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)

Cell aging involves damages and losses of genetic materials including the gradual shortening of telomeres. Telomeres, the ends of chromosomes, have a variety of functions, and the most notable ones include those involved in retaining genome integrity and stability and in regulating cell lifespan. Early loss or damage of telomeres causes premature aging, whereas excessive gain of telomeres confers immortality upon some cancer cells. However, the opposing changes in telomere structures and their associated cellular effects on aging and immortalization are forcefully regulated by the enzyme telomerase. Telomerase is a large protein-RNA complex that has telomeric DNA reverse transcriptase activity. Although a wealthy body of information has been obtained on the involvement of telomerase in tumorigenesis, its structure of the holoenzyme, the mode of its action, its cellular function in aging, and the pathways of its regulatory mechanisms have not been entirely understood. Recent research on telomerase has become an increasing investigative effort to uncover the molecular mechanisms of aging and aging-related diseases. This article will briefly review now telomerase may impact aging, what potential in vivo significance the regulation of telomerase may have on aging, how signals are transduced from telomerase and telomere to different cellular effects, and how telomerase itself is controlled in mammalian cells.
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PMID:Signaling on telomerase: a master switch in cell aging and immortalization. 1201 28

Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. E-cadherin was discovered as a protein associated with beta-catenin which plays a crucial role in cell-cell adhesion. To further understand the molecular basis of Wnt signaling pathway and E-cadherin in brain tumorigenesis, the expression of four Wnt genes (Wnt1, Wnt5a, Wnt10b and Wnt13) and E-cadherin were analyzed by reverse transcriptase-polymerase chain reaction. In addition, their downstream effector, beta-catenin, was also investigated. The results showed that the expression of Wnt5a (41/45), Wnt10b (37/45), and Wnt13 (35/45) were found in brain tumors, whereas Wnt1 (6/45) was shown to be less related. Interestingly, E-cadherin was only expressed in a few cases of astrocytoma (2/16), whereas it was expressed in most meningioma (14/15) and pituitary adenoma tumors (12/14). There was no apparent difference of beta-catenin expression profile in brain tumors; however, the sequencing data of beta-catenin showed two mutations on speculative phosphorylation sites, S73F and S23G in astrocytoma. Furthermore, an in vitro functional assay showed that S73F and S23G mutants of beta-catenin did not affect transcriptional activity in TCF-4-leuciferase reporter construct, suggesting that they may need more complex factors to participate in astrocytoma. Taken together, our data suggest that the mutations of beta-catenin together with E-cadherin and Wnt signaling might be involved in brain tumorigenesis.
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PMID:Differential expression of Wnt genes, beta-catenin and E-cadherin in human brain tumors. 1204 19

Telomeres are crucial for chromosomal stability and cell viability. Activation of telomerase, a specialized reverse transcriptase, is the predominant mechanism for maintaining telomere length and function in yeasts and human cells. Telomere maintenance is regarded as a key element in the immortalization of cells and hence in oncogenesis. Although more than 90% of all malignant tumors display telomerase activity, there appear to be alternatives to this mechanism. Alternative lengthening of telomeres (ALT) in the absence of telomerase has been described in various organisms and recently also in immortalized and transformed human cells. This article will discuss how ALT is detected and how it affects telomere morphology. It will review the frequency and relevance of ALT in in vitro immortalized cell lines, tumor-derived cell lines, and primary tumors. We have only begun to link mechanisms by means of which ALT may act in immortalized human cells to the growing knowledge about telomeres, and we can look forward to further fascinating insights into telomere biology. Our review will also emphasize recent advances in our understanding of the induction and repression of ALT and the demonstration of ALT in cancer cells in the light of new treatment strategies targeted against telomere maintenance mechanisms.
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PMID:Telomere lengthening in telomerase-negative cells: the ends are coming together. 1207 May 95

Peroxisome proliferator-activated receptor (PPAR) alpha is a ligand-activated transcription factor that has been linked with rodent hepatocarcinogenesis. It has been suggested that PPARalpha mRNA expression levels are an important determinant of rodent hepatic tumorigenicity. Previous work in rat mammary gland epithelial cells showed significantly increased PPARalpha mRNA expression in carcinomas, suggesting the possible role of this isoform in rodent mammary gland carcinogenesis. In this study we sought to determine whether PPARalpha is expressed and dynamically regulated in human breast cancer MCF-7 and MDA-MB-231 cells. Having established the presence of PPARalpha in both cell types, we then examined the consequence of PPARalpha activation, by its ligands Wy-14,643 and clofibrate, on proliferation. With real-time reverse transcriptase-polymerase chain reaction, we showed that PPARalpha mRNA was dynamically regulated in MDA-MB-231 cells and that PPARalpha activation significantly increased proliferation of the cell line. In contrast, PPARalpha expression in MCF-7 cells did not change with proliferation during culture and was present at significantly lower levels than in MDA-MB-231 cells. However, PPARalpha ligand activation still significantly increased the proliferation of MCF-7 cells. The promotion of proliferation in breast cancer cell lines following PPARalpha activation was in stark contrast to the effects of PPARgamma-activating ligands that decrease proliferation in human breast cancer cells. Our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. Hence, this pathway may be significant in mammary gland tumorigenesis.
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PMID:Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231. 1220 67

