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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In animals, exposure to polyaromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (3-MC) is known to induce the expression of two unique cytochrome P450 genes, CYP1A1 and CYP1A2. These genes are thought to have originated by a gene duplication event and diverged no more than 250 million years ago (D. W. Nerbert and F. J. Gonzalez, 1987, Annu. Rev. Biochem. 56, 945-993). Lower vertebrates, such as fish, diverged from land animals before this time and are thought to express only a single CYP1 gene. In this paper, we present evidence to refute this hypothesis and report the isolation and complete genomic nucleotide sequence of two distinct CYP1 genes in rainbow trout. Genomic clones encoding the entire CYP1A1 and CYP1A2 genes were characterized. DNA sequence analysis revealed that both genes contained seven exons and six introns. Exons 1-7 of CYP1A1 and CYP1A2 were highly similar in length and nucleotide sequence. In contrast, the 5'-flanking region and introns 1, 2, 5, and 6 of both genes were significantly less conserved. Two xenobiotic regulatory elements (XREs) were identified in the 5'-flanking region of CYP1A1 but not in that of CYP1A2. The 5'-most start site of transcription was determined to begin at a cytosine residue 27 bases downstream of the putative TATA box of both genes. Northern blot analysis demonstrated that exposure to 3-MC resulted in an increase in CYP1 mRNA levels in the liver. RNase protection assays conducted with riboprobes specific for either CYP1A1 or CYP1A2 confirmed that the transcripts of both genes were expressed in rainbow trout liver in response to 3-MC treatment.
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PMID:Two unique CYP1 genes are expressed in response to 3-methylcholanthrene treatment in rainbow trout. 816 Dec 4

A method is described for the detection, chemical characterization and sequence placement of post-transcriptionally modified nucleotides in RNA. Molecular masses of oligonucleotides produced by RNase T1 hydrolysis can be measured by electrospray mass spectrometry with errors of less than 1 Da, which provides exact base composition, and recognition of modifications resulting from incremental increases in mass. Used in conjunction with combined liquid chromatography-mass spectrometry and gene sequence data, modified residues can be completely characterized at the nucleoside level, and assigned to sequence sites within oligonucleotides defined by selective RNase cleavage. The procedures are demonstrated using E.coli 5S rRNA, in which all RNase T1 fragments predicted from the rDNA sequence are identified solely on the basis of their molecular masses, and using E.coli 16S rRNA for analysis of post-transcriptional modification, including placement of 3-methyluridine at position 1498. The principles described are generally applicable to other covalent structural modifications of RNA which produce a change in mass, such as those resulting from editing, photochemical cross-linking, or xenobiotic modification.
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PMID:A novel method for the determination of post-transcriptional modification in RNA by mass spectrometry. 823 93

Expression of class 3 aldehyde dehydrogenase (ALDH-3) is constitutive or inducible, depending on the tissue. ALDH-3 induction occurs both during neoplastic development and after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to study the regulation of ALDH-3 gene expression, ALDH-3 genomic sequences have been obtained from normal rat genomic DNA. Two overlapping genomic fragments (ALDH-UTR-1 and ALDH-NL2) contain the entire ALDH-3 gene along with considerable 5'- and 3'-flanking sequences. The rat ALDH-3 gene spans approximately 9 kilobases in length and consists of eleven exons; ten coding and one 5'-noncoding. The region 5' to exon one contains several putative transcription factor binding elements which may be important in the TCDD inducibility of this gene. These include a xenobiotic response element (XRE), a drug response element (DRE), LAP and Ap1 binding sites, and one Sp1 site. There are considerable differences in organization between the rat and human class 3 ALDH genes. Primer extension and RNase protection analysis indicate that both basal and TCDD-inducible expression of the ALDH-3 gene utilize the same multiple transcription start sites.
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PMID:Organization and characterization of the rat class 3 aldehyde dehydrogenase gene. 850 94

