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 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

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

Retroviral DNA integration occurs throughout the genome; however, local "hot spots" exist where a strong preference for certain sites over others are seen, and more global preferences associated with genes have been reported. Previous data from our laboratory suggested that there are fewer integration events into a DNA template when it is undergoing active transcription than when it is not. Because these data were generated by using a stably transfected foreign gene that was only weakly inducible, we have extended this observation by comparing integration events into a highly inducible endogenous gene under both induced and uninduced transcriptional states. To examine the influence of transcription on site selection directly, we analyzed the frequency and distribution of integration of avian retrovirus DNA into the metallothionein gene, before and after its induction to a highly sustained level of expression by addition of ZnSO4. We found a 6-fold reduction in integration events after 100-fold induction of transcription. This result implies that, despite an apparent preference for integration of retroviral DNA into transcribed regions of host DNA, high-level transcription can be inhibitory to the integration process. Several possible models for our observation are as follows. First, when a DNA template is undergoing active transcription, integration might be blocked by the RNA polymerase II complex because of steric hindrance. Alternatively, the integrase complex may require DNA to be in a double-stranded conformation, which would not be the case during active transcription. Last, transcription might lead to remodeling of chromatin into a structure that is less favorable for integration.
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PMID:Relationship between retroviral DNA-integration-site selection and host cell transcription. 1567 23

The development of sensitive, biologically based indicators of contaminant exposure (i.e., biomarkers) is an ongoing topic of research. These indicators have been proposed as a first-tier method of identifying contaminant exposure. The primary objective of this research was to implement a biomarker-based method of exposure assessment using caged fish and real-time reverse-transcriptase polymerase chain reaction (rtRT-PCR) measurements of gene expression. Primers were developed for the CYPIA, metallothionein, and vitellogenin genes in rainbow trout (Oncorhynchyus mykiss), cutbow trout (Oncorhynchyus clarkii x mykiss), and Atlantic salmon (Salmo salar). Each of these genes has been shown to respond specifically to planar aromatic compounds, heavy metals, and environmental estrogens, respectively. Juvenile fish were placed in cages and exposed in situ at reference and contaminated sites on the Cache la Poudre River (CO, USA), the Arkansas River (CO, USA), the St. John River (NB, Canada), and two urban creeks near Dayton (OH, USA). Quantitative gene expression was determined using rtRT-PCR. Biomarker expression profiles were obtained that demonstrated differences in CYPIA, metallothionein, and vitellogenin mRNA production unique to each site, indicating that specific types of compounds were bioavailable and present in sufficient concentrations to elicit transcriptional responses in the organism. These findings support the use of a biomarker-based approach to exposure identification and assessment.
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PMID:Gene expression in caged fish as a first-tier indicator of contaminant exposure in streams. 1644 90

Cadmium (Cd) exposure results in injury to the proximal tubule characterized by polyuria and proteinuria. Kidney injury molecule-1 (Kim-1) is a transmembrane glycoprotein not normally detected in the mature kidney, but is upregulated and shed into the urine following nephrotoxic injury. In this study, we determine if Kim-1 might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. Weekly urine samples were analyzed for Kim-1, protein, creatinine, metallothionein, and Clara cell protein CC-16. Significant levels of Kim-1 were detected in the urine by 6 weeks and continued to increase throughout the treatment period. This appearance of Kim-1 occurred 4-5 weeks before the onset of proteinuria, and 1-3 weeks before the appearance of metallothionein and CC-16. Higher doses of Cd gave rise to higher Kim-1 excretion. Reverse transcriptase-polymerase chain reaction (RT-PCR) expression analysis showed that Kim-1 transcript levels were increased after 6 weeks at the low dose of Cd. Immunohistochemical analysis showed that Kim-1 was present in proximal tubule cells of the Cd-treated rats. Our results suggest that Kim-1 may be a useful biomarker of early stages of Cd-induced proximal tubule injury.
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PMID:Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. 1768 58

