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, 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

Recently, mammalian heparanase was cloned, and its probable function in tumor progression was reported. However, its expression in human clinical cancers has not been fully studied. Thus we determined the heparanase mRNA expression in 30 esophageal cancer cell lines and 144 clinical samples including 38 esophageal squamous cell carcinomas, 71 gastric adenocarcinomas, and 35 colorectal adenocarcinomas. The fresh surgical specimens of cancer tissue (T) and its paired normal tissue (N) were used. The heparanase mRNA was evaluated by reverse transcriptase-polymerase chain reaction, and the T/N expression ratio was determined in clinical cases. All 30 esophageal cancer cell lines expressed heparanase mRNA. The T/N ratio was determined as high (> or =1.3), equal (0.8 approximately 1.2) or low (< or = 0.7) in each clinical case. In cases of esophageal cancer, 7 showed high, 10 equal and 21 low expression. In cases of colorectal cancer, 3 showed high, 16 equal and 16 low expression. On the other hand, 42 showed high, 22 equal and 7 low expression in cases of gastric cancer. The frequency of high expression cases was greater in gastric cancer than in esophageal or colorectal cancers (p < 0.05). There were no differences in clinicopathologic factors including prognosis between high and low expression cases of each cancer. Our mRNA study of heparanase indicated that its expression status was different among gastrointestinal cancers. The clinical and pathological impact was low compared to other proteinases, although further studies are recommended for final conclusion.
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PMID:Heparanase expression in clinical digestive malignancies. 1129 76

Ovarian surface epithelium (OSE) is the tissue of origin for the majority of ovarian cancers. The mechanism underlying the neoplastic transformation of OSE to ovarian cancer is poorly understood. Activin, a member of the transforming growth factor-beta superfamily, has been shown to increase cell proliferation in ovarian cancer cells. The present study was carried out to investigate the expression and regulation of activin/inhibin subunits and activin receptors in normal and neoplastic OSE. Using reverse transcriptase-polymerase chain reaction and Southern blot analysis, the mRNA levels of alpha, betaA and betaB subunits and activin receptor type IIA and IIB were analyzed in normal OSE and the ovarian cancer cell line, OVCAR-3 cells. The alpha and betaA subunits were highly expressed in normal OSE when compared to OVCAR-3 cells. By contrast, betaB subunit was highly expressed in OVCAR-3 cells, when compared to normal OSE cells. Interestingly, activin receptor IIB mRNA levels were significantly higher in OVCAR-3 when compared to normal OSE cells, whereas activin receptor IIA mRNA levels were the same in both cell types. To characterize the growth modulatory role of activin during neoplastic progression, normal OSE and OVCAR-3 cells were treated with recombinant human activin A (rh-activin A). At concentrations of 1,10 and 100 ng/ml, rh-activin A stimulated the growth of OVCAR-3 cells, but not of normal OSE. Treatment with follistatin, binding protein of activin, attenuates the stimulatory effect of activin. To determine whether the growth stimulatory action of activin in the neoplastic OSE is mediated via an autocrine regulatory mechanism, OVCAR-3 cells were treated with rh-activin A in a dose- and time-dependent manner and the expression levels of activin/inhibin subunits and activin receptors were investigated. Treatments with activin increased the alpha and betaA subunit mRNA levels in a dose- and time-dependent manner. However, no difference was observed in levels of betaB subunit, or in activin receptor type IIA and IIB mRNAs following activin treatments in OVCAR-3 cells. Taken together, these results suggest that different levels of activin/inhibin and activin receptor isoforms are expressed in normal and neoplastic OSE cells. In addition, the altered expression of the activin/inhibin subunits, as well as the cell proliferative effect of activin observed in OVCAR-3 but not in normal OSE cells, indicate that activin may act as an autocrine regulator of neoplastic OSE progression.
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PMID:Differential expression of activin/inhibin subunit and activin receptor mRNAs in normal and neoplastic ovarian surface epithelium (OSE). 1130 76

