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)

Reverse transcriptase plays an essential role in the early steps of the replicative cycle of retroviruses. Because of the resistance against nucleoside analogue inhibitors such as 3'-azido-2',3'-dideoxythymidine, the importance of the investigation of non-nucleoside analogue inhibitors is increasing. We have investigated the influence of trifluoperazine (TFP--a species of phenothiazines) and its newly prepared TFP-metal complexes (TFP-VO(IV), TFP-Cu(II), TFP-Ni(II), TFP-Pd(II), TFP-Sn(IV)). The compounds were tested on Moloney murine leukemia virus reverse transcriptase assay. The inhibitory effect of metal complexes was higher than that of TFP. TFP-VO(IV) showed higher effectiveness compared the added effect of parent tricyclic chemical and metal. Therefore we concluded that the improved biological action depends on the formation of metal complexes. This phenothiazine and its metal coordination complexes could become a new non-nucleoside analogue group of compounds inhibiting the retrovirus replication.
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PMID:Trifluoperazine and its metal complexes inhibit the Moloney leukemia virus reverse transcriptase. 967 43

We investigated whether the multisubunit holoenzyme complex of RNA polymerase II (Pol II) and mediator is universally required for transcription in budding yeast. DeltaCTD Pol II lacking the carboxy-terminal domain of the large subunit cannot assemble with mediator but can still transcribe the CUP1 gene. CUP1 transcripts made by DeltaCTD Pol II initiated correctly and some extended past the normal poly(A) site yielding a novel dicistronic mRNA. Most CUP1 transcripts made by DeltaCTD Pol II were degraded but could be stabilized by deletion of the XRN1 gene. Unlike other genes, transcription of CUP1 and HSP82 also persisted after inactivation of the CTD kinase Kin28 or the mediator subunit Srb4. The upstream-activating sequence (UAS) of the CUP1 promoter was sufficient to drive Cu2+ inducible transcription without Srb4 and heat shock inducible transcription without the CTD. We conclude that the Pol II holoenzyme is not essential for all UAS-dependent activated transcription in yeast.
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PMID:Activated transcription independent of the RNA polymerase II holoenzyme in budding yeast. 971 4

The aim of this study was to investigate the involvement of endothelins (ET) in brain injury. The effect of ET was studied in the isolated basilar artery (BA) taken from control, sham-operated, and cold-lesioned rats. Cold lesion was induced by application of a precooled (-78 degrees C) copper cylinder (outer diameter 5 mm) for 60 seconds to the intact dura over the parietal cortex. After precontraction with prostaglandin (PG) F2alpha, ET-3 (10(-10) to 10(-8) mol/L) dilated BA with a pD2 (negative log of the half-maximal concentration) of 9.06+/-0.031 (mean +/- SD) and a maximal effect (Emax) of 1.64+/-1.0 mN at 3 x 10(-9) mol/L in sham-operated animals. This dilation was reduced 24 and 48 hours after cold lesion by 33% and 73%, respectively, at 3 x 10(-9) mol/L. The effects of acetylcholine (10(-8) to 10(-4) mol/L) and sodium nitroprusside (10(-3) mol/L) were unaltered. Activation of the ETB receptor in thoracic aorta by the specific agonist IRL 1620 also resulted in a reduced dilation (51% by 48 hours after cold lesion). Reverse transcriptase-polymerase chain reaction of the BA showed unaltered expression of mRNA for the ETB receptor after cold lesion whereas ETB immunoreactivity in BA and in its intraparenchymal arteries was reduced at 24 and 48 hours. In contrast to the reduction of ET-3-induced dilation, the constrictor effects of ET-1 and ET-3 were retained after cold lesion. Endothelin-1 (10(-12) to 10(-6) mol/L) dose-dependently contracted segments of untreated control BA segments under resting conditions with a pD2 of 8.03+/-0.22 and an Emax of 6.35+/-0.70 mN. Further evidence that the constrictor ability of BA was not influenced by cold lesion is given by the unaltered response to 124 mmol/L K+ and 10(-6) mol/L serotonin. We conclude that the ETB receptor of BA after cold lesion is downregulated specifically, apparently at the posttranscriptional level. Because the ETB-mediated dilation in thoracic aorta was also reduced, downregulation of the ETB receptor apparently is not restricted to cerebral arteries. The nitric oxide-cyclic guanosine monophosphate system in BA is, however, intact.
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PMID:Delayed loss of ETB receptor-mediated vasorelaxation after cold lesion of the rat parietal cortex. 985 Jan 48

