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)

The literature on various isolated carcinogen-DNA adducts indicates clearly that the binding of chemical carcinogens to DNA is highly specific. Since DNA in eukaryotic cells is complexed with chromosomal proteins and organized into transcriptionally active and inactive chromatin, chemical carcinogens also might show binding specificities at the chromatin level. Using Escherichia coli RNA polymerase and the endogenous engaged RNA polymerase I as specific probes to monitor respectively the physiologically inactive and active nucleolar chromatin template function, this paper reports that aflatoxin B1, after metabolic activation either in vivo or in vitro, binds preferentially to the physiologically active regions of rat liver nucleolar chromatin, and that this binding specificity is largely lost after the removal of chromosomal proteins from the nucleoli.
Carcinogenesis 1983
PMID:Preferential binding of aflatoxin B1 to the transcriptionally active regions of rat liver nucleolar chromatin in vivo and in vitro. 640 39

DNA isolated from rat liver by intensive deproteinization with chloroform/isoamyl alcohol and phenol contains low molecular weight peptides in a quantity of about 20 micrograms/mg DNA. These peptides show high specific activity in inhibiting transcription in a reconstituted cell-free system with prokaryotic and eukaryotic RNA polymerase. Their level is markedly decreased in DNA prepared from Novikoff hepatoma cells. Moreover the amino acid analysis and the pattern of analytical separation by high performance liquid chromatography (HPLC) show some biochemical differences between DNA-binding peptides extracted from rat liver and Novikoff hepatoma cells. The possibility that carcinogenesis may involve mechanisms which lead to selective removal of some components of the DNA-binding peptides, is discussed.
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PMID:DNA-binding peptides from rat liver and Novikoff hepatoma cells: quantitative level and possible biochemical differences. 668 24

Recent studies from this laboratory have shown that several chemical carcinogens, i.e., aflatoxin B1, N-OH-2-acetyl-aminofluorene, actinomycin D, and methylazoxymethanol acetate, when administered in vivo, have all produced a selective and dramatic inhibition of rat liver nuclear RNA polymerase II activity. To determine whether this inhibition is related to carcinogenesis, aflatoxin B1 is used as a model system to test tissue, sex, and animal species specificity that is known to be characteristic of carcinogenesis. The results show that aflatoxin B1 (3 mg/kg body weight, i.p., 2h) inhibits RNA polymerase II activity only in the target tissue, liver, and not in the non-target tissues, e.g., lung and brain. It inhibits liver RNA polymerase II activity preferentially in male over female rats, and has no effect on mouse liver RNA polymerase II activity. These results are in good agreement with the specificities of aflatoxin B1 carcinogenesis in the whole animal systems. Furthermore, with the four principal aflatoxins tested, the order of inhibitor effect on RNA polymerase II is: B1 greater than G1 greater than B2, G2. It is concluded, therefore, that the inhibition of RNA polymerase II activity and carcinogenesis are likely to be related and that it is theoretically sound to use this inhibition as a diagnostic tool to screen potential carcinogens.
Carcinogenesis 1982
PMID:Tissue, sex, and animal species specificity of aflatoxin B1 inhibition of nuclear RNA polymerase II activity. 681 78

Adult rat hepatocytes in primary culture were used to study the effect of tryptophan pyrolysis products on the transcriptional process. Hepatocytes were treated with 1, 5 and 10 micrograms/ml of 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]-indole (Trp-P-1) or 3-amino-1-methyl-5H-pyrido-[4,3-b]-indole (Trp-P-2) for 2 and 4 h. The ultrastructural study revealed the appearance of nucleolar microsegregation accompanied by a reduction in peri- and interchromatin fibrils and granules in hepatocytes exposed to 10 micrograms/ml of each pyrolysate for 1 or 2 h. Biochemical investigation showed that the incorporation of [3H]uridine into nuclear RNA of treated hepatocytes was strongly decreased. Time- and concentration-related inhibition have been established; however, the inhibitory effect of Trp-P-1 was always superior to that of Trp-P-2. The determination of Mg2+-dependent RNA polymerase activity in an in vitro system functioning with isolated rat liver nuclei incubated in the presence of Trp-P-1 or Trp-P-2 showed a 40% inhibition of this activity. After a 1-h exposure of hepatocytes to 5 and 10 micrograms/ml of Trp-P-1, the recovery of RNA synthesis capacity was complete by 2 h and that of normal ultrastructural aspect was achieved within 4 h. All these results indicated that Trp-P-1 and Try-P-2 acted at the nucleolar level by a blockade of pre-rRNA synthesis and at the extranucleolar by decreasing the ultrastructural RNP responsible for hnRNA synthesis.
Carcinogenesis 1983
PMID:Ultrastructural and biochemical alterations induced by tryptophan pyrolysis products on rat hepatocytes in primary culture. I. Action on the transcriptional process. 683 20

