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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.
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PMID:Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. 1040 9

Telomerase is a ribonucleoprotein which has a RNA template to bind and extend telomere ends, so prolonging the life of tumour cells. The aim of this study was to determine whether transcriptase function of telomerase could be inhibited by the reverse transcriptase inhibitors (RTI); azydothymidine (AZT), dideoxyinosine (ddI) and AZT-5' triphosphate (AZT-TP). We examined their effects on the proliferation of cancer cells and the antitumour effects of cisplatin in vitro. The three agents did not cause major changes in telomerase activity or telomere length in MCAS cells. However, in HEC-1 cells changes in telomerase activity and telomere length were observed that were dependent on the RTI concentration and duration of exposure. ddI and AZT-TP reduced telomerase activity and shortened the length of the telomere. In the presence of RTI, the antitumour effects of cisplatin were enhanced. This was particularly evident in HEC-1 cells where there was a marked reduction in cell proliferation, appearance of morphological changes and senescent-like cells in the presence of ddI or AZT-TP. In MCAS cells, TP53 expression was increased by ddI and AZT-TP, while p21 expression was unchanged. In HEC-1 cells the expression of both TP53 and P21 was increased by ddI. Continuous administration of RTI enhanced the cell growth inhibition of cisplatin. RTI also inhibited the proliferation of some cells.
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PMID:Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines. 1053 89

While pituitary tumors can be induced in rats by the administration of estrogen, susceptibility to such tumors is highly strain dependent. In this study, 21-day-old male rats of two strains-Fischer 344 (F344) strain, which is particularly susceptible to pituitary tumors, and Sprague-Dawley (SD) strain, which is relatively resistant, were treated with diethylstilbestrol (DES) over a period of 10 days. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze the expression levels of two tumor suppressor genes, p53 and rb, in the pituitaries. In SD rats, both p53 and rb mRNA appeared to increase in response to DES treatment, while in F344 rats they remained undetectable. Western blot analysis revealed that protein levels of cyclin D, which is a cell cycle regulating protein thought to be a potential oncogene, decreased in response to DES treatment in F344 rats but remained constant in SD rats. The observed differences in the expression levels of p53, rb and cyclin D suggest that they might be involved in the primary process of estrogen-induced pituitary tumor development prior to detectable tumor growth.
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PMID:Potential involvement of tumor suppressor gene expression in the formation of estrogen-inducible pituitary tumors in rats. 1081 Dec 86

Molecular analysis of mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in peripheral blood T-lymphocytes can provide information on mechanisms of somatic in vivo mutation in populations exposed to exogenous carcinogens and in individuals with inherent susceptibility to cancer and other diseases. To study possible mutational changes associated with smoking as a risk factor for lung cancer, we analyzed HPRT mutations in T-cells of newly diagnosed, nonsmoking and smoking lung cancer patients before treatment. Reverse transcriptase polymerase chain reaction (RT-PCR) and DNA sequencing methods were used to identify 146 independent mutations, 73 each from 32 nonsmoking and 31 smoking cases. In 35 T-cell mutants, the HPRT cDNA showed loss of an entire exon, indicating a splicing mutation. Among the remaining 111 fully characterized mutations in the coding region, single base pair (bp) substitutions predominated with 79% (48/61) in nonsmokers and 90% (45/50) in smokers. Frameshift and small deletion (1-24 bp) mutations were found in 18 mutants. The distribution of base pair substitutions was nonrandom, with significant clustering at previously identified hotspot positions 143, 197 and 617 in the HPRT coding sequence (P< or =0.008). One additional hotspot, GC-->TA at position 606, was observed only in smokers (P=0.006). The frequency of GC>TA transversions was higher in smokers (13%) than in nonsmokers (6%). Conversely, smokers had a lower frequency of GC>AT transitions (24%) than nonsmokers (35%). This smoking-associated shift of the HPRT mutational spectrum, although not statistically significant, is consistent with the in vitro mutagenicity of benzo(a)pyrene (BaP), a prominent carcinogen of tobacco smoke, and with known differences in the TP53 mutational spectrum in lung tumors of smokers and nonsmokers. Among nonsmokers, the HPRT mutational spectra in healthy population controls and lung cancer patients were similar, but there was a marginally significant difference (P=0.07) in the distribution of base pair substitutions between smoking controls and patients. These results suggest that (i) general mechanisms of somatic mutagenesis in individuals with possible predisposition to cancer (e.g. nonsmoking lung cancer patients) are not different from those in normal healthy individuals, and (ii) the HPRT gene in T-cells is a useful reporter locus for smoking-associated somatic in vivo mutations occurring early in lung cancer development.
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PMID:Mutational spectra at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in T-lymphocytes of nonsmoking and smoking lung cancer patients. 1086 57

