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)

The mechanism of tumor cell killing by HO-221, a novel benzoylphenylurea derivative that shows broad-spectrum antitumor activities, was studied. HO-221 strongly inhibited the activity of mammalian DNA polymerase alpha but not that of DNA polymerases beta or gamma. The inhibition was equivalent to that induced by aphidicolin and ara-CTP, which were selective inhibitors of the enzyme. Furthermore, the inhibition by HO-221 of DNA polymerase alpha was found to be non-competitive with respect to dCTP as a substrate, unlike that induced by aphidicolin and ara-CTP. The inhibition was reduced the addition of an excess of DNA polymerase alpha but not by excess amounts of activated DNA as a template primer. These results suggest that HO-221 inhibits the activity of DNA polymerase alpha by direct interaction with the enzyme in contrast to the impairment of template activity through intercalation into DNA induced by anthracycline compounds. On the other hand, HO-221 showed almost no effect on RNA polymerase activity, the reverse transcriptase activity of avian myeloblastosis virus or protein synthesis in a cell-free system. The flow-cytometry analysis revealed that HO-221 accumulated HL-60 cells in G1-S phases at a low concentration but increased the number of cells in the G1 phase at a higher concentration, stopping cell-cycle progression. The results suggest a correlation between cell-cycle progression and inhibition by HO-221 of DNA polymerase alpha, which plays a role in DNA replication during the S phase in living cells.
Cancer Chemother Pharmacol 1990
PMID:Mechanism of tumor cell killing by HO-221, a novel antitumor compound. 170 66

Reverse transcriptase (RT) transcribes viral RNA into DNA to be integrated into the host genome. To study epidemiological aspects of human leukemias and lymphomas which are known to express retroviruses, clinical specimens in this report were assayed for divalent cation-dependent viral-specific RT. The assay was carried out with cells solubilized with a detergent to release RT enzyme. RT was purified with poly(U)-Sepharose which fixed all DNA polymerases and assayed with 4 synthetic homopolymers, oligonucleotide primed-templates, poly(rA)-oligo(dT)12-18 or poly(dA)-oligo(dT)12-18 with Mg2+, poly(rC)-oligo(dG)12-18 or poly(rCm)-oligo(dG)12-18 with Mn2+ as divalent cation and [methyl-3H]thymidine 5'-triphosphate or deoxy[8-3H]guanosine 5-triphosphate respectively. Radioactivity incorporation of the precipitate allows quantitation of RT activity. One Hodgkin's disease, one out of 2 B lymphomas, one out of 2 T lymphomas, eight out of 12 leukemias were found to be positive for RT activity as well as acquired immunodeficiency syndrome (AIDS) patients, known to express RT. The obtained RT activity in hematological malignancies was found to be comparable to positive controls such as RT enzymes purified from avian myeloblastosis and Moloney murine leukemia viruses.
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PMID:Presence of reverse transcriptase in human leukemias and lymphomas. 170 70

A general transcription factor IID which binds to the TATA box promoter element on RNA polymerase II genes regulates and initiates eukaryotic mRNA synthesis. A quantitative polymerase chain reaction procedure was developed and the human transcription factor IID (hTFIID) transcript was measured in normal human tissues, lung carcinomas, lung carcinoma cell lines, and breast carcinomas. In some normal tissues such as liver, fetal lung, and placenta, relatively low to moderate levels of hTFIID mRNA were detected. In contrast, hTFIID transcript was highly expressed in nearly all solid lung carcinomas and cell lines including both small cell lung cancer and non-small cell lung cancer. hTFIID mRNA was present to a greater extent in small cell lung cancer than non-small cell lung cancer in solid tumors and cell lines. In solid carcinomas of breast, overexpression of hTFIID was also detected. A serum induction study using a serum-starved small cell lung cancer cell line, Lu134BS, indicated hTFIID transcription to be rapidly induced at 15 min following stimulation and its response essentially similar to that of protooncogene, c-fos. These results indicate the involvement of the expression of the general transcription factor hTFIID in lung and breast carcinoma, such as being associated with poor differentiation and high mitotic activity.
Cancer Res 1992 Jan 15
PMID:A general transcription initiation factor, human transcription factor IID, overexpressed in human lung and breast carcinoma and rapidly induced with serum stimulation. 172 4