DNA isolated from cell nuclei by intensive deproteinization with chloroform/isoamyl alcohol and phenol extractons contains a low molecular weight peptidic fraction in a quantity of about 20 micrograms/mg DNA. These peptides were characterized by chromatography on CM-Sephadex, Sephadex G-25, high performance liquid chromatography on microBondapak C18 and amino acid composition. The peptides control transcription in a reconstituted cell-free system with prokaryotic and eukaryotic RNA polymerase and stabilize the structure of double stranded DNA, while increasing its melting point. Their level is markedly decreased (by about 40%) in DNA prepared from tumor cells as compared to normal cell DNA. Transcriptional studies showed only a slightly increased template activity of DNA extracted at pH 9.5 versus DNA extracted at pH 6.0 for DNA preparations from tumor cells. However, there was a marked increase in template activity for DNA preparations treated at pH 9.5 from normal cells--232%, 124%, 97% and 78% for rat liver, mouse liver, mouse thymus and fibroblast L-929 cells, respectively. Also there was no difference in the melting point between these two preparations of DNA from tumor cells; normal cell DNA preparations showed increased melting point of preparations treated at pH 6.5. The data obtained indicate that the loss of low molecular weight peptides from tumor DNA during carcinogenesis is responsible for uncontrolled gene expression observed in cancer.
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PMID:Low molecular weight peptidic fraction in the chromatin from normal and cancer cells: control of transcription. 741 71

Using immunostaining, immunoblot, reverse-transcriptase polymerase chain reaction and Southern blot, we found that expressions of CD44 isoforms and E-cadherin were very closely linked and were correlated with the differentiation status in human urothelial cell lines and clinical specimens of transitional cell carcinoma. Normal urothelium, well to moderately differentiated cell lines and surgical samples expressed E-cadherin and large CD44 isoforms containing exon v6, which was pivotal in metastasis of rat pancreatic cell line model. Poorly differentiated cell lines and surgical samples, were E-cadherin-negative and expressed primarily standard form CD44, which did not contain exon v6. We concluded that CD44v6 isoforms and E-cadherin were both down-regulated during the carcinogenesis of urothelium. The large exon v6 containing CD44 isoforms were readily detected in normal urothelium, therefore, were not likely linked to cancer metastasis. E-cadherin and CD44v6 may be used as differentiation markers for human urothelial tumors. Immunohistochemical study solely with antibody against epitopes encoded by exon v6 alone is not informative enough as other alternatively spliced exons may change the function of CD44v6 isoforms.
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PMID:Correlation of expression of CD44 isoforms and E-cadherin with differentiation in human urothelial cell lines and transitional cell carcinoma. 753 58

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multisite carcinogen. Although the hepatocarcinogenic actions of TCDD have received the most attention, it has been demonstrated in several rodent carcinogenicity bioassays that TCDD causes a dose-related increase in thyroid follicular cell adenomas and carcinomas. The purpose of the present experiment was to investigate the dose-response relationship for thyroid function alterations in female Sprague-Dawley rats following chronic treatment with TCDD. TCDD was administered via oral gavage biweekly for 30 weeks at average daily equivalent doses of 0.1-125 ng/kg/day, thereby more than encompassing the dose range historically used in previous TCDD rodent bioassays. The endpoints examined include serum levels of thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH). In addition, the induction of the dioxin-responsive genes UDP-glucuronosyltransferase-1 (UGT1) and cytochrome P450 1A1 (CYP1A1) in liver were measured using reverse-transcriptase-polymerase chain reaction (RT-PCR). In agreement with previous hypotheses, TCDD appears to alter thyroid function via a secondary mechanism, namely increased excretion of T4-glucuronide resulting from TCDD induction of UGT1. The observed follicular cell hyperplasia and hypertrophy are consistent with the observed elevated TSH levels and may represent the early stages in the progression of thyroid carcinogenesis. Therefore, TCDD induces alterations in thyroid hormone function, probably as a result of chronic perturbations of liver-pituitary-thyroid axis.
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PMID:Alterations in thyroid function in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. 754 Mar 35