Endothelins (ETs) exert several functions in human melanocytes, including proliferation, dendrite formation, and melanin synthesis. Among the ET receptors, the non-selective endothelin-B (ETB) receptor is the major receptor in melanocytes and malignant melanoma (MM) cells. In spite of the important role of ETs and their receptors in the growth and differentiation of melanocytes, the distribution and expression levels of ETB receptors in tissue sections of benign and malignant pigment cell lesions is still unknown. We combined immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to study ETB receptor expression in benign and malignant pigment cell lesions and in normal skin. Immunohistochemistry on paraffin-embedded tissue sections of 159 cases revealed a significant increase in intensity of ETB receptor expression from common nevi over dysplastic nevi and primary MM to metastatic MM. Quantitative PCR using realtime detection on 75 samples confirmed the immunohistochemical results. These data add the ETB receptor to the growing list of tumor progression markers in MM and suggest that ETs play a role in the progression of MM in the skin.
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PMID:Expression of the endothelin-B receptor in pigment cell lesions of the skin. Evidence for its role as tumor progression marker in malignant melanoma. 1140 77

The elevation of circulating hepatocyte growth factor (HGF) concentrations is associated with tumor progression and prognosis in cancer patients. We aimed to clarify whether peripheral blood mononuclear cells (PBMC) of cancer patients can produce circulating HGF. In sera and PBMC supematants of 39 cancer patients and 55 control subjects, we measured HGF concentrations by enzyme-linked immunosorbent assay and analyzed HGF expression in PBMC by reverse transcriptase-polymerase chain reaction and Western blotting. Compared with primary cancer patients and control subjects, recurrent cancer patients showed higher serum HGF concentrations (p < 0.05, p < 0.01 respectively), higher HGF concentrations in PBMC supernatants (p < 0.01 for both) and more frequent HGF mRNA expression in PBMC. Additionally, HGF mRNA was induced in PBMC of a control subject cultured with the sera of recurrent cancer patients. These results indicate that PBMC of recurrent cancer patients can produce HGF and that their sera may contain substances that induce HGF mRNA expression.
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PMID:Hepatocyte growth factor production by peripheral blood mononuclear cells of recurrent cancer patients. 1150 46

Our previous study showed that high-grade astrocytomas often expressed high interleukin (IL)-1beta production. Coexpression of IL-1beta and IL-6 has been found in a number of glioma samples and glioma cell lines. To characterize the expression of IL-6 in the human glioma microenvironment, we investigated surgically excised human gliomas, human glioblastoma xenografts, and human glioblastoma cell lines using the reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). In the 29 primary gliomas, transcripts of IL-6 were less frequently detectable (55.6%) than those of IL-1beta (72.4%) or those of IL-10, IL-8, or IL-1alpha (>80% each). As for IL-6 gene expression, little or no transcription was observed in low-grade astrocytomas, oligodendroglial tumors, and 1 ependymoma. Strong IL-6 gene expression was found in only 5 of 9 glioblastomas. Immunohistochemically, IL-6 antigen was localized in the tumor cells and macrophages in 4 of 7 glioblastomas. In 3 glioblastomas transplanted into nude mice, both IL-1beta and IL-6 were detected only in 1, but othercytokines (IL-8, IL-10, and IL-1alpha) were detected in all 3 xenografts by RT-PCR. Two cell lines both showed IL-6 expression at the mRNA level, and in a cell line with a high level of IL-6 and IL-1beta transcripts, significant production of IL-6 was observed by IHC and ELISA. We concluded that IL-6 produced in tumor tissue may be involved in tumor progression in some glioblastomas, but not in low-grade astrocytomas and oligodendroglial tumors, and that IL-6 gene expression is closely correlated with IL-1beta expression in biopsy tissue, xenografts, and cultures of human gliomas.
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PMID:Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines. 1151 69

CD44 is a cell-surface molecule that has been shown to have several splicing isoforms. In various human tumors, such as primary colon and breast tumors, and their metastases, alterations of CD44 isoform expression have been reported. The present study was performed to investigate CD44 alternative transcript splicing in gynecologic malignancies. We performed reverse transcriptase polymerase chain reaction (RT-PCR) analysis of CD44 splice variant expression on mRNA transcripts from ovarian carcinomas (six primary and 15 metastatic tumors) from 21 patients and from cervical carcinomas (25 primary and two metastatic tumors) from 25 patients. We also performed this analysis on five different ovarian carcinoma cell lines established from ascitic fluid and primary tumors, and two cervical carcinoma cell lines. We included eight normal female genital tissue specimens and one additional placenta specimen in our RT-PCR analysis for comparison with CD44 expression of carcinomas. The CD44H isoform was amplified in all of the specimens. None of eight normal tissue specimens, including myometrium and ovary, expressed CD44R1 transcripts. But the CD44R1 transcript was expressed in 2/6 (33.3%) primary ovarian carcinomas and in 7/15 (46.6%) metastatic ovarian carcinomas. In cervical carcinoma, 13/25 (52.0%) primary tumors and 2/2 (100.0%) metastatic tumors expressed CD44R1. The CD44R1 transcript was expressed increasingly during ovarian and cervical tumor progression (P = 0.026 and P = 0.002, respectively). In conclusion, the frequency of CD44R1 transcript expression increased during ovarian and cervical carcinoma progression, and analysis of CD44 splice variants may be useful in detecting primary and metastatic gynecologic malignancies.
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PMID:Expression of the CD44 adhesion molecule in primary and metastatic gynecologic malignancies and their cell lines. 1157 76

