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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Telomerase is a ribonucleoprotein complex with reverse-transcriptase activity responsible for telomere reconstitution. High telomerase activity was found in cancer cells, but not in differentiated homologous nonmalignant tissues. We demonstrated previously that the disappearance of telomerase activity is a reliable marker of tumor cell killing in human cancer cell lines. We have investigated the possibility of evaluating chemosensitivity of neoplastic cells of different origin [ovary, lung, breast, gastrointestinal, skin (melanoma)] obtained from cancer patients, by measuring residual telomerase activity after drug treatment in vitro. Using the classical telomeric repeat amplification protocol ("TRAP") assay based on polymerase chain reaction, we examined telomerase activity of untreated or drug-treated tumor cell suspensions, derived from the processing of surgical specimens. Feasibility and reproducibility of the assay were evaluated according to various parameters, including drug concentration, time of in vitro culture, and type of tumor. The results indicated that the assay is highly sensitive and reproducible, and can be performed using surgical specimens in a reasonable percentage of cases, ranging from 40% (breast cancer) to 100% (ovarian cancer). Moreover, the assay provides comparable results using a wide range of tumor cells, and the presence of normal cells does not interfere with the results. Prolonged tumor cell culture is not required because the assay can be completed within 24 to 72 hours after sample collection. In conclusion, the present investigation provides the technical bases for future studies to evaluate whether this assay would be able to predict patient's response to antitumor agents.
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PMID:Suppression of telomerase activity as an indicator of drug-induced cytotoxicity against cancer cells: in vitro studies with fresh human tumor samples. 1046 37

Tumor-associated trypsin inhibitor (TATI) is a 6-kDa peptide, which is identical to the pancreatic-secretory-trypsin inhibitor (PSTI). TATI is produced by several tumors and cancer cell lines, and is used as a serum marker for mucinous ovarian cancer. Elevated serum levels of TATI have also been observed in renal-cell carcinoma (RCC). However, it is unclear whether the increase of serum TATI in this disease is caused by production of TATI by the tumor tissue, by the acute-phase reaction frequently associated with cancer, or by impaired renal function. We examined the expression of TATI in malignant and histologically normal renal tissue by immunohistochemistry, in situ hybridization and reverse-transcriptase-polymerase-chain reaction (RT-PCR). Furthermore, we measured pre-operative serum TATI levels in 21 patients with RCC. Immunohistochemically, TATI was detected in 13 of 20 histologically normal renal-tissue samples, but not in 32 tissue samples from RCC. By RT-PCR, TATI mRNA was detected in all of 10 histologically normal kidneys and in 6 of 11 RCCs, while in situ hybridization analysis gave negative results. Pre-operative serum TATI was elevated in 57% of RCC patients. We also studied expression of TATI mRNA and protein in 7 renal-cancer cell lines, by RT-PCR and immunofluorometric assay respectively: 6 cancer cell lines were positive for TATI mRNA, while 4 of them also produced TATI protein at low levels. These results indicate that TATI is synthesized by the histologically normal renal tissue and by some renal cancers, and suggest that the elevation of serum TATI associated with renal-cell carcinoma may be caused by the release of TATI produced by the tumor.
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PMID:Tumor-associated trypsin inhibitor in normal and malignant renal tissue and in serum of renal-cell carcinoma patients. 1050 84

The breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are likely to participate in DNA lesion processing. Oxidative lesions, such as 8-oxoguanine, occur in DNA after endogenous or exogenous oxidative stress. We show that deficiency for either BRCA1 or BRCA2 in human cancer cells leads to a block of the RNA polymerase II transcription machinery at the 8-oxoguanine site and impairs the transcription-coupled repair of the lesion, leading to a high mutation rate. Expression of wild-type BRCA1 from a recombinant adenovirus fully complements the repair defect in BRCA1-deficient cells. These results represent the first demonstration of the essential contribution of BRCA1 and BRCA2 gene products in the repair of the 8-oxoguanine oxidative damage specifically located on the transcribed strand in human cells. This suggests that cells from individuals predisposed to breast and/or ovarian cancer may undergo a high rate of mutations because of the deficiency of this damage repair pathway after oxidative stress.
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PMID:BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. 1103 1

Vaccinia virus is being investigated as a replicating vector for tumor-directed gene therapy. However, the majority of cancer patients have preformed immunologic reactivity against vaccinia virus, as a result of smallpox vaccination, which may limit its use as a vector. The Yaba-like disease (YLD) virus was investigated here as an alternative, replicating poxvirus for cancer gene therapy. We have demonstrated that the YLD virus does not cross-react with vaccinia virus antibodies, and it replicates efficiently in human tumor cells. YLD virus can be expanded and purified to high titer in CV-1 cells under conditions utilized for vaccinia virus. The YLD virus RNA polymerase was able to express genes regulated by a synthetic promoter designed for use in orthopoxviruses. We sequenced the YLD virus TK gene and created a shuttle plasmid, which allowed the recombination of the green fluorescent protein (GFP) gene into the YLD virus. In a murine model of ovarian cancer, up to 38% of cells in the tumor expressed the GFP transgene 12 days after intraperitoneal virus delivery. YLD virus has favorable characteristics as a vector for cancer gene therapy, and this potential should be explored further.
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PMID:Yaba-like disease virus: an alternative replicating poxvirus vector for cancer gene therapy. 1158 98