The tyrosinase promoter has been used to target expression of the mutated human T24 Ha-ras oncogene in pigment-producing cells of transgenic mice. Two independent founder mice carrying the transgene survived and showed the same distinct phenotype of mutated coat color, deeply pigmented skin with multiple nevi, and twirling behavior. The offspring of one of these founders were developed into a line that stably expressed the same phenotype. Histopathological analysis of the tissues revealed hyperpigmentation and/or melanocytic hyperplasia in the skin, eyes, inner ear, and meningeal membranes in the brain. Reverse transcriptase-polymerase chain reaction analysis revealed expression of the transgene in skin, brain, and spleen. We propose that these transgenic mice will be a model for studying the process of multistage melanoma carcinogenesis and a system for evaluating potential chemopreventive agents.
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PMID:Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter. 766 20

We demonstrate here that stilbene estrogen (diethylstilbestrol) is converted to nuclear protein binding metabolite(s) both in vitro and in vivo. In vitro reaction of DES with nuclei from hamster liver or kidney in the presence of cumene hydroperoxide or NADPH revealed binding of [3H]DES in nuclear proteins (histones; nonhistones precipitable by 2% TCA, NH2; nonhistones soluble in 2% TCA, NH30). The binding was significantly inhibited by cytochromes P450 inhibitors. In an in vitro system [3H]DES quinone, one of the metabolites of DES, was able to bind to pure nonhistone proteins RNA polymerase and DNA polymerase. The binding of [3H]DES quinone to nonhistones RNA polymerase and DNA polymerase was inhibited by low molecular weight thiols, i.e. glutathione and cysteine, or thiol modifiers, such as n-ethylmaleimide, dithionitrobenzoic acid and hydroxymercuric benzoate. DES and DES metabolites inhibited transcriptional activity. In vivo [3H]DES was able to bind to nuclear proteins of hamster liver, kidneys and testes. The level of in vivo [3H]DES binding to all three types of nuclear proteins (histones, NH2, NH30) in the kidney (target organ) was two or more fold higher than that observed in the liver or testis (nontarget organs). Four nuclear NH30 proteins (mol wts.: 56, 37, 33 and 28 kDa) were irreversibly bound to [3H]DES in vivo. The in vivo binding of [3H]DES to transcriptionally active chromatin NH30 proteins also was observed. The data reported here establish that DES was able to bind to liver or kidney nuclear proteins in vitro, which was catalyzed by nuclear enzymes when fortified with an appropriate cofactor. DES quinone may be one of the protein binding metabolites. DES and DES metabolites inhibited transcriptional activity. The level of in vivo binding of [3H] DES to nuclear proteins of kidney (target organ) was double in comparison with that observed in liver or testis (nontarget organs). In vivo modifications in the chromatin proteins may be a factor in the development of DES-induced renal carcinogenesis is not clear.
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PMID:In vivo binding of diethylstilbestrol to nuclear proteins of kidneys of Syrian hamsters. 773 58

Gene expression is governed by multiple cellular processes including transcription, splicing, and translation. Among them, transcriptional regulation is the main regulatory mechanism. Transcription process can be divided into pre-initiation, initiation, elongation and termination, and transcriptional regulation is especially governed through the pre-initiation step. Eukaryotic RNA polymerase alone is not able to initiate specific transcription, but general transcription factors (GTFs) is required for this reaction. In pre-initiation step, many GTFs and RNA polymerase gather at the core promoter of a gene, and form a large initiation complex. There are another class of factors: transcription regulatory factors (TRFs) responsible for the regulation such as tissue-specific/timing-specific transcription and induction/repression of transcription. TRFs directly bind to cis-acting DNA elements which are generally referred enhancers (for activation) or silencers (for repression), and regulate the rate of formation of initiation complex. A TRFs can be divided into at most 4 domains: domains for binding to DNA, regulation of transcription, interaction to other proteins and ligand binding. A number of TRFs can be categorized into rather small numbers of families such as b-zip, Zn-finger, etc. which have a characteristic combination with functional motifs. The third class of transcription factor is referred as a mediator/coactivator, that binds to both TRFs and GTFs, and can transduce the regulatory signal from enhancer to promoter. We can describe many biological processes by a term of transcriptional regulation, such as carcinogenesis, development, morphogenesis, infection and immunity, cell growth and hormone action, etc. However, further studies on chromain/nuclear matrix structure, molecular anatomy of transcription factors, and network of transcription factors are required for understanding of the relationship between biological processes and transcriptional regulation.
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PMID:[Regulation of gene expression and recent advance on transcription studies]. 775 63


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