Influence of water solutions of chemically pure adaptogen--synthetic analog of Rhodiola Rosea extract phenol composition (SAR) on functional activity of hemopoietic and tumor cells of mice with Ehrlich ascite cancer was studied in vitro. The periodical character of SAR effects was shown to be different for both types of cells, and at 1 x 10(-2) and 1 x 10(-26) M concentrations simultaneous stimulation of blood marrow cells colony-forming activity and inhibition of the latter in tumor elements was revealed. Essential changes of reactions of both cell types after adding the DNA-dependent RNA polymerase blocker Actinomycin D permit to suggest SAR effects to be connected with drug influence on the membrane RNA of the target cells.
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PMID:[Mechanism of differential effect of low dose adaptogens on the functional activity of normal and transformed cellular elements in vitro]. 179 47

The anthracycline antibiotic doxorubicin produces a characteristic myopathy in cardiac muscle that limits its use in cancer therapy. We have shown in cultured neonatal rat cardiac muscle cells that doxorubicin treatment resulted in a rapid, selective decrease in the expression of muscle-specific genes, which preceded other changes characteristic of doxorubicin cardiomyopathy. Doxorubicin selectively and dramatically decreased the levels of mRNA for the sarcomeric genes, alpha-actin, troponin I, and myosin light chain 2, as well as the muscle-specific, but nonsarcomeric M isoform of creatine kinase. However, doxorubicin did not affect nonmuscle gene transcripts (pyruvate kinase, ferritin heavy chain, and beta-actin). Actinomycin D, an inhibitor of DNA-dependent RNA polymerase, did not show a similar selective decrease of muscle-specific mRNAs but, rather, produced a nonspecific, dose-dependent decrease of muscle and nonmuscle transcripts. The doxorubicin effect on muscle gene expression was limited to cardiac muscle; cultured skeletal myocytes were resistant to the effects of doxorubicin at 100-fold greater doses than those causing changes in mRNA levels in cardiac muscle cells. These effects of doxorubicin were reproduced in vivo; rats injected with doxorubicin showed a dose-dependent decrease in the levels of mRNAs for alpha-actin, troponin I, myosin light chain 2, and M isoform of creatine kinase in cardiac but not skeletal muscle. These selective changes in gene expression in cardiocyte cultures and cardiac muscle precede classical ultrastructural changes and may explain the myofibrillar loss that characterizes doxorubicin cardiac injury.
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PMID:Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. 234 36

This study has evaluated changes in RNA synthesis in livers under the distant influence of a malignant tumor. A transplantable-induced sarcoma (MCG 101), transplanted on inbred adult mice (C57BL/6J), was used. Activities of DNA-dependent RNA polymerase (EC 2.7.7.6) were measured in relation to RNA content and translational activity. Liver nuclei from freely fed sarcoma-bearing mice had increased RNA synthesis. As a consequence of this, RNA content per DNA was increased in liver tissue. This was independent of depressed food intake and malnutrition. Elevated RNA synthesis, proportional to the tumor burden was due to an increased proportion of chromatin-engaged RNA polymerase I and II activities. RNA polymerase III activity (template-engaged form) was unchanged when evaluated in isolated nuclei, but appeared to be increased in partially purified extracts of nuclei. RNA content in tumor-host liver was a composite of increased levels of rRNA and tRNA, whereas the levels of poly(A)+ mRNA could not be measured as increased. Overall translational activities in vitro of mRNA from liver tissue of tumor-bearing, pair-weighed, and freely fed tumor-free controls were qualitatively and quantitatively different. mRNA from tumor-bearing mice directed an increased synthesis, particularly of larger proteins (above 55,000 daltons) compared with control animals. The results support the conclusion that previous evidence of elevated net protein synthesis in tumor-host liver is accompanied by increased transcription of genes coding for RNA and also for some or several hepatic proteins.
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PMID:Nuclear RNA polymerase activity in tumor-host livers. 241 3

An aqueous extract from the marine red alga, Schizymenia pacifica has been tested in a cell free system for its effect on reverse transcriptase from avian retrovirus (avian myeloblastosis virus), and mammalian retrovirus (Rauscher murine leukemia virus). The extract inhibited reverse transcriptase from both these retroviruses but showed almost no effect, if any, on the activity of cellular DNA polymerase alpha and RNA polymerase II in vitro. Consequently it is unlikely to have an adverse effect on the growth of cultured cell. The inhibitory activity of the extract was stable over a relatively wide pH range (pH 1-11) and was not lost after pronase digestion. Inhibitory activity of the extract was lost after boiling at 100 degrees C in 0.67 N HCl, and after treatment with 100 mM NaIO4. The active principle in the extract has an apparent molecular weight in excess of 100,000 daltons. This new reverse transcriptase inhibitor is probably a polysaccharide.
J Cancer Res Clin Oncol 1987
PMID:Antiretroviral activity in a marine red alga: reverse transcriptase inhibition by an aqueous extract of Schizymenia pacifica. 244 71

