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)

Telomerase is an RNA-dependent DNA polymerase that maintains the tandem arrays of telomeric repeats at the eukaryotic chromosome ends. Because of its ability to replenish lost telomeric sequences, telomerase is thought to be required for cell proliferation. At present, very little information on the role of telomerase in aging is available. In the present study, we tested the telomerase activity of Fischer 344 rat testis and liver at 6, 12, 18 and 24 months of age. As the testis is an androgen-dependent tissue, we also investigated the changes of testosterone and mRNA levels of androgen receptor in this tissue. Our results show that the telomerase activity of Fischer 344 rat testis significantly reduced at 24 months of age compared to 6 months of age, and that the mRNA level of telomerase protein component 1 (TLP-1) show a corresponding decrease with the telomerase activity. Interestingly, this down-regulation was not observed in the liver. The testosterone level in testis increased until 18 months of age, but reduced by 50% at 24 months of age. Our conclusions are that the telomerase activity is age-dependent and its change is a tissue-specific phenomenon.
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PMID:Downregulation of telomerase in rat during the aging process. 1042 Sep 88

Telomerase is a unique reverse transcriptase involved in the maintenance of telomeric DNA, which is generally undetectable in normal human somatic cells. However, it has been found in organs of normal adult rodents including the liver. In order to elucidate relevant control mechanisms operating in normal somatic cells, we examined telomerase activity in primary cultured rat hepatocytes. During culture under serum-free conditions, rat hepatocytes rapidly lose the ability of organ-specific expression of serum albumin, apolipoprotein A-I, and hepatocyte nuclear factor 4, and the capacity for cytochrome P-450 induction by xenobiotics. The telomerase activity was found to be concomitantly increased about 2. 5-fold at 48 h and 3-fold at 72 h. Northern blot and RT-PCR analyses with primary cultured hepatocytes revealed the associated accumulation of rat telomerase RNA subunits (TR), and the mRNAs for a telomerase reverse transcriptase (TERT) and a telomerase-associated protein (TEP1). The activity of hepatocyte telomerase, which was elevated during the primary culture, increased further when the cells were stimulated with hepatocyte growth factor. In this case, however, the levels of TR, TERT, and TEP1 mRNA did not show any detectable changes.
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PMID:Up-regulation of telomerase in primary cultured rat hepatocytes. 1042 30

Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes and maintains telomeric DNA. Studies of telomeres and telomerase are facilitated by the large number of linear DNA molecules found in ciliated protozoa, such as Tetrahymena thermophila. To examine the expression of telomerase, we investigated the transcription of the RNA polymerase III-directed gene encoding the RNA subunit (TER1) of this enzyme. A chimeric gene containing the Glaucoma chattoni TER1 transcribed region flanked by 5' and 3' Tetrahymena regions was used to identify promoter elements following transformation of Tetrahymena cells. Disruption of a conserved proximal sequence element (PSE) located at -55 in the Tetrahymena TER1 5' flanking region eliminated expression of the chimeric gene. In addition, mutation of an A/T-rich element at -25 decreased expression markedly. A gel mobility shift assay and protein-DNA cross-linking identified a PSE-binding polypeptide of 50-60 kDa in Tetrahymena extracts. Gel filtration analysis revealed a native molecular mass of approximately 160 kDa for this binding activity. Our results point to a similar architecture between ciliate telomerase RNA and metazoan U6 small nuclear RNA promoters.
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PMID:Identification of an essential proximal sequence element in the promoter of the telomerase RNA gene of Tetrahymena thermophila. 1051 20

The localization of a reverse transcriptase-related protein in salivary gland polytene chromosomes was investigated by immunohistochemistry in two species of Chironomus. The antibodies used were raised against a recombinant protein containing phylogenetically conserved motifs of reverse transcriptases and derived from an abundant non-LTR element previously identified in Chironomus. Immunoreactive protein was found in some telomeres, in a centromeric region, in a few interstitial bands and in Balbiani ring 3. The telomeric signal was probably dependent on transcription and increased dramatically when telomeric heat shock puffs were induced. A correlation with transcription was also seen in Balbiani ring 3, the immunobinding of which disappeared after inhibition of transcription with actinomycin D.
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PMID:Histochemical localization of reverse transcriptase in polytene chromosomes of chironomids. 1052 66

Telomerase is a ribonucleoprotein complex that adds telomeric DNA repeats to the ends of most eukaryotic chromosomes. The reverse transcriptase subunit of telomerase (TERT) differs from retroviral reverse transcriptases in having a long basic amino-terminal extension. We made a large library containing random mutations in the amino terminus of the EST2 gene, which encodes the Saccharomyces cerevisiae TERT, and selected functional alleles by their ability to rescue senescence of telomerase-negative cells. Through analysis of 265 mutations, the amino terminus of Est2p was found to contain at least four essential regions. This domain structure was verified by a combination of deletion and alanine-block mutations. Mutations within two essential domains of the protein reduced RNA binding, suggesting that the amino terminus of Est2p makes important contacts with the intrinsic RNA component of telomerase. A mutant close to the amino terminus retained RNA binding and in vitro enzymatic activity but was defective in vivo, suggesting a role in interaction with other macromolecular components of telomerase.
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PMID:Essential functions of amino-terminal domains in the yeast telomerase catalytic subunit revealed by selection for viable mutants. 1055 13