A role for neuropeptide receptors in glial tumorigenesis has recently been proposed. Although angiotensin receptors are known to mediate proliferative effects in many cell types, including brain astrocytes, the possible participation of these receptors in glial tumorigenesis remains unknown. In the present study, we have examined the expression of the molecularly defined angiotensin receptor subtypes AT(1a), AT(1b), and AT(2) in normal perinatal rat astrocytes and in a panel of tumor adult astrocytoma cells, using the reverse transcriptase-polymerase chain reaction (RT-PCR). Subsequently, we compared the mitogenic effect of the angiotensins A(1-8), A(2-8), A(3-8) and the heptapeptide "metabolite" A(1-7), on both normal and tumor astrocytes, measured in terms of the incorporation of tritiated thymidine. Our results indicate that AT(1a), AT(1b), and AT(2) angiotensin receptor mRNA is commonly expressed by many of these cells. Of notable exception is the astrocytoma U373 which was not found to express AT(1) or AT(2) mRNA. Chronic (24-h) incubation of cells with A(1-8) and A(1-7) lead to the induction of mitogenesis, even in the AT(1) and AT(2) mRNA negative astrocytoma cell line U373. Moreover, pharmacological analysis indicated that the observed mitogenic effects are not mediated by the AT(1) or AT(2) type receptors, but rather by a novel, specific A((1-7)) angiotensin receptor, since mitogenesis was shown to be partially blocked by the A(1-7) analogue D-Ala(7)A(1-7) and by the protease inhibitor orthophenanthroline (100 microM). Using Fura-2 spectrophotometry, we found that activation of this receptor does not alter intracellular calcium levels; however, preincubation with the protein kinase kinase inhibitor U0126 (10 microM) was found to inhibit these mitogenic effects partially. Overall, these results which demonstrate that normal and tumor astrocytes express a greater variety of angiotensin receptor subtypes than previously thought, support the idea that A(1-7) and its receptor signaling system may play an important role in shaping the astrocyte population during development. Moreover, the untimely expression of this A((1-7)) receptor may represent an important etiological component in the development of brain astrocytomas.
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PMID:Multiple angiotensin receptor subtypes in normal and tumor astrocytes in vitro. 1220 96

Transgenic mice were generated in which a 2.2-kb segment of the 5'-flanking sequence of the mouse oviduct-specific glycoprotein (OGP) gene was used to drive expression of the simian virus 40 large T antigen (Tag). These mice spontaneously developed tumors in the female reproductive tract. Analysis using reverse transcriptase-polymerase chain reaction showed that the 2.2-kb OGP 5'-flanking region drove Tag mRNA expression in the oviduct, uterus, vagina, and ovary, but not in other tissues. Histological and immunohistochemical analyses revealed that the tumor cells were distributed in the oviduct, endometrium, myometrium, and vagina; and had atypical features, abnormal mitosis, and Tag expression. Ovariectomy suppressed Tag expression, and thereby, blocked tumorigenesis in the transgenic mice. Estradiol administration to ovariectomized transgenic mice led to dramatic hyperplasia of the reproductive tract tissues in association with enhanced Tag expression, both in intensity and distribution. These results demonstrated that a 2.2-kb fragment of the 5'-flanking sequence of the mouse OGP gene was capable of directing the expression of Tag and inducing tumorigenesis in female reproductive tract tissues in an estrogen-dependent manner. Estrogen response elements present in the promoter region were functional in vivo. These transgenic mice represent a unique model, since they develop tumors in the oviducts as well as in other tissues derived from the Mullerian duct.
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PMID:Mouse transgenic for murine oviduct-specific glycoprotein promoter-driven simian virus 40 large T-antigen: tumor formation and its hormonal regulation. 1220 26

The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.
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PMID:Human telomerase and its regulation. 1220 97

