions. Considerable evidence suggests that hormones and growth factors are crucially involved in regulating telomerase activity and gene expression of telomerase reverse transcriptase (TERT). This review briefly summarises our current understanding of how hormones and growth factors regulate the telomerase and telomere network and how deregulation can induce ageing and related diseases such as cancer.
Mol Cell Endocrinol 2005 Aug 30
PMID:Hormones and growth factors regulate telomerase activity in ageing and cancer. 1600 42

Telomerase activity is suppressed in normal human somatic tissues but is activated in cancer cells and immortal cell lines. The reverse transcriptase (RT) subunit human telomerase reverse transcriptase (hTERT) is the key regulator of telomerase activity. The hTERT promoter contains E-box elements and may allow upstream stimulatory factor (USF), a basic helix-loop-helix (bHLH) leucine zipper family proteins, to bind and regulate the expression. In this study, we investigated whether and how USF effect on hTERT. Through luciferase reporter assays, we found that both USF1 and USF2 possess a comparable effect on the inhibition of hTERT expression. Immunoprecipitation (IP) and immunoblotting (IB) analysis reveal that the suppression of hTERT by USF was not through the interaction of USF with c-myc or mad, nor disturbed the cellular protein levels of those. In gel mobility shift and chromatin immunoprecipitation (CHIP) assays, we found that the USF suppression is through direct binding at the E-box site of hTERT promoter and rendering the effect actively. Analysis on clinical normal and tumor tissues reveal that the expression of USF1 and USF2 was lower in the tumor tissues, correlated with hTERT expression and telomerase activity. Taking together, our results demonstrate that USF is a negative transcriptional repressor for hTERT in oral cancer cells. It is possible that USF lose the inhibitory effect on hTERT expression leading to telomerase reactivation and oral carcinogenesis.
Mol Carcinog 2005 Nov
PMID:Upstream stimulatory factor (USF) as a transcriptional suppressor of human telomerase reverse transcriptase (hTERT) in oral cancer cells. 1601 Jun 90

In this study, we describe a novel approach to human cancer therapy that is based upon trans-splicing ribozyme-mediated replacement of cancer-specific RNAs with new transcripts that exert therapeutic activities. We have developed a specific ribozyme that can reprogram human telomerase reverse transcriptase (hTERT) RNA to induce transgene activity selectively in cancer cells that express the RNA. The ribozyme-mediated triggering of the transgene expression was accomplished via a high-fidelity trans-splicing reaction with the targeted residue in the hTERT-expressing cells. The ribozyme also induced cytotoxic activity in various hTERT-expressing cancer cells, hence selectively retarding the growth of those cells. Efficient and specific cell regression was also detected with ganciclovir (GCV) treatment only in hTERT-positive cancer cells, which were established to express stably the specific ribozyme that contains the herpes simplex virus thymidine kinase (HSV-tk) gene. Tissue-specific expression of the ribozyme could further augment the target specificity of the ribozyme. Importantly, we observed efficient regression of tumors with GCV treatment in mice that had been inoculated subcutaneously with hTERT-positive cancer cells that stably expressed the specific ribozyme that contains HSV-tk. These results suggest that the hTERT RNA-targeting trans-splicing ribozyme could be a powerful agent for tumor-targeted specific gene therapy.
Mol Ther 2005 Nov
PMID:Specific regression of human cancer cells by ribozyme-mediated targeted replacement of tumor-specific transcript. 1604 Feb 78


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