We report the sequences of two coordinately induced murine glutathione transferase genes, mGSTM1 (GT8.7, Yb1) and mGSTM3 (GT9.3). Genomic clones covering the entire mGSTM1 gene were isolated; comparison of the mGSTM1 gene with genomic sequences from rat class-mu glutathione transferase genes suggests that the mGSTM1 gene is orthologous to the rGSTM1 (rat3, Yb1) gene. The start of mGSTM1 mRNA transcription was mapped by primer extension and RNase protection to 37 nucleotides upstream from the initiation codon. The 160 nucleotides 5'-proximal to the start of transcription match exactly the 5'-end of the class-mu glutathione transferase cDNA clone pmGT10. An mRNA transcript was found approximately 2.0 kb upstream from the start of mGSTM1 transcription; its sequence does not show significant similarity to other sequences in the DNA or protein sequence databases. The mGSTM1 gene contains a TATAAA sequence at -31 nucleotides upstream from the start of transcription, but no exact match to the antioxidant response element (RGTGACNNNGC), the xenobiotic response element (TNGCGTG), or the AP-1 consensus (TGASTMA) is found in the 5'-flanking region, although near matches are found in the 5'-flanking region, in intron 1, and in other parts of the gene. A genomic clone containing the first five exons of the mGSTM3 gene was also isolated. The mGSTM3 gene contains several repetitive elements--two upstream from the start of transcription and one within intron 2--that disrupt its similarity with the mGSTM1 gene. The 5'-flanking sequence of the mGSTM3 gene does not contain a TATAAA sequence or any exact matches to ARE or XRE consensus sequences, although an Sp1 binding site is found at -66. mGSTM3 and mGSTM1 diverge substantially outside their exons and share less than 60% sequence identity in the 5'-flanking region. Thus, it is likely that the mGSTM1-mGSTM3 gene duplication predates the rat-mouse divergence. The strongest region of conservation between the mGSTM1 gene and the mGSTM3 gene occurs in exon 3, intron 3, and exon 4; this region also shares strong similarity with the rGSTM1 (rat3, Yb1) and rGSTM2 (rat4, Yb2) genes.
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PMID:The structure of two murine class-mu glutathione transferase genes coordinately induced by butylated hydroxyanisole. 851 23

Sigma receptor is a protein that interacts with a variety of psychotomimetic drugs including cocaine and amphetamines and is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. Here we report on the structure and organization of the human gene coding for this receptor. The gene is approximately 7 kbp long and contains four exons, interrupted by three introns. Exon 3 is the shortest (93 bp), and exon 4 is the longest (1,132 bp). Among the introns, intron 3 is the longest (approximately 1,250 bp). Exon 2 codes for the single transmembrane domain present in the receptor. 5' rapid amplification of cDNA end reactions with mRNA from the JAR human trophoblast cell line have identified 56 bp upstream of the translation start codon as the initiation site for transcription. This transcription start site has been confirmed by RNase protection analysis. Structural analysis of the 5' flanking region has revealed that the gene is TATA-less. This region, however, contains a CCAATC box in the reverse complement and several GC boxes that are recognition sites for SP1. There are also consensus sequences for the liver-specific transcription factor nuclear factor-1/L, for a variety of cytokine responsive factors, and for the xenobiotic responsive factor called the arylhydrocarbon receptor. Southern blot analysis of the genomic DNA from Chinese hamster-human and mouse-human hybrid cell lines and fluorescent in situ hybridization with human metaphase chromosome spreads have shown that the gene is located on human chromosome 9, band p13, a region known to be associated with different psychiatric disorders.
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PMID:Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene. 945 37

UDP-glucuronosyltransferase UGT1A7 catalyzes the glucuronidation of benzo(a)pyrene metabolites and other bulky aromatic compounds. Both UGT1A7 mRNA and an associated enzyme activity (benzo(a)pyrene7, 8-dihydrodioltransferase activity) are markedly increased in livers of rats treated with beta-naphthoflavone or 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz). Nuclear runoff assays show that the effects of both inducers are primarily due to transcriptional activation. A 27-kilobase region that included the UGT1A7/UGT1A6 promoter regions was cloned. Primer extension and RNase protection studies indicated >/=30 transcription start sites in five clusters between bases -85 and -40 respective to the translation start codon. There was no recognizable TATA box, but the promoter region is TA-rich. Sequence analysis revealed potential binding sites for CCAAT enhancer-binding protein, activator protein 1, and hepatic nuclear factors 1, 3, and 4, but no xenobiotic response elements or antioxidant response elements, implicated in the regulation of other genes by beta-naphthoflavone or oltipraz, were found. A UGT1A7 gene reporter plasmid directed strong constitutive expression in transient transfection assays using primary rat hepatocytes. Treatment with 3-methylcholanthrene or oltipraz had no effect compared with similarly treated pGL3-Basic-transfected cells. These results suggest that the regulatory elements controlling xenobiotic inducibility of UGT1A7 transcription are located either 5' or 3' of bases -1600 to +54. One possibility is that the polycyclic aromatic-mediated regulation of UGT1A7 occurs via the xenobiotic response element flanking the UGT1A6 locus 7 kilobase pairs downstream.
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PMID:Transcriptional activation of the UDP-glucuronosyltransferase 1A7 gene in rat liver by aryl hydrocarbon receptor ligands and oltipraz. 948 89