Menkes disease is an X-linked recessive disorder of the copper membrane transport system caused by mutations to the Menkes (MNK) gene. We identified three novel mutations of the MNK gene in three unrelated Japanese patients with classical Menkes disease by analyzing reverse-transcriptase polymerase chain reaction products and genomic DNA of the MNK gene. Firstly, an insertional mutation was found, 1173 ins A, which led to a premature termination and resulted in a very immature Menkes protein. Secondly, we found a point mutation, T2763G, resulting in a leucine-to-arginine conversion, which we predicted would cause a change in the secondary structure of the Menkes protein. Finally, we identified a splicing mutation, 2317 + 5G > C, which resulted in the skipping of both exons 8 and 9 or exon 9 only, and led to a truncation of the protein. Each of these mutations is hypothesized to destroy copper-ATPase-mediated copper transport. We propose that each of these mutations in the MNK gene plays a causative role in the disease.
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PMID:Identification of three novel mutations in the MNK gene in three unrelated Japanese patients with classical Menkes disease. 1031 89

The general transcription factor (TF) IIE is required for mRNA synthesis of many, but not all, genes in yeast. In the transcription process, TFIIE regulates TFIIH kinase activity that phosphorylates the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II. The CTD and the CTD kinase Kin28, a subunit of TFIIH, have been shown to be dispensable for activation of several heat shock genes and the copper metallothionein gene CUP1. Here we analyzed requirement of TFIIE for transcription of these genes and found that TFIIE is necessary for activation of the heat shock genes by heat shock transcription factor Hsf1. By contrast, transcription of CUP1 mediated by both Hsf1 and copper-activated transcription factor Ace1 was inducible after inactivating TFIIE. These results show that both TFIIE and the CTD/the CTD kinase exhibit "gene specificities" which are overlapping, but not identical to each other, and thereby suggest that TFIIE functions with or without involvement of the CTD/the CTD kinase depending on the gene to be transcribed.
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PMID:Activator-specific requirement for the general transcription factor IIE in yeast. 1044 94

The Long-Evans Cinnamon (LEC) rat is a mutant strain characterized by abnormal copper metabolism and a high incidence of hepatitis and hepatoma. Using a yeast-based assay which scores mutants in p53 gene transcripts as red colonies, we detected frequent mutations in the liver of LEC rats. The majority (50-60%) of these were frameshift mutations caused by the insertion of an extra adenine (A) in the regions containing six consecutive adenines. The rate of A insertion was calculated to be 6.9-9.0% of the total p53 cDNA. Insertions of an extra adenine were found almost exclusively in the mRNA (cDNA), especially in the (A)(6) tract located at the most 5'-side (exon 4) among the three (A)(6) tracts (exons 4, 7, and 8), but rarely in the corresponding sites of genomic DNA. Wild-type p53 cDNA was transcribed in vitro into mRNA with the use of SP6 RNA polymerase and tested by the yeast functional assay. Subsequent sequencing detected A insertions at an overall rate of 1.6% in exons 7 and 8 but none in exon 4. This indicates that the A insertion in the exon 4 (A)(6) tract was an in vivo phenomenon rather than an artifact in reverse transcription or polymerase chain reaction. The percentage of red colonies increased sharply to about 20% of the liver samples in the acute hepatitis stage, and returned to control level of those in the chronic hepatitis stage, and increased again slightly to those in the neoplastic stage. The percentage of red colonies correlated with the serum GOT level (r=0.96, p<0.001) but not with the contents of copper and 8-hydroxydeoxyguanosine in the liver of LEC rats. Ethanol treatment of hepatic cell lines also increased the rate of transcriptional slippage at the (A)(6) tract. These findings indicate that cellular damage is responsible for the increase in the rate of mutation at the transcriptional level, and suggest that cellular damage degrades transcriptional fidelity, thereby further impairing cellular functions.
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PMID:Transcriptional slippage of p53 gene enhanced by cellular damage in rat liver: monitoring the slippage by a yeast functional assay. 1075 4