It has been proposed that the regulation of telomerase takes place at the transcriptional level, the expression of the catalytic subunit human telomerase reverse transcriptase (hTERT) being crucial for telomerase activity (TA). Recently, differential splicing of hTERT mRNA has been demonstrated in various tissues during embryonal development, and it has been suggested that only full-length transcripts translate into functionally active telomerase. With this in view, we analyzed the different hTERT transcripts by reverse transcriptase-polymerase chain reaction in neuroblastic tumors and compared the results with the TA, the tumor growth fraction, and the MYCN status. In a series of 38 neuroblastic tumors, high TA and full-length hTERT transcripts were found in nine samples, whereas nine samples showed absence of both enzymatic activity and hTERT transcripts. Interestingly, in another eight samples, low or absent TA coincided with a lack of full-length hTERT transcripts. Eleven samples contained hTERT transcripts with low or undetectable TA and one sample had low TA but no hTERT transcripts. TA correlated with MYCN amplification and was weakly associated with the proliferative activity. Moreover, a significant correlation with tumor progression was observed. Our findings point at a posttranscriptional regulation of TA in a subset of neuroblastic tumors. Because high TA was detected only in tumors with full-length hTERT transcripts, reverse transcriptase-polymerase chain reaction analysis of archival neuroblastic tumor samples might help to appraise the malignant potential in individual cases.
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PMID:Regulation of telomerase activity by alternate splicing of human telomerase reverse transcriptase mRNA in a subset of neuroblastomas. 1169 53

Shortening of the telomeric DNA at the chromosome ends is presumed to limit the lifespan of human cells and elicit a signal for the onset of cellular senescence. To continually proliferate across the senescent checkpoint, cells must restore and preserve telomere length. This can be achieved by telomerase, which has the reverse transcriptase activity. Telomerase activity is negative in human normal somatic cells but can be detected in most tumor cells. The enzyme is proposed to be an essential factor in cell immortalization and cancer progression. In this review we discuss the structure and function of telomere and telomerase and their roles in cell immortalization and oncogenesis. Simultaneously the experimental studies of telomerase assays for cancer detection and diagnosis are reviewed. Finally, we discuss the potential use of inhibitors of telomerase in anti-cancer therapy.
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PMID:Telomere and telomerase in oncology. 1194 6

In order to discover global gene expression patterns characterizing subgroups of colon cancer, microarrays were hybridized to labeled RNAs obtained from seventeen colonic specimens (nine carcinomas and eight normal samples). Using a hierarchical agglomerative method, the samples grouped naturally into two major clusters, in perfect concordance with pathological reports (colon cancer versus normal colon). Using a variant of the unpaired t-test, selected genes were ordered according to an index of importance. In order to confirm microarray data, we performed quantitative, real-time reverse transcriptase-polymerase chain reaction (TaqMan RT-PCR) on RNAs from 13 colorectal tumors and 13 normal tissues (seven of which were matched normal-tumor pairs). RT-PCR was performed on the gro1, B-factor, adlican, and endothelin converting enzyme-1 genes and confirmed microarray findings. Two hundred and fifty genes were identified, some of which were previously reported as being involved in colon cancer. We conclude that cDNA microarraying, combined with bioinformatics tools, can accurately classify colon specimens according to current histopathological taxonomy. Moreover, this technology holds promise of providing invaluable insight into specific gene roles in the development and progression of colon cancer. Our data suggests that a large-scale approach may be undertaken with the purpose of identifying biomarkers relevant to cancer progression.
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PMID:Application of cDNA microarrays to generate a molecular taxonomy capable of distinguishing between colon cancer and normal colon. 1210 25


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