In the present study, expression and regulation of hCG receptor mRNA were analyzed in four established human ovarian cancer cell lines using different concentrations of hCG, EGF, and 8-bromo-cAMP for different periods between 6 and 72 h. The cells were examined for the hCG receptor using the reverse-transcriptase polymerase chain reaction with specific primers amplifying the hCG receptor gene. Receptor mRNA was found in all cell lines. In the line OVCAR-3, it was expressed in all samples independent of kind and concentration of the receptor agonist and incubation period. In the line COLO-704, the hCG receptor gene was expressed only in unstimulated samples, but not in the samples incubated with a receptor agonist. The cell line EFO-21 showed a downregulation of receptor mRNA after 24 h of treatment with 25 IU/ml hCG and after 6 h of treatment with 250 IU/ml hCG or 100 ng/ml EGF. The mRNA reappeared within 24-48 h. The cell line EFO-27 showed a downregulation of receptor mRNA after 6 h of incubation with 250 IU/ml hCG. Agarose gel electrophoresis and sequencing of the polymerase chain reaction products revealed four cDNA fragments resulting from an alternative splicing of the primary transcript. The results of the study demonstrate that the expression of hCG receptor mRNA in ovarian cancer cell lines varies considerably under different experimental conditions. We showed that ovarian cancer cells can produce hCG receptors when needed or wanted. The inherent mechanisms which rule this phenomenon need further evaluation.
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PMID:The expression of hCG receptor mRNA in four human ovarian cancer cell lines varies considerably under different experimental conditions. 1274 22

The BRCA1 gene was isolated in 1994; germline mutations of this gene are known to confer susceptibility to breast and ovarian cancer in high-risk families. Since its discovery, several mutations have been identified in this gene; these are scattered throughout the gene, and include insertion and deletion frameshifts, base substitutions, and inferred regulatory mutations. It role in the pathogenesis of breast cancer, which accounts for almost 95%, although unproven to date, cannot be ruled out. The functional inactivation of both copies of this gene in sporadic tumor cells does not follow the traditional mode: the loss of function in BRCA1 is not accompanied by underlying mutation of the gene in tumor cells with loss of heterozygosity for the BRCA1 gene. Several studies now suggest that an alternate mechanism of inactivation, involving promoter hypermethylation that results in reduced expression of the gene, may be common to a significant proportion of sporadic breast and ovarian cancers. BRCA1 as a tumor suppressor plays an important role in maintaining genomic stability. BRCA1 has the ability to interact with numerous proteins and to form complexes that are involved in recognizing and subsequently repairing DNA. BRCA1 contains several functional domains that directly or indirectly interact with a variety of proteins via protein-protein interaction; these include tumor suppressors (BRCA2, p53, Rb and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell cycle regulators (cyclins and cyclin dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP), DNA damage-sensing complex and mismatch repair proteins (BRCA1- Associated Surveillance Complex; BASC) and signal transducer and activator of transcription (STAT) among others Formation of foci containing BRCA1 by inherited mutations, or epigenetic mechanisms (promoter methylation) in sporadic cancers leads to a loss of DNA repair ability, disrupts the potential to form complexes with other proteins that are crucial for DNA repair pathways. Thus, BRCA1 plays a significant role in maintaining genomic stability and serves as a tumor suppressor in breast cancer tumorigenesis.
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PMID:BRCA1 in cancer, cell cycle and genomic stability. 1295 14

In a woman with cervical cancer and a distant lesion, the histologic distinction of metastatic cervical cancer versus another primary tumor or metastases from another cancer can be difficult and has important clinical implications. Criteria for inclusion in the study were a history of primary cervical cancer and a new lesion in which the pathologic differential diagnosis was metastatic cervical cancer versus new primary versus metastatic ovarian carcinoma. Ten cases were identified. The cervical cancers and the other lesion(s) were tested for human papillomavirus DNA by in situ hybridization and human papillomavirus RNA (E6/E7) by reverse transcriptase in situ polymerase chain reaction. Human papillomavirus DNA was detected in the primary cervical cancer by in situ hybridization in five of nine cases; viral RNA was detected by reverse transcriptase in situ polymerase chain reaction in nine of nine cases (one case was not available for viral testing). In six cases, human papillomavirus was detected in the subsequent lesion (three lung, one cervical lymph node, two retroperitoneum), documenting the latter was metastatic cervical cancer. Human papillomavirus was not detected in the other four cases (two lung, two retroperitoneum in women with ovarian cancer), documenting that they were either primary lung cancers or metastatic ovarian cancers, respectively. Reverse transcriptase in situ polymerase chain reaction for human papillomavirus RNA is a reliable method to differentiate metastatic cervical carcinoma from either a new primary tumor or a metastasis from another cancer.
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PMID:Utility of HPV analysis for evaluation of possible metastatic disease in women with cervical cancer. 1466 43