Human dihydrodiol dehydrogenase (DD) isoforms are aldo-keto reductases (AKRs) that activate polycyclic aromatic hydrocarbons (PAHs) by oxidizing trans-dihydrodiol proximate carcinogens to reactive and redox-active ortho-quinones. Of these, human AKR1C1 (DD1) and AKR1C2 (DD2) oxidize trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the cytotoxic and genotoxic metabolite benzo[a]pyrene-7,8-dione (BPQ) with the highest catalytic efficiency. Exposure of HepG2 cells to a panel of inducers revealed that mRNA encoding one or more human AKR1C member(s) was induced (3- to 10-fold) by benzo[a]pyrene and other polycyclic aromatic compounds (bi-functional inducers), electrophilic Michael acceptors and phenolic antioxidants (monofunctional inducers), and reactive oxygen species (ROS). The induction of AKR1C mRNA by bifunctional inducers was delayed with respect to the induction of CYP1A1 mRNA, and AKR1C mRNA was not induced by the nonmetabolizable aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These data suggest that, in contrast to the CYPs, induction of AKR1C member(s) by PAHs and other bifunctional inducers is mediated indirectly via an antioxidant response element rather than a xenobiotic response element. Immunoblot and enzymatic assays confirmed that the increases in AKR1C mRNA were faithfully translated into functional AKR1C protein(s). The increased DD activity in HepG2 lysates was inhibited only by high concentrations of ursodeoxycholate, which suggested that AKR1C2 (DD2, bile-acid-binding protein) was not the isoform induced. RNase protection assays identified AKR1C1 (DD1) mRNA as the transcript which was up-regulated by mono- and bi-functional inducers and ROS in both human hepatoma (HepG2) and colon carcinoma (HT29) cells. BPQ, the electrophilic and redox-cycling product of the AKR1C1 reaction, also induced AKR1C1 expression. Thus, BPQ formation by AKR1C1 results in both a chemical (redox-cycling) and a genetic (AKR1C1 induction) amplification of ROS in PAH-exposed cells. Because ROS have been implicated in both tumor initiation and tumor promotion, the amplification of ROS by this pathway may play a significant role in PAH carcinogenesis.
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PMID:Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. 997 8

Altered expression of hepatic CYP2E1 by xenobiotic or physiological stimuli is largely mediated through post-transcriptional mechanisms that may include altered CYP2E1 mRNA translation and/or protein degradation. Examination of the polyribosomal distribution of rat hepatic P450 mRNAs indicated that, whereas nearly all of the CYP2B, CYP3A, and CYP4A mRNAs were recovered in the polysomal fractions, indicating active translation, approximately 30-40% of CYP2E1 mRNA was not associated with polysomes and therefore not actively engaged in protein synthesis. To examine the CYP2E1 mRNA molecule for sequences that might affect its translational efficiency, a series of CYP2E1 recombinant RNAs (rcRNAs) with modified 5' or 3' untranslated regions (UTRs) was translated in vitro using the rabbit reticulocyte lysate system. Deletion of most of the CYP2E1 5' UTR, which was predicted to contain secondary structure, increased in vitro CYP2E1 protein synthesis. Polysomal distribution analyses of 5'-modified rcRNAs demonstrated that, as seen for hepatic CYP2E1 mRNA, a substantial fraction of each CYP2E1 rcRNA was not associated with polysomes. The polysomal distribution analyses of the CYP2E1 rcRNAs also confirmed that the observed changes in CYP2E1 protein synthesis were associated with altered ribosomal loading. Deletion of the poly(A) tail, and partial or complete deletion of the 3' UTR, decreased CYP2E1 protein synthesis. These changes in protein synthesis were accompanied by increased degradation of the CYP2E1 rcRNAs. Incubation with translational inhibitors, but not increased levels of RNase inhibitor, decreased the degradation of the rcRNAs during in vitro translation. In conclusion, these studies suggest that secondary structure in the 5' UTR of CYP2E1 mRNA is at least partially responsible for the inefficient translation of this mRNA. The poly(A) tail and sequences contained within the 3' UTR appear to be important for protecting CYP2E1 mRNA from RNase activity associated with the translation machinery.
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PMID:Post-transcriptional regulation of rat CYP2E1 expression: role of CYP2E1 mRNA untranslated regions in control of translational efficiency and message stability. 1072 4

