Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Three oligonucleotide probes, complementary to tetM sequences, were labelled non-radiometrically using the DIG-oligonucleotide tailing kit and evaluated for their specificity for the detection of plasmid mediated tetracycline resistance in Neisseria gonorrhoeae. Only Probe 3, 5'-GCT CAA CAA TTC TGT TCC AGC-3', was specific for tetM. It hybridized with the tetM-containing 25.2-MDa plasmids from all of the 232 TRNG and the 130 PP/TRNG isolates used in the study. Its sensitivity, determined by dot-blot hybridization, was 0.1 pg of pJ13 plasmid DNA or 10(4) cells. It did not hybridize with the DNA from non-PPNG, CMRNG and tetracycline susceptible isolates from seven other Neisseria species (N. meningitidis, N. subflava, N. cinerea, N. lactamica, N. sicca, N. mucosa, and N. flavescens), Moraxella spp. and Haemophilus influenzae. Probe 3 also hybridized to DNA of three tetracycline resistant P. magnus (MIC = 16 micrograms ml-1) isolates which presumptively carried the tetM determinant. Therefore, probe 3 can be used by reference laboratories as a confirmatory test for TRNG, as well as isolates from other genera containing the tetM determinant.
Mol Cell Probes 1994 Jun
PMID:Detection of the tetM determinant in Neisseria gonorrhoeae using a non-radioactively labelled oligonucleotide probe. 796 93

The genetic determinants required for invasion of epithelial cells by Shigella flexneri and for the subsequent bacterial spreading are encoded by the large virulence plasmid. Expression of the virulence genes is under the control of various genes on the large plasmid as well as on the chromosome. We previously identified one of the virulence-associated loci near phoBR in the NotI-C fragment of the chromosome of S. flexneri 2a YSH6000 and designated the locus vacC. The vacC mutant showed decreased levels of IpaC, and IpaD proteins as well as transcription of ipa, an operon essential for bacterial invasion (N. Okada, C. Sasakawa, T. Tobe, M. Yamada, S. Nagai, K. A. Talukder, K. Komatsu, S. Kanegasaki, and M. Yoshikawa, Mol. Microbiol. 5:187-195, 1991). To elucidate the molecular nature of the vacC locus, we cloned the vacC region from YSH6000 on a 1.8-kb SalI-BamHI DNA fragment. The nucleotide sequence of the 1,822-bp vacC clone was highly (> 98%) homologous to the tgt region of Escherichia coli K-12, which is located at 9.3 min on the linkage map. Complementation tests indicated that the vacC function was encoded by an open reading frame expressing a 42.5-kDa protein, which corresponded to the tgt gene of E. coli K-12, coding for tRNA-guanine transglycosylase (Tgt) (K. Reuter, R. Slany, F. Ullrich, and H. Kersten, J. Bacteriol. 173:2256-2264, 1991). The cloned tgt gene from E. coli K-12 restored the virulence phenotype to the vacC mutant of YSH6000. Characterization of the vacC mutant indicated that levels of VirG, a protein essential for bacterial spreading, and VirF, the positive regulator for the expression of the virG and ipaBCD operons, decreased significantly compared with those of the wild type. Similar phenotypic changes occurred in vacC mutants constructed by insertion of a neomycin resistance gene in shigellae and enteroinvasive E. coli strains, consistent with the hypothesis that the vacC (tgt) gene contributes to the pathogenicity of Shigella flexneri.
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PMID:vacC, a virulence-associated chromosomal locus of Shigella flexneri, is homologous to tgt, a gene encoding tRNA-guanine transglycosylase (Tgt) of Escherichia coli K-12. 804 93

Strain A/J mice received intraperitoneal injections of benz[j]aceanthrylene (B[j]A) or benzo[a]pyrene (B[a]P). At 24, 48, and 72 h, lung tissues were removed for analysis of B[a]P- or B[j]A-derived DNA adduct formation during the first 3 d of exposure. One group of mice exposed to these hydrocarbons was kept for 8 mo to determine lung tumor multiplicity, the occurrence of mutations in codons 12 and 61 of the Ki-ras gene in the tumors that arose, the relationship between Ki-ras oncogene mutations in tumors, and the presence and quantity of genomic DNA adducts. The major DNA adduct in the lungs of mice exposed to B[a]P was N2-(10 beta-[+B, 7 alpha, 9 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene]yl)-deoxyguanosine (BPDE-I-dGuo) arising from bay-region diolepoxide activation of B[a]P and was consistent with the occurrence of tumors with mutations GGT-->TGT (56%), GGT-->GTT (25%), and GGT-->GAT (19%) in codon 12, all involving mutations of a guanine. B[j]A, a demethylated analogue of 3-methylcholanthrene (3-MCA) with an unsaturated cyclopenta ring, produced 16-to 60-fold more tumors at equivalent doses than did B[a]P; the mutations in tumors were GGT-->TGT (4%), GGT-->GTT (30%), and GGT-->CGT (65%). Analysis of adduction patterns in DNA suggested that B[j]A was activated to form DNA-binding derivatives in A/J mouse lungs primarily at the cyclopenta ring even though B[j]A contains a bay region. As reported in the published literature, the mutation spectrum induced by 3-MCA in Ki-ras codon 12 of mouse cells is similar to that of B[a]P but not to that of its close relative B[j]A. In contrast to B[j]A, 3-MCA is activated mostly via a bay-region diol-epoxide since its cyclopenta ring is saturated and not easily epoxidates. Therefore, we propose that the GGT-->CGT mutations produced by B[j]A in Ki-ras codon 12 were mostly the result of cyclopenta-ring-derived adducts.
Mol Carcinog 1993
PMID:Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. 821 37