Disruption of the function of tumor suppressor proteins occasionally can be dependent on their subcellular localization. In about 40% of the breast cancer tissues, p53 is found in the cytoplasm as opposed to the nucleus, where it resides in normal breast cells. This means that the regulation of subcellular location of p53 is an important mechanism in controlling its function. The transport factors required for the nuclear export of p53 and the mechanisms of their nuclear export have been extensively characterized. However, little is known about the mechanism of nuclear import of p53. p53 contains putative nuclear localization signals (NLSs) which would interact with a nuclear transport factor, importin alpha. In this report we demonstrate that importin alpha binds to NLSI in p53 and mediates the nuclear import of p53. Reverse transcriptase-polymerase chain reaction and sequencing analyses showed that a truncated importin alpha deleted the region encoding the putative NLS-binding domain of p53, suggesting that it could not bind to NLSs of p53 proteins. Binding of importin alpha to p53 was confirmed by using yeast two-hybrid assay. When expressed in CHO-K1 cells, the truncated importin alpha predominantly localized to the cytoplasm. In truncated importin alpha expressing cells, p53 preferentially localized to cytoplasmic sites as well. A significant increase in the p21(waf1/cip1) mRNA level and induction of apoptosis were also observed in importin alpha overexpressing cells. These results strongly suggest that importin alpha functions as a component of the NLS receptor for p53 and mediates nuclear import of p53.
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PMID:Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53. 1093 Apr 27

The human homolog of KET, p63, bears strong homology to the tumor suppressor p53 and plays an essential role in epithelial development. CUSP, the most abundant cutaneous product of p63, has been identified as an autoantigen in chronic ulcerative stomatitis (CUS). The original report of KET expression at least partially contradicts p63 expression subsequently reported by many different groups. We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera. Northern analysis reveals p63 RNA in skin, thymus, placenta, skeletal muscle, kidney, and lung, with non-transactivating p63 RNA in skin, thymus, and placenta. Reverse transcriptase polymerase chain reaction (rtPCR) assays show abundant non-transactivating p63 RNA, and little to no transactivating p63 RNA, in human basal cell carcinoma as well as in normal skin adjacent to the tumors. p63 RNA expression was not detected in brain, heart, colon, spleen, liver, or small intestine. Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart. Focal p63 expression within tissues, the complex array of isoforms encoded by the gene, and the specificity of the probes and antibodies utilized, may all contribute to contradictory accounts of CUSP/p63 expression.
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PMID:CUSP/p63 expression in rat and human tissues. 1153 71

