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)

About half of the familial breast cancer cases are found to bear mutations in the breast cancer susceptibility gene 1 (BRCA1). The majority of BRCA1 mutations produce a truncated protein and BRCA1-associated breast tumors exhibit a number of defined tumor phenotypes. The function of BRCA1 has been examined in gene knockout mice in which the nullizygous mice die early in utero, but this lethality can be partially rescued by a nullizygous p53 mutation. Wild-type BRCA1 protein binds to a number of cellular proteins, including DNA repair protein Rad51, tumor suppressor p53, RNA polymerase II holoenzyme, RNA helicase A, CtBP-interacting protein, c-myc, BRCA1-associated RING domain protein (BARD1), BRCA2 protein, etc. These proteins likely mediate the involvement of BRCA1 in DNA repair, transcriptional transactivation, and cell cycle control. Overall, BRCA1 protein may act as a converging vehicle for cell regulatory proteins to associate with. Therefore, mutations in BRCA1 may affect the composition of these complexes on which dysregulation of cellular functions with eventual development of malignancy is expected.
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PMID:The functions of breast cancer susceptibility gene 1 (BRCA1) product and its associated proteins. 1019 18

The morphological changes of argyrophilic nucleolar organizer regions (AgNORs) were studied in two human breast cancer cell lines, MCF-7 and HBC-4. Treatment with an RNA polymerase inhibitor (actinomycin D) reduced the size of AgNORs and increased the number of AgNORs. Messenger RNA polymerase inhibitor (alpha-amanitin) also increased the number of AgNORs. However, translational blocking agents closely related to ribosomal RNA (cycloheximide and anisomycin) caused a decrease in the number of AgNORs, which seemed to fuse to an aggregate around the nucleolus and formed a single large spherical AgNOR in the final stage. These changes were observed typically when cells were treated with 5-fluorouracil or 5-fluorouridine. These morphological changes in the AgNORs pattern, AgNORs aggregation, might reflect certain damage in ribosomal RNA.
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PMID:In vitro changes of the nuclear AgNORs pattern induced by RNA inhibitors and 5-fluorouracil in human breast cancer cells, MCF-7 and HBC-4. 1038 Nov 35

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

Basic fibroblast growth factor (bFGF) is a classical mitogen in fibroblasts and endothelial cells. Our previous studies have demonstrated that bFGF inhibits the growth of MCF-7 human breast cancer cells. The aim of the present study was to examine the effect of bFGF on cis-diamminedichloroplatinum(cisplatin)-induced cytotoxicity in MCF-7 breast cancer cells as compared to normal endothelial cells. MCF-7/NCF cells transduced with a vector expressing the bFGF gene and overexpressing its product, and MCF-7/N2 cells transduced with the backbone vector were incubated with a combination of bFGF and cisplatin for 5 days; results were compared with those obtained with bovine aortic endothelial cells. Cell proliferation was assessed with the sulforhodamine B colorimetric cytotoxicity assay. Apoptosis was quantitatively determined by flow-cytometric analysis for DNA damage and the apoptotic death assay for DNA fragmentation, and qualitatively by electron microscopy. Reverse transcriptase/polymerase chain reaction analysis and an enzyme immunoassay were used to determine the mRNA and protein level, respectively, of the anti-apoptotic bcl-2 gene product. We found that bFGF enhanced cisplatin-induced cytotoxicity in MCF-7 breast cancer sublines. bFGF enhanced proliferation of normal endothelial cells and did not increase cisplatin-induced cytotoxicity. This effect was accompanied by down-regulation of the anti-apoptotic protooncogene bcl-2 and the enhancement of cisplatin-induced apoptosis. We suggest that the improved understanding of the role of bFGF in the differential modulation of the response of breast cancer and normal endothelial cells to chemotherapy may enable active intervention to alter the therapeutic ratio favorably in breast cancer patients.
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PMID:Basic fibroblast growth factor potentiates cisplatinum-induced cytotoxicity in MCF-7 human breast cancer cells. 1047 68

We have investigated the mechanisms by which radiation inhibits proliferation of human breast cancer cells in culture. Radiation, within the dose range used for treatment of humans, decreased the rate of proliferation of estrogen-independent MDA-MB-231 cells more effectively than it did that of estrogen-dependent MCF-7 cells. The rate of proliferation of MDA-MB-231 cells was also inhibited to a greater extent than that of MCF-7 cells by purified TGFB1. Using an ELISA specific for activated TGFB1, we found that conditioned medium from irradiated MDA-MB-231 or MCF-7 cells contained twofold more TGFB1 than that from nonirradiated cells. Conditioned medium from irradiated breast cancer cells, but not from nonirradiated cells, inhibited the growth of untreated MDA-MB-231 cells. The inhibitory activity was blocked by an anti-TGFB1 neutralizing antibody. An approximately twofold increase in the TGFB1 mRNA in irradiated cells compared to controls was found using semiquantitative reverse-transcriptase PCR. Last, the mRNA for insulin-like growth factor binding protein 3, a reported target of the cell inhibitory activity of TGFB1, was increased threefold upon irradiation. Our results demonstrate that the TGFB1 is increased after irradiation and that the activation of the TGFB1 signaling pathway may sensitize cells to the effects of radiation.
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PMID:Regulation of transforming growth factor beta1 by radiation in cells of two human breast cancer cell lines. 1052 25