Transplantable erythroblastic leukemia was induced by 300-rad irradiation of C3H mice. Conditions for in vitro growth of the leukemic cells were studied. None of interleukin-3, granulocyte/macrophage colony-stimulating factor and erythropoietin could support the growth of the cells in vitro. In contrast, the leukemic cells grew into a stroma-dependent cell line, ELM-D, in close contact with the stromal cell layer of 900-rad-irradiated long-term bone marrow culture. A stroma-independent cell line, termed ELM-I-1, was further established from the non-adherent population in the co-culture of the leukemic cells, ELM-D, with stromal cells. Reverse transcriptase activity was not detectable in ELM-D or ELM-I-1 cells. Studies on binding and cross-linking of 125I-erythropoietin showed that ELM-I-1 cells had erythropoietin receptors, and two major radiolabeled protein products with molecular weights of 120 kDa and 140 kDa were detected on sodium dodecyl sulfate/polyacrylamide gel electrophoresis under reducing conditions.
Jpn J Cancer Res 1988 Aug
PMID:Stromal cell-dependent growth of leukemic cells from murine erythroblastic leukemia. 246 Apr 23

The transcriptional and replicative activities of hepatic nuclei during DNA damage induced by 1,2-dichloroethane (DCE), a hepatocarcinogen, were examined. DNA damage was measured by DNA alkylation in rodents exposed to DCE. A time-dependent DNA damage in vivo and in vitro was observed. A significant inhibition of RNA synthesis was observed when transcription was carried out in vitro using nuclei of DCE-treated animal. The inhibition in RNA synthesis persisted even when 50% of DNA damage was removed. Similarly, nuclear DNA synthesis in vitro was also significantly inhibited during DNA damage. However, DNA synthesis was recovered rapidly even though 50% of DNA damage persisted. Results on the effect of alpha-amanitin on RNA synthesis suggest that 50-70% of synthesis was carried out by RNA polymerase II.
Cancer Biochem Biophys 1988 Nov
PMID:DNA damage in rodent liver by 1,2-dichloroethane, a hepatocarcinogen. 247 72

Glucocorticoids inhibit the proliferation of murine T-lymphoma P1798 cells. P1798 cells do not die in the presence of dexamethasone, and the process of inhibition of proliferation is completely reversible. As cells cease to divide, expression of a number of genes is inhibited. Among these are genes the expression of which is regulated in some manner that is linked to cell proliferation. We have undertaken to study the mechanism whereby glucocorticoids inhibit the expression of genes in P1798 cells. Three model systems will be reviewed. In all cases, these appear to be examples of secondary regulation. Glucocorticoid-mediated inhibition of transcription of the DNA encoding ribosomal RNA (rDNA) has been investigated in some detail. The data indicate that dexamethasone causes a decrease in the amount or activity of an RNA polymerase I transcription initiation factor. This factor exhibits a short biological half-life and the data are consistent with the hypothesis that glucocorticoids regulate the synthesis of this transcription factor. The gene encoding thymidine kinase appears to be regulated in a similar fashion. On this basis, we propose that glucocorticoids may have the general property of regulating the synthesis of certain transcription factors. Glucocorticoids also regulate the translation of a certain class of mRNAs, including those that encode ribosomal proteins. These are characterized by a low efficiency of translation in untreated cells. Upon exposure to dexamethasone, the translation of these mRNAs is disproportionately inhibited. We speculate that translation of the mRNAs encoding certain transcription factors may be regulated in a similar fashion. Specifically, we propose that transcription of certain proliferation-related genes may be dependent upon factors of short biological half-life. These are encoded by mRNAs that are poorly translated under optimal growth conditions. Any slight perturbation in translation efficiency, as caused by glucocorticoids, results in a disproportionate inhibition of synthesis of these hypothetical transcription factors. Transcription of a class of proliferation-related genes ceases as a result.
Cancer Res 1989 Apr 15
PMID:Glucocorticoid inhibition of gene expression and proliferation of murine lymphoid cells in vitro. 270 66


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