We describe the establishment and characterization of a new multiple myeloma (MM) cell line, KYdelta-1, which expressed delta/kappa type immunoglobulin (Ig). The patient was a 65-year-old woman with MM, who presented extramedullary dissemination, lymphadenopathy and short survival. The KYdelta-1 cell line was derived from the pleural fluid obtained in the terminal phase of the disease. The cells expressed delta/kappa Ig in the cytoplasm, and CD10, CD29, CD33, CD38, CD44, CD54, and HLA-DR antigens on the cell surface. Chromosomal analysis revealed two independent translocations, t(3;14)(p21;q32) and t(3;11)(p21;q13), which were confirmed by fluorescence in situ hybridization using chromosome painting probes. Reverse transcriptase-mediated polymerase chain reaction (PCR) and Northern blot analyses demonstrated overexpression of the CCND1 gene, suggesting alteration of the BCL1-CCND1 locus. We thus performed long-distance inverse PCR using nested primers for the Calpha constant region of immunoglobulin heavy chain gene (IGH) and obtained a clone that encompassed the 11q13/IGH fusion. Nucleotide sequencing determined that the fusion occurred at the Salpha2 switch region and at the centromeric side of the major translocation cluster of BCL1. The other IGH allele consisted of a VDJ complex that was adjacent to the Cdelta constant gene, indicating that a class switch-like mechanism from the C(mu) to Cdelta was involved in the production of the Ig delta heavy chain. Point mutations within the P53 and N-RAS genes were presumably related to the rapidly progressive disease in this particular MM patient.
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PMID:Establishment and characterization of a new human myeloma cell line, KYdelta-1, producing the delta/kappa type immunoglobulin. 1167 73

A natural animal model for human head and neck squamous cell carcinoma (H/N SCC) has not been described. The domestic cat has a high spontaneous occurrence of oropharyngeal SCC, which is similar to the human disease in aggressiveness and incurability. We have developed a cell line (SCCF1) from a laryngeal SCC of a cat. Keratinocytes were maintained in culture for greater than 50 passages. SCCF1 had strong cytokeratin immunohistochemical staining, weak vimentin staining, and no p53 staining. Ultrastructual features included cytokeratin filaments and desmosomes, as well as features of anaplasia (irregular cytoplasmic and nuclear margins, surface filopodia, and abnormal intermediate filament production). Karyotype analysis revealed aneuploidy, with a stemline chromosomal number of 34. The cells grew logarithmically for 6 d until confluency. SCCF1 expressed parathyroid hormone-related protein (PTHrP) messenger ribonucleic acid (mRNA) and protein, and secreted the protein into the medium. Treatment of SCCF1 with transforming growth factor-beta increased PTHrP production but did not affect PTHrP mRNA stability. Reverse transcriptase-polymerase chain reaction was used to amplify a 282-base pair region of feline PTHrP mRNA, encoding portions of the pre-pro and coding regions. The complementary deoxyribonucleic acid (cDNA) was cloned and sequenced. The cDNA and the predicted amino acid sequences had a high degree of homology to human and canine PTHrP. RT-PCR was used to confirm alternate splicing of PTHrP mRNA for translation of PTHrP 1-139 and PTHrP 1-141. The SCCF1 cell line will permit mechanistic experiments on genetic dysregulation in neoplastic keratinocytes of the feline oropharynx, and development of an in vitro model for H/N cancer.
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PMID:Feline head and neck squamous cell carcinoma cell line: characterization, production of parathyroid hormone-related protein, and regulation by transforming growth factor-beta. 1177 73

The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.
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PMID:Mutations in CHEK2 associated with prostate cancer risk. 1253 88

The Bfl-1 gene, which was isolated from human fetal liver and only recently described, is a member of the Bcl-2 gene family. Reverse transcriptase-polymerase chain reaction was performed on RNA drawn from 30 breast cancer tissues to compare the expression of the Bfl-1 gene with other prognostic factors. The median relative ratio was 3.0 (range, 0.12-26.83) and the Bfl-1 gene expression rate was 36.7% (11/30). There was no statistically significant relationship between the clinicopathologic parameters of patients and the expression value of Bfl-1 gene. The level of Bfl-1 gene expression was higher in more advanced breast cancers than in early cancers. There was no significant relationship between the expression values and currently acknowledged prognostic factors, but a higher expression pattern was noticed in the groups of positive hormone receptors and negative p53 and negative c-erbB2, albeit statistically not significant. It seems that the increased expression of the Bfl-1 gene serves as a contributory factor in breast cancer, in the same way that another group of genes, the Bcl-2 family, contributes to apoptosis.
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PMID:Bfl-1 gene expression in breast cancer: its relationship with other prognostic factors. 1269 20


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