1alpha,25-dihydroxyvitamin D(3) (VD) is a pleiotropic nuclear hormone that also has effects on cell cycle regulation. VD and its synthetic analogues are known inhibitors of cellular growth and inducers of apoptosis, however, the primary mediator genes of these effects largely remain unknown. In order to identify novel targets for VD, that may be involved in the regulation of the cell cycle, a differential display PCR (ddPCR) approach was applied to the MCF-7 human breast cancer cell line, which provided the gene for cyclin C as an interesting candidate. Quantitative assessment of cyclin C expression showed that the gene was significantly upregulated by VD and its analogues, EB1089 and CB1093 both on the level of mRNA expression and more so on the level of protein expression in MCF-7 cells. Upregulation of cyclin C protein expression could also be confirmed in MeWo human melanoma and in U937 human promyelocytic leukemia cells. This observation adds a new gene candidate to the list of primary VD responding genes. Cyclin C is not a typical cyclin, as it apparently modulates the activity of the RNA polymerase II complex, which provides fresh insight into the mechanisms of cell cycle and general transcriptional regulation by VD and its analogues.
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PMID:Cyclin C is a primary 1alpha,25-dihydroxyvitamin D(3) responding gene. 1067 18

Nerve growth factor (NGF) is known to exert a mitogenic effect on human breast cancer cells through proto-TrkA activation. Reverse transcriptase-PCR analysis of proto-TrkA expression in human breast carcinoma specimens and cell lines revealed trkA transcript in 12 of 14 human breast carcinoma specimens and in all of four cell lines tested. While cytofluorimetric and Western blot analysis indicated proto-TrkA expression in three of the four cell lines, NGF stimulated growth in only two of the three positive cell lines. Inhibition of NGF-induced MAPK activation by an antibody directed against the extracellular domain of TrkA but not by an inhibitor of TrkA phosphorylation demonstrated the requirement of NGF binding but not of proto-TrkA kinase activity for MAPK activation, suggesting the recruitment of another kinase for transmission of the mitogenic signaling. Indeed, NGF induced tyrosine phosphorylation and stimulated kinase activity of p185(HER2), a kinase receptor of the HER family. A TrkA phosphorylation inhibitor did not affect this activation. Moreover, the two receptors were coprecipitated by antibodies directed against proto-TrkA and p185(HER2). Down-modulation of p185(HER2) expression in a breast carcinoma line transfected with a construct containing an anti-p185(HER2) antibody sequence and expressing proto-TrkA impaired NGF-induced MAPK activation and proliferation. Together these data show that in cells expressing low levels of TrkA such as breast carcinoma cells, NGF must recruit other overexpressed receptors such as p185(HER2) in order to generate a biological signal that can induce breast cancer cell growth.
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PMID:Nerve growth factor cooperates with p185(HER2) in activating growth of human breast carcinoma cells. 1068 13

The presence of axillary lymph node metastasis in patients with breast cancer is a major prognostic factor and also determines the use of adjuvant chemotherapy. Micrometastasis has been arbitrary defined as deposits of < 2 mm dimension. Earlier studies of micrometastases failed to demonstrate prognostic relevance. However, when larger numbers of patients were followed up for longer periods, micrometastasis was shown to be a significantly poor prognostic parameter with patients having a survival rate similar to those with macrometastasis or nodal disease. There are no compelling reasons to retain the term "micrometastasis" in the light of these findings and our understanding of tumor biology. Routine histological examination of axillary lymph nodes is a notoriously inaccurate method for the detection of metastases. When serial or multilevel sectioning and/or immunohistochemical staining for cytokeratin were employed, detection rates increased by as much as 33%. Reverse transcriptase-polymerase chain reaction and Southern blotting for CK19 may be a more accurate method of examination. However, there are inherent technical problems associated with this method, and the recent finding of a pseudogene with great homology to CK19 in normal peripheral blood nucleated cells further emphasises the need for caution in this approach. It is not cost-effective to employ serial sectioning and immunohistochemistry when examining the axillary contents. However, the introduction of sentinel-node biopsy may allow detailed examination of the single node most likely to harbour a metastatic tumor.
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PMID:The prognostic dilemma of nodal micrometastases in breast carcinoma. 1089 73

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

Tumor cells can reach every anatomic district, organ and tissue through the peripheral blood circulation. Tumor cell shedding is considered an early event in the multi-phase process of metastasis, and the possibility of detecting tumor cells in the bloodstream and/or bone marrow before clinical evidence of distant metastases needs to be explored. The use of new sophisticated diagnostic and investigative techniques has boosted the study of tumor cell contamination of bone marrow and peripheral blood. Molecular techniques, such as reverse-transcriptase polymerase chain reaction, may be useful tools to reach this target, but, today, immunocytochemistry is still considered the gold standard to assess new techniques to detect isolated tumor cells in hematopoietic tissue. Little is known about the biology of isolated tumor cells in the peripheral blood or bone marrow. Two crucial points need to be evaluated: the identification of specific markers of breast cancer cells with clonogenic potential and their biologic properties, and the prognostic impact of the detection of isolated tumor cells in the bone marrow or peripheral blood stem cell collections.
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PMID:Detection of breast cancer cells in the bone marrow or peripheral blood: methods and prognostic significance. 1093 95


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