tRNA-guanine transglycosylase (TGT) is the enzyme responsible for the posttranscriptional modification of specific tRNAs (Asn, Asp, His and Tyr) with queuine. In E. coli this modification occurs via a two-step reaction: (1) TGT-catalyzed base exchange of guanosine-34 with preQ1 (7-aminomethyl-7-deazaguanine) and (2) addition of a cyclopentenediol moiety to the preQ1-34 tRNA. E. coli TGT is normally expressed at very low levels (approximately 1 mg from 500 g cells). The sequence of the queuine operon of E. coli has recently been reported by Reuter et al. (1991). We have cloned the tgt gene into an overexpressing vector in order to provide a more efficient preparation of TGT. A simple, four-step purification scheme yields 78 mg of homogeneous TGT per liter of cell culture (A600 = 5 to 6). Amino-terminal protein sequencing confirms the identity of the recombinant protein and indicates that the initiator methionine is retained in the mature form. Native-PAGE of TGT and SDS-PAGE of cross-linked TGT are most consistent with a hexameric quaternary structure for the enzyme. The cross-linking data also suggests that the enzyme exists as a dimer of trimers of identical 42.5 kDa subunits (total M(r) = 255 kDa. The enzyme is inactivated by cross-linking with the bisimidoester, dimethylsuberimidate. Substrate (tRNA) protects the enzyme against cross-linking and inactivation by dimethylsuberimidate and against inactivation by modification with ethylacetimidate, a monofunctional, imidoester. This indicates that the enzymic residues (presumably lysines) that are involved in cross-linking and the inactivation are in the active site of the enzyme.
J Mol Biol 1993 May 20
PMID:tRNA-guanine transglycosylase from Escherichia coli. Overexpression, purification and quaternary structure. 832 79

A variety of neoplasms of the human nervous system were analyzed for the presence of mutations in the p53 tumor suppressor gene. DNA was extracted from frozen or formalin-fixed, paraffin-embedded material. Single-strand conformation polymorphism (SSCP) analysis for exons 5-8 was followed by direct DNA sequencing. Mutations leading to an amino acid change were found in three of 11 (27%) low-grade (World Health Organization (WHO) Grade II) astrocytomas. They were located in codon 183 (TCA-->TGA) of exon 5, codon 237 (ATG-->ATA) of exon 7, and codon 273 (CGT-->CAT) of exon 8. In one of these cases, the sequence indicated loss of the wild-type allele. Of 12 juvenile pilocytic astrocytomas (WHO Grade I), none contained a p53 mutation, suggesting a different molecular basis for this childhood neoplasm. Except for a mutation in one of seven (14%) meningeal hemangiopericytomas (codon 238; TGT-->TTT, Cys-->Phe), no mutations were observed in exons 5-8 of the p53 gene in any of the following tumors of the nervous system and its coverings: 13 schwannomas, 12 central neurocytomas, 22 meningiomas, 10 choroid plexus papillomas and carcinomas, and 30 neuroblastomas of the sympathetic nervous system. These and published data support the view that p53 mutations are frequently involved both in low-grade and progressive (anaplastic) astrocytomas, including glioblastomas multiforme. Oligodendrogliomas, medulloblastomas, meningiomas, and hemangiopericytomas rarely (< 15%) show p53 mutations in exons 5-8, whereas none of the remaining nervous system neoplasms revealed evidence of an involvement of the p53 gene in their development.
Mol Carcinog 1993
PMID:Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system. 839 97

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) translocation associated with acute myelogenous leukemia and encodes a protein with a central 118-amino-acid domain with 69% homology to the Drosophila pair-rule gene, runt. We demonstrate that AML-1 is a DNA-binding protein which specifically interacts with a sequence belonging to the group of enhancer core motifs, TGT/cGGT. Electrophoretic mobility shift analysis of cell extracts identified two AML-1-containing protein-DNA complexes whose electrophoretic mobilities were slower than those of complexes formed with AML-1 produced in vitro. Mixing of in vitro-produced AML-1 with cell extracts prior to gel mobility shift analysis resulted in the formation of higher-order complexes. Deletion mutagenesis of AML-1 revealed that the runt homology domain mediates both sequence-specific DNA binding and protein-protein interactions. The hybrid product, AML-1/ETO, which results from the (8;21) translocation and retains the runt homology domain, both recognizes the AML-1 consensus sequence and interacts with other cellular proteins.
Mol Cell Biol 1993 Oct
PMID:Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. 841 32