Reverse transcriptase-polymerase chain reaction has been used to isolate one metallothionein isoform (MT-20) complementary DNA from RNA extracted from mussel gill. Another cDNA, isolated by screening a Mytilus edulis cDNA mantle library using the first cDNA as probe, codes for the MT-10 IV isoform. Northern blot analysis using these cDNAs revealed different expression of these isoforms. Induction with CdC1(2) caused high levels of both MT messenger RNAs, especially the MT-20, which was induced by cadmium salt but not by zinc and copper salts. An induction of MT-10 was detected with ZnCl(2). These results show that genes encoding distinct MT isoforms are differentially regulated by heavy metals.
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PMID:Metallothionein Isoforms in Mytilus edulis (Mollusca, Bivalvia): Complementary DNA Characterization and Quantification of Expression in Different Organs after Exposure to Cadmium, Zinc, and Copper. 1081 60

Menkes disease is an X-linked recessive disorder of the copper membrane transport system caused by mutations in the ATP7A gene. While various mutations in the ATP7A gene have been reported, a genotype-phenotype correlation has not been clearly defined. A novel mutation in the ATP7A gene in a Japanese patient with classical Menkes disease was identified via analysis of reverse-transcriptase polymerase chain reaction products and genomic DNA of the ATP7A gene. The nonsense mutation, L718X, was found to result in premature termination and immature ATP7A protein, unlikely to have normal functioning. Therefore, this nonsense mutation of the ATP7A gene is proposed to play a causative role in presenting the classical Menkes phenotype. Furthermore, four novel polymorphisms, C1535T (L464L), C2151T (T669I), G2253A (R703H), and C3677T (H1178Y) were also identified.
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PMID:Novel mutation of L718X in the ATP7A gene in a Japanese patient with classical Menkes disease, and four novel polymorphisms in the Japanese population. 1104 17

The yeast CUP1 gene is activated by the copper-dependent binding of the transcriptional activator, Ace1p. An episome containing transcriptionally active or inactive CUP1 was purified in its native chromatin structure from yeast cells. The amount of RNA polymerase II on CUP1 in the purified episomes correlated with its transcriptional activity in vivo. Chromatin structures were examined by using the monomer extension technique to map translational positions of nucleosomes. The chromatin structure of an episome containing inactive CUP1 isolated from ace1Delta cells is organized into clusters of overlapping nucleosome positions separated by linkers. Novel nucleosome positions that include the linkers are occupied in the presence of Ace1p. Repositioning was observed over the entire CUP1 gene and its flanking regions, possibly over the entire episome. Mutation of the TATA boxes to prevent transcription did not prevent repositioning, implicating a chromatin remodeling activity recruited by Ace1p. These observations provide direct evidence in vivo for the nucleosome sliding mechanism proposed for remodeling complexes in vitro and indicate that remodeling is not restricted to the promoter but occurs over a chromatin domain including CUP1 and its flanking sequences.
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PMID:Remodeling of yeast CUP1 chromatin involves activator-dependent repositioning of nucleosomes over the entire gene and flanking sequences. 1113 41

We have shown that the open reading frame ybbI in the genomic sequence of Escherichia coli K-12 encodes the regulator of expression of the copper-exporting ATPase, CopA. In vivo studies showed that ybbI (designated cueR for copper export regulator gene) was required for copper tolerance during growth, that disruption of cueR caused loss of copA expression and that copA gene expression was regulated by cueR and by copper or silver ions. Expression of a lacZ reporter gene under the control of the copA promoter was approximately proportional to the concentration of cupric ions in the medium, but increased more rapidly in response to silver ion concentrations. The start of the copA transcript was located by primer extension mapping, and DNase I protection assays showed that the CueR protein binds in vitro to a dyad symmetrical sequence within a 19 bp spacer sequence in the copA promoter. CueR binding occurs in vitro in both the presence and the absence of RNA polymerase with or without copper ions present but, in the presence of CueR, RNA polymerase and copper ions, permanganate-sensitive transcription complexes were formed. CueR is predicted to have an N-terminal helix-turn-helix sequence and shows similarity to MerR family regulators.
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PMID:CueR (YbbI) of Escherichia coli is a MerR family regulator controlling expression of the copper exporter CopA. 1113 69


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