A means of regulating the fate of intracellular proteins is their covalent conjugation to ubiquitin-like proteins. A recently discovered ubiquitin-like protein is called "diubiquitin" because it consists of two ubiquitin-like domains in head-to-tail arrangement. Human diubiquitin is encoded at the telomeric end of the MHC class I locus and was previously found to be expressed in dendritic cells and mature B cells. We have extended the expression analysis of diubiquitin by reverse transcriptase-PCR and Northern blotting in primary endothelial cells and human cancer cell lines derived from nine different tissues. Diubiquitin expression was found to be generally and synergistically inducible with the cytokines IFN-gamma and TNF-alpha but not with IFN-alpha. Diubiquitin mRNA expression was induced within 2 h after cytokine stimulation and was independent of protein neosynthesis but dependent on proteasome activity. The mouse homologue of diubiquitin which is also encoded in the MHC class I locus was likewise induced with IFN-gamma and TNF-alpha. A general and synergistic induction with IFN-gamma and TNF-alpha suggests that diubiquitin may exert its functions in antigen presentation or other cellular processes controlled by these two cytokines.
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PMID:A ubiquitin-like protein which is synergistically inducible by interferon-gamma and tumor necrosis factor-alpha. 1060 13

Telomerase is an essential enzyme that maintains telomeres on eukaryotic chromosomes. In mammals, telomerase is required for the lifelong proliferative capacity of normal regenerative and reproductive tissues and for sustained growth in a dedifferentiated state. Although the importance of telomeres was first elucidated in plants 60 years ago, little is known about the role of telomeres and telomerase in plant growth and development. Here we report the cloning and characterization of the Arabidopsis telomerase reverse transcriptase (TERT) gene, AtTERT. AtTERT is predicted to encode a highly basic protein of 131 kDa that harbors the reverse transcriptase and telomerase-specific motifs common to all known TERT proteins. AtTERT mRNA is 10-20 times more abundant in callus, which has high levels of telomerase activity, versus leaves, which contain no detectable telomerase. Plants homozygous for a transfer DNA insertion into the AtTERT gene lack telomerase activity, confirming the identity and function of this gene. Because telomeres in wild-type Arabidopsis are short, the discovery that telomerase-null plants are viable for at least two generations was unexpected. In the absence of telomerase, telomeres decline by approximately 500 bp per generation, a rate 10 times slower than seen in telomerase-deficient mice. This gradual loss of telomeric DNA may reflect a reduced rate of nucleotide depletion per round of DNA replication, or the requirement for fewer cell divisions per organismal generation. Nevertheless, progressive telomere shortening in the mutants, however slow, ultimately should be lethal.
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PMID:Disruption of the telomerase catalytic subunit gene from Arabidopsis inactivates telomerase and leads to a slow loss of telomeric DNA. 1061 Dec 95

The ribonucleoprotein (RNP) enzyme telomerase synthesizes telomere DNA and maintains telomere length in eukaryotic cells. This review describes recent findings that provide new understanding, of the functions of telomeres and telomerase. Telomerase has an essential RNA moiety in which a short sequence acts as the template for synthesis of telomeric DNA. Recent results show that, besides acting as a template, the telomerase RNA plays essential roles in the enzymatic functions of telomerase that are as critical as those provided by the protein reverse transcriptase subunit of telomerase. Analysis of telomerase RNA mutants in yeast has provided evidence that telomerase is an oligomeric/dimeric enzyme containing at least two telomerase RNA molecules and two enzyme-active sites. Recent data suggest that this telomerase RNP also plays a critical role in capping short telomeres. Thus, the length of a telomere is only one determinant of whether it is sufficiently long to function as a cap, stabilizing the chromosome end. Several lines of evidence converge on the notion that for telomere length regulation and other telomere functions, the very few last repeats at the tip of the telomere are the most crucial.
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PMID:The telomere and telomerase: how Do they interact? 1061 27

Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.
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PMID:Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos. 1062 28

Reactivation of telomerase, an RNA-dependent DNA polymerase that synthesizes new telomeric repeats at the end of chromosomes, is a very common feature in human cancers. Telomerase is thought to be essential in maintaining the proliferative capacity of tumor cells and, as a consequence, it could represent an attractive target for new anti-cancer therapies. In this study, we generated a hammerhead ribozyme composed of a catalytic domain with flanking sequences complementary to the RNA component of human telomerase and designed to cleave specifically a site located at the end of the telomerase template sequence. In vitro the ribozyme induced cleavage of a synthetic RNA substrate obtained by cloning a portion of the RNA component of human telomerase. The extent of cleavage was dependent on the ribozyme/substrate ratio as well as the Mg2+ concentration. Moreover, when added to cell extracts from two human melanoma cell lines (JR8 and M14), or three melanoma surgical specimens, the ribozyme inhibited telomerase activity in a concentration- and time-dependent manner. When the ribozyme was delivered to growing JR8 melanoma cells by (N-(1-(2,3 dioleoxyloxy)propil)-N,N,N trimethylammonium methylsulfate-mediated transfer, a marked inhibition of telomerase activity was observed. Next, the ribozyme sequence was cloned in an expression vector and JR8 cells were transfected with it. The cell clones obtained showed a reduced telomerase activity and telomerase RNA levels and expressed the ribozyme. Moreover, ribozyme transfectants had significantly longer doubling times than control cells and showed a dendritic appearance in monolayer culture. No telomere shortening, however, was observed in these clones. Overall, our results indicate that the hammerhead ribozyme is a potentially useful tool for the inactivation of telomerase in human tumors.
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PMID:Inhibition of telomerase activity by a hammerhead ribozyme targeting the RNA component of telomerase in human melanoma cells. 1065 84


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