Because RNA polymerase is a powerful motor, transmission of transcription-generated forces might directly alter DNA structure, chromatin or gene activity in mammalian cells. Here we show that transcription-generated supercoils streaming dynamically from active promoters have considerable consequences for DNA structure and function in cells. Using a tamoxifen-activatable Cre recombinase to excise a test segment of chromatin positioned between divergently transcribed metallothionein-IIa promoters, we found the degree of dynamic supercoiling to increase as transcription intensified, and it was very sensitive to the specific arrangement of promoters and cis elements. Using psoralen as an in vivo probe confirmed that, during transcription, sufficient supercoiling is produced to enable transitions to conformations other than B-DNA in elements such as the human MYC far upstream element (FUSE), which in turn recruit structure-sensitive regulatory proteins, such as FUSE Binding Protein (FBP) and FBP-Interacting Repressor (FIR). These results indicate that mechanical stresses, constrained by architectural features of DNA and chromatin, may broadly contribute to gene regulation.
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PMID:The functional response of upstream DNA to dynamic supercoiling in vivo. 1825 Jun 29

Mouse MT-I (metallothionein-I) transcription is regulated by MTF-1 (metal-response-element-binding transcription factor-1) which is recruited to the promoter in response to zinc. Cr(VI) [chromium(VI)] pretreatment blocks zinc-activation of the endogenous MT-I gene and attenuates zinc-activation of MT-I-promoter-driven luciferase reporter genes in transient transfection assays. Chromatin immunoprecipitation assays revealed that Cr(VI) only modestly reduces recruitment of MTF-1 to the MT-I promoter in response to zinc, but drastically reduces the recruitment of RNA polymerase II. These results suggest that Cr(VI) inhibits the ability of MTF-1 to transactivate this gene in response to zinc. Zinc has recently been shown to induce the formation of a co-activator complex containing MTF-1 and the histone acetyltransferase p300 which plays an essential role in the activation of MT-I transcription. In the present study, co-immunoprecipitation assays demonstrated that Cr(VI) pretreatment blocks the zinc-induced formation of this co-activator complex. Thus Cr(VI) inhibits mouse MT-I gene expression in response to zinc by interfering with the ability of MTF-1 to form a co-activator complex containing p300 and recruiting RNA polymerase II to the promoter.
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PMID:Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex. 1860 88

The relationship among transcriptional activators, nucleosome repositioning activity and transcription machinery at the yeast CUP1 gene was addressed. CUP1 encodes a cysteine-rich, copper-binding metallothionein that protects cells against copper toxicity through its ability to sequester copper. The induction of CUP1 requires the presence of Ace1p and the binding of Ace1p at the CUP1 promoter during activation provides evidence that Ace1p is directly involved in CUP1 induction. Furthermore, transcriptional activation of CUP1 resulted in nucleosome repositioning at the CUP1 promoter and sequences further downstream in the coding region, suggesting a gene-wide chromatin remodeling activity. Such remodeling activity depends on the presence of transcription activator Ace1p. The recruitment of RNA polymerase II also requires the presence of Ace1p. Therefore, these observations provide insight into the molecular mechanism of CUP1 activation.
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PMID:Chromatin repositioning activity and transcription machinery are both recruited by Ace1p in yeast CUP1 activation. 2260 98

This review has focused on several parameters related to the delivery of carcinogenic metal compounds to the cell nucleus as a basis for understanding the intermediates formed between metals and cellular components and the effect of these intermediates on DNA structure and function. Emphasis has been placed on metal interactions at the cellular membrane, including lipid peroxidation, metal interactions with glutathione and their relation to membrane injury, and metal effects on the membrane bound enzyme, Na(+)/K(+) ATPase. Metal binding to metallothionein is also considered, particularly as related to transport and utilization of metal ions and to genetic defects in these processes exemplified in Menkes disease. The ability of cadmium to induce the synthesis of metallothionein more strongly than zinc is also discussed in relation to other toxic and carcinogenic metals. The effects of metal ions on purified DNA and RNA polymerase systems are presented with some of the recent studies using biological ligand-metal complexes. This review points out the importance of considering how metals affect in vitro systems when presented as ionic forms or complexed to relevant biological ligands.
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PMID:In vitro assessment of the toxicity of metal compounds : IV. Disposition of metals in cells: Interactions with membranes, glutathione, metallothionein, and DNA. 2426 54


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