We have studied the sequence specificity in the binding of the potent antitumor drug actinomycin D (AMD) to single-stranded DNA (ssDNA) by fluorescence and NMR spectroscopy and by molecular modeling. The significant absorption and emission changes accompanying the interaction of the fluorescent derivative 7-amino-AMD with DNAs varying in length and base composition were used to calculate affinity constants for the drug-DNA complexes. The guanine-containing trinucleotide sequences AGT, AGA, and TGT embedded within 25-base oligonucleotides, constituted favorable binding sites. In contrast, the sequence TGA did not bind the drug appreciably. Among the DNAs studied, the highest affinity was for the tetranucleotide sequence TAGT. The binding was length dependent, an oligonucleotide of at least 14 bases being required for effective complex formation (Ka > 10(4) M1=). AMD also bound to poly(d(AGT)). Gel electrophoresis confirmed that the complex was formed between the drug and individual unstructured DNA strands. The 1H NMR spectra of oligonucleotides containing the TAGT site and their complexes with AMD provided further insight into the mode(s) of interaction. A comparison of the measured chemical shifts with those estimated from ring-current calculations provided strong evidence for a hemi-intercalation of AMD between the A and G purine bases with a preference for one of two possible relative orientations. The latter were modeled as complexes with the sequence T3AGT3 and refined by force field calculations with the AMBER program. The biological implications for this novel form of interaction of AMD with single-stranded DNA are discussed.
J Mol Biol 1996 Sep 13
PMID:Actinomycin D binding to single-stranded DNA: sequence specificity and hemi-intercalation model from fluorescence and 1H NMR spectroscopy. 880 79

Screening of a hybrid Barbus barbus-B. meridionalis genome was performed for CA, GA, TAT, TCT, TAG, TGT, TATT, TACT, ATCT motifs, and simultaneously on another fish species, tilapia S. melanotheron. Sequences of positive clones were obtained for Barbus and revealed that repetitive structure significantly depends on the motif: most TAT and TATT repeats contain small numbers of repeats, and these repeats are highly heterogeneous, whereas other motifs (we mainly obtained CA and GATA repeats) form longer and much more homogeneous arrays. Polymorphism data from five loci in two different species of barbel show that perfectly repetitive loci are much more variable than imperfect loci (TAT and TATT). We compared the frequency of positive clones for different repeat motifs between barbel and tilapia. For dinucleotide repeats (CA and GA), the comparison was extended to additional fish species, trout and sea bass, which were screened in nearly identical conditions for these motifs. The most salient feature of these comparisons reveals that arrays of dinucleotide motifs are significantly under-represented and shorter in Barbus than in other fish species. We propose an explanation that can account for most features of microsatellites characterizing the genome of barbel. A bias toward deletion affecting slipped-strand mispairing events would lead to shortening and loss of microsatellite loci. Such a bias would represent an efficient way of eliminating useless DNA from polyploidized species with an excessive amount of DNA.
Mol Ecol 1997 Feb
PMID:Does polyploidy lead to fewer and shorter microsatellites in Barbus (Teleostei:Cyprinidae)? 906 42

The aptamer mechanism of action involves the direct interaction of oligonucleotide with protein and is responsible for the biological effects of many pharmacologically active oligodeoxynucleotides. In the work reported here, we have determined the effects of aptamers on the secondary, tertiary, and quaternary structures of the proteins with which they interact using interferon-gamma and the interferon-gamma-inhibitory aptamer oligonucleotide, 5'-GGG GTT GGT TGT GTT GGG TGT TGT GT, as a model system. CD, fluorescence spectroscopy studies, and antibody binding studies in this system demonstrate that the interferon-gamma-inhibitory aptamer oligonucleotide causes significant changes in secondary and tertiary structures of interferon-gamma. These structural changes do not result in, or resemble, protein denaturation or aggregation, and the results suggest that aptamer oligodeoxynucleotides can significantly alter the structure of the proteins they interact with.
Mol Pharmacol 1998 May
PMID:Interferon-gamma-inhibitory oligodeoxynucleotides alter the conformation of interferon-gamma. 958 20

We have identified a human homolog of the Xenopus forkhead activin signal transducer-1 (xFAST-1). Although significantly different in sequence from its Xenopus counterpart, hFAST-1 shared with xFAST-1 the ability to bind to human Smad2 and activate an activin response element (ARE). The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand. The hFAST-1 protein was shown to bind to a novel DNA motif, TGT (G/T) (T/G)ATT, an exact copy of which was present within the ARE. A single copy of this motif could activate a reporter in a TGF beta-dependent fashion but only when an adjacent Smad-binding element was present in the construct. These data suggest that responses to TGF beta family members may be mediated by a DNA-binding complex formed by hFAST-1, hSmad2, and hSmad4.
Mol Cell 1998 Jul
PMID:Characterization of human FAST-1, a TGF beta and activin signal transducer. 970 98


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