Transforming growth factor-beta (TGF-beta) belongs to a superfamily of structurally related polypeptides involved in various biological processes, including cell growth, proliferation and differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling. We tried to define the different expression patterns of the TGF-beta receptors by investigating the female reproductive organs during the menstrual cycle and endometrial tumorigenesis, because their role in these processes is still unclear. In this study, we examined the expression of the TGF-beta type I and type II receptors in normal (n=13) and carcinomatous (n=42) endometrial tissue specimens using reverse transcriptase polymerase chain reaction and immunological (Western blot and enzyme linked immunosorbent assay) methods. Two uncommon female genital tract tumors, rhabdomyosarcoma of the uterine cervix and uterine carcinosarcoma, were also included. There were no significant differences between normal and cancerous endometrial tissues regarding the TGF-beta receptors mRNA levels. However, we observed a markedly low TGF-beta type I receptor protein level (P<0.028; Mann-Whitney-U test), while the malignant endometrium showed a significantly higher TGF-beta type II receptor protein level (P<0.007; Mann-Whitney-U test) than the normal endometrium. Moreover, significantly elevated TGF-beta receptor type II protein level was noted when depth of myometrial invasion of endometrial carcinomas was considered (P<0.05; Mann-Whitney-U test). In contrast to uterine carcinosarcoma, in which no detectable mRNA for TGF-beta type II receptor was found, we noted expression of both TGF-beta receptors in rhabdomyosarcoma of the uterine cervix. However, neither rhabdomyosarcoma of the uterine cervix nor uterine carcinosarcoma displayed TGFbetaRI and TGFbetaRII protein expression. This observation corroborates the complexity of the deregulation of TGF-beta receptor expression in human endometrial cancer.
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PMID:Expression of TGF-beta type I and II receptors in normal and cancerous human endometrium. 1221 93

The features and functions of prostatic neuroendocrine (NE) cells remain ill-defined. Neuroendocrine differentiation (NED) in adenocarcinoma of the human prostate (CaP) is associated with more aggressive disease, but the underlying mediators are poorly understood. We examined these issues in transgenic mice that utilize regulatory elements from the cryptdin-2 gene (Defcr2) to express simian virus 40 large T antigen (TAg) in prostatic NE cells. CR2-TAg mice develop prostatic intraepithelial neoplasia at 8 weeks of age, 1 week after the onset of TAg expression. An invasive phase follows 2-4 weeks later, with lymph node, liver, lung, brain, and bone metastases appearing within 16 weeks. DNA microarray studies revealed 122 mRNAs that were increased >/=2-fold in duplicate assays of 16-week-old CR2-TAg versus normal prostates. Thirty two transcripts encode proteins associated with neurons and endocrine cells (e.g. basic helix loop helix, SRY-related high mobility group box and sine-oculis homeobox transcription factors, Hu RNA-binding proteins, neuronatin, Racgap1, collapsin response mediator protein-1, synaptotagmin-1, proprotein convertase, and secretogranins). Follow-up studies of candidate mediators and biomarkers of differentiation/growth in the microarray data set involved real time quantitative reverse transcriptase-PCR assays of laser capture microdissected NE cells from CR2-TAg prostates plus liver metastases, and immunohistochemical comparisons of transgenic mouse prostates and 35 human CaP samples. Our findings include (a) expression of the bHLH mouse achaete-scute homolog (mASH1) in normal and CR2-TAg NE cells and foci of NED in human CaP, (b) glutamic acid decarboxylase and its product (gamma-aminobutyric acid) in neoplastic NE cells juxtaposed next to cohorts of normal gamma-aminobutyric acid receptor expressing secretory cells (a potential route for paracrine interactions between these two epithelial lineages), and (c) aromatic l-amino-acid decarboxylase, but not its dopamine/serotonin products, in CR2-TAg NE cells and NED. These results underscore the value of CR2-TAg mice for characterizing normal NE cell biology and tumorigenesis.
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PMID:Molecular characterization of a metastatic neuroendocrine cell cancer arising in the prostates of transgenic mice. 1222 43

Chromosomal instability is one of the most important characteristics underlying tumorigenesis. Certain colorectal cancers with chromosomal instability have been shown to have inactivation of a spindle assembly checkpoint party due to mutation of Bub1, a mitotic checkpoint gene. We performed sequencing analysis on reverse transcriptase-polymerase chain reaction (RT-PCR) product of the Bub1 cDNA (entire coding sequence) from 8 human gastric cancer cell lines. In addition, genomic PCR products of Bub1 exon 8, 10, 12, 15 and kinase domain from 9 oral cancer cell lines were analyzed by polymerase chain reaction-single-stand conformation polymorphism (PCR-SSCP). Although sequencing analysis of the Bub1 cDNA revealed several point mutations in 8 gastric cancer cell lines, we could not confirm the mutations by analyzing genomic DNA. Furthermore, genomic PCR-SSCP analysis revealed no mutations in exon 8, 10, 12, 15 and kinase domain of the Bub1 gene in any oral cancer cell lines examined. These results suggest that mutation of the Bub1 gene might not play a role in human stomach and oral carcinogenesis.
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PMID:No mutations of the Bub1 gene in human gastric and oral cancer cell lines. 1237 25


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