Mutations in BRCA1 predominantly lead to elevated risks of breast and ovarian cancers. In contrast to the tissue-specific nature of BRCA1tumors, the normal BRCA1 gene product functions in diverse nuclear events including transcription, DNA repair, and DNA damage checkpoint. Recent findings of physical and functional associations between BRCA1 and the RNA polymerase II (RNAPII)-dependent transcription machinery may shed some light on this longstanding paradox of BRCA1 biology. Eukaryotic gene expression is now known to be a continuous process, whereby each step is physically and functionally connected to the next. In particular, RNAPII plays a pivotal role in coordinating transcription with various pre-mRNA processing events and stress response. Interestingly, BRCA1 preferentially interacts with the processive form of RNAPII and proteins that regulate RNAPII activity and movement during transcription elongation. In response to DNA damage, BRCA1 dissociates from RNAPII and localizes to DNA damage sites. We propose that BRCA1 may coordinate multiple steps in gene expression, including transcription initiation, elongation, and pre-mRNA processing via its interactions with the transcription machinery at selected gene loci. The same BRCA1-associated transcription apparatus may serve as a sensor for stress signals and facilitate the transition from a transcription state to checkpoint/DNA repair state. Such a coordinating role of BRCA1 in gene expression may ensure the appropriate quantity and quality of the mature transcripts for certain breast and ovarian cancer-related genes, as well as the genetic integrity of the breast and ovary tissues.
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PMID:BRCA1: a locus-specific "liaison" in gene expression and genetic integrity. 1572 43

The SR-related-CTD-associated-factors (SCAFs) have the ability to interact with the C-terminal domain of the RNA polymerase II, linking this way transcription to splicing. SRA1 (SR-A1) gene, encoding for a human high-molecular weight SCAF protein, is located on chromosome 19, between the IRF3 and the R-RAS oncogene and it has been demonstrated from members of our group that SRA1 is constitutively expressed in most of the human tissues, while it is overexpressed in a subset of ovarian tumors. In this study, we examine the expression of SRA1 gene in 111 ovarian malignant tissues and in the human ovarian carcinoma cell lines OVCAR-3, TOV21-G, and ES-2, using a semi-quantitative RT-PCR method. SRA1 gene was overexpressed in 61/111 (55%) of ovarian carcinomas. This higher expression was positively associated to the size of the tumor (p<0.001), the grade and the stage of the disease (p=0.003 and p=0.006, respectively), and the debulking success (p<0.001). Kaplan-Meier survival analysis revealed that lower SRA1 expression increases the probability of both the longer overall and the progression free survival of the patients. Multivariate Cox regression analysis revealed that SRA1 may be used as an independent prognostic biomarker in ovarian cancer. Our results suggest that SRA1 is associated with cancer progression and may possibly be characterized as a new marker of unfavorable prognosis for ovarian cancer.
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PMID:Expression analysis and prognostic significance of the SRA1 gene, in ovarian cancer. 1663 Nov 23

The tethered RuII half-sandwich complexes [eta(6):eta(1)-C(6)H(5)(CH(2))(n)NH(2))RuCl(2)] 1 (n = 3) and 2 (n = 2) have been synthesized as potential bifunctional anticancer complexes, and their X-ray crystal structures have been determined. They hydrolyze rapidly in aqueous solution to give predominantly mono-aqua mono-chlorido species. Mono-9EtG adducts, where 9EtG = 9-ethylguanine, form rapidly, but the second 9EtG binds more slowly and more weakly. In the X-ray crystal structure of the di-9EtG adduct [(eta(6):eta(1)-C(6)H(5)(CH(2))(3)NH(2))Ru(9EtG)2](CF(3)SO(3))(2).H(2)O (8.H(2)O), one of the Ru-N7 bonds is significantly longer than the other (2.1588(18) vs 2.101(2) A). The bound guanine bases adopt a head-to-head configuration, stabilized by tether NH2 hydrogen bonding to C6O of 9EtG. The X-ray crystal structure of the dinitrato complex [(eta(6):eta(1)-C(6)H(5)(CH(2))(3)NH(2))Ru(NO(3))(2)] (3) showed both nitrates to be bound to ruthenium. This complex readily rutheniated calf thymus DNA but failed to produce stop sites on pSP73KB plasmid DNA during DNA transcription by an RNA polymerase. This suggested that only monofunctional DNA adducts formed, as did interstrand cross-linking assays. Also, the unwinding angle induced in negatively supercoiled DNA (9 +/- 1 degrees) was less than that induced by cisplatin (13 degrees). These findings may explain why complexes such as 1 and 2 exhibited low cytotoxicities (IC(50) values >100 microM) toward A2780 human ovarian cancer cells.
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PMID:Bifunctional amine-tethered ruthenium(II) arene complexes form monofunctional adducts on DNA. 1785 Jan 43


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