The liver is an essential organ that produces several serum proteins, stores vital nutrients, and detoxifies many carcinogenic and xenobiotic compounds. Various growth factors positively regulate liver growth, but only a few negative regulators are known. Among the latter are the transforming growth factor beta (TGF-beta) superfamily members TGF-beta1 and activin A. To study the function of novel activin family members, we have cloned and generated mice deficient in the activin betaC and betaE genes. Expression analyses demonstrated that these novel genes are liver specific in adult mice. Here, we show by RNase protection that activin betaC transcripts are present in the liver beginning at embryonic day 11.5 (E11.5) whereas activin betaE expression is detected starting from E17.5. Gene targeting in embryonic stem cells was used to generate mice with null mutations in either the individual activin betaC and betaE genes or both genes. In contrast to the structurally related activin betaA and betaB subunits, which are necessary for embryonic development and pituitary follicle-stimulating hormone homeostasis, mice deficient in activin betaC and betaE were viable, survived to adulthood, and demonstrated no reproductive abnormalities. Although activin betaC and betaE mRNAs are abundantly expressed in the liver of wild-type mice, the single and double mutants did not show any defects in liver development and function. Furthermore, in the homozygous mutant mice, liver regeneration after >70% partial hepatectomy was comparable to that in wild-type mice. Our results suggest that activin betaC and betaE are not essential for either embryonic development or liver function.
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PMID:Activin betaC and betaE genes are not essential for mouse liver growth, differentiation, and regeneration. 1091 94

The UGT1 complex codes for a subfamily of homologous "1A7-like" UDP-glucuronosyltransferases (UGTs), including UGT1A7 and UGT1A8. Little information is available regarding either the substrate specificities or regulation of the UGT1A7-like forms from rats. We compared the activities and tissue expression of UGT1A7 and UGT1A8, which exhibit 77% identity in their amino terminal sequence. UGT1A7 shows broad specificity, catalyzing the glucuronidation of 31 of 40 randomly selected substrates (100 muM) at rates >0.1 nmol/mg/min. UGT1A7 substrates included both planar and nonplanar compounds, mono- and polycyclic aromatics, and compounds with bulky side chain ring substitutions. UGT1A8 exhibited a narrower substrate specificity that completely overlapped with UGT1A7. UGT1A8 was most active toward the 1-OH, 4-OH, 5-OH, 6-OH, 7-OH, 10-OH, 11-OH, and 12-OH derivatives of benzo[a]pyrene. Other effective UGT1A8 substrates (>0.1 nmol/mg/min) included 9-OH-benzo[a]pyrene, 1-naphthol, 4-methylumbelliferone, 7-hydroxycoumarin, chrysin, quercetin, 4-nitrophenol, and estriol. In general, substrates preferred by UGT1A8 were polyaromatic planar structures with nonbulky substituents and a superimposable 1-naphtho ring structure. Studies of the tissue expression of the UGT1A7 and 1A8 mRNAs using RNase protection analysis suggested that each is expressed in liver and kidney of control rats. A major difference is the higher expression of UGT1A7 mRNA in intestine. These studies suggest complementary functions of the UGT1A7 and UGT1A8 forms in xenobiotic metabolism. Further studies are necessary to determine whether their relative contributions change as a function of development, hormonal status, or exposure to inducing agents.
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PMID:Analysis of substrate specificities and tissue expression of rat UDP-glucuronosyltransferases UGT1A7 and UGT1A8. 1550 8


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