Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
Mol Carcinog 1991
PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

In the accompanying paper, we present and analyse the sequence of a "superactivator" mutant allele of the CYP1 (HAP1) gene. This locus encodes a trans-acting pleiotropic positive regulator of the transcription of both isocytochrome c structural genes. In this paper, we present the genetic localization of the mutation and the sequence of the wild-type fragment that includes the mutation. The mutated phenotype that commutes the expression of the two isocytochrome structural genes (superactivation of CYP3 and inhibition of CYC1) results from a transversion in an AGT codon (serine) in the wild-type to an AGG codon (arginine) in the mutant. Moreover, we show that the missense mutation that affects the amino acid preceding the first cysteine of the "Zn finger" is responsible on its own account for the entire mutated phenotype. In all seven yeast regulatory proteins analysed so far, this position is occupied by a neutral amino acid (serine, alanine or glycine), thus the serine-arginine replacement is a radical one. This result is consistent with the hypothesis of alternative and mutually exclusive Zn fingers, formed either at low or high redox potential, recognizing the target sequences identified in the upstream regions of the CYC1 and CYP3 isocytochrome c structural genes.
J Mol Biol 1988 Nov 20
PMID:CYP1 (HAP1) regulator of oxygen-dependent gene expression in yeast. II. Missense mutation suggests alternative Zn fingers as discriminating agents of gene control. 285 59

A mutant cell line that shows high resistance to the photosynthesis-inhibiting herbicide atrazine was selected from cultured photomixotrophic Nicotiana tabacum cv. Samsun NN cells by repeated exposure to toxic levels of the herbicide. This resistance was confirmed by measurements of Hill reaction activity in isolated thylakoid membranes. Nucleotide sequencing revealed that the resistant cell line had a point mutation in its chloroplast psbA gene. The 264th codon, AGT (serine) was changed to ACT (threonine) in this mutant. This new type of mutation also conferred moderate cross-resistance to diuron and subsequently was stable in the absence of continued selection pressure.
Mol Gen Genet 1988 Oct
PMID:Selection of an atrazine-resistant tobacco cell line having a mutant psbA gene. 323 12

Cerulenin, an antifungal antibiotic produced by Cephalosporium caerulens, is a potent inhibitor of fatty acid synthase in various organisms, including Saccharomyces cerevisiae. The antibiotic inhibits the enzyme by binding covalently to the active center cysteine of the condensing enzyme domain. We isolated 12 cerulenin-resistant mutants of S. cerevisiae following treatment with ethyl methanesulfonate. The mechanism of cerulenin resistance in one of the mutants, KNCR-1, was studied. Growth of the mutant was over 20 times more resistant to cerulenin than that of the wild-type strain. Tetrad analysis suggested that all mutants mapped at the same locus, FAS2, the gene encoding the alpha subunit of the fatty acid synthase. The isolated fatty acid synthase, purified from the mutant KNCR-1, was highly resistant to cerulenin. The cerulenin concentration causing 50% inhibition (IC50) of the enzyme activity was measured to be 400 microM, whereas the IC50 value was 15 microM for the enzyme isolated from the wild-type strain, indicating a 30-fold increase in resistance to cerulenin. The FAS2 gene was cloned from the mutant. Sequence replacement experiments suggested that an 0.8 kb EcoRV-HindIII fragment closely correlated with cerulenin resistance. Sequence analysis of this region revealed that the GGT codon encoding Gly-1257 of the FAS2 gene was altered to AGT in the mutant, resulting in the codon for Ser. Furthermore, a recombinant FAS2 gene, in which the 0.8 Kb EcoRV-HindIII fragment of the wild-type FAS2 gene was replaced with the same region from the mutant, when introduced into FAS2-defective S. cerevisiae complemented the FAS2 phenotype and showed cerulenin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Gen Genet 1994 Jul 08
PMID:Cerulenin-resistant mutants of Saccharomyces cerevisiae with an altered fatty acid synthase gene. 804 67

Mutations in the p53 tumor suppressor gene are detected in approximately half of non-melanoma skin cancers. The type of base-pair changes observed strongly suggests solar radiation as the causative mutagen. Mutations are distributed nonrandomly and form moderate hotspots. We studied the capacity of ultraviolet B light (UVB, 280-320 nm) to induce base-pair changes into the p53 exon 7 sequence extending from nt 14067 to 14075 in human skin fibroblasts. This sequence contains hotspot codon 248. UVB induced mostly C-->A and G-->T transversions. The base-pair change with the highest relative abundance was C-->A in the first position of codon 250 (CCC-->ACC), followed by (in diminishing relative abundance) G-->T in the third position of codon 249 (AGG-->AGT), C-->A in the first position of codon 248 (CGG-->AGG), and C-->A in the third position of codon 247 (AAC-->AAA). The C-->T transition in the third position of codon 247 (AAC-->AAT) occurred with moderate efficiency. These base-pair changes are compatible with pyrimidine photodimers as premutagenic lesions, but they could also form opposite 8-hydroxyguanine, which is the major oxidation product of guanine. No evidence was obtained for the presence of tandem double CC-->TT transitions in the untranscribed strand at codons 247/248 and 250. The relative abundance of mutations induced by UVB in the p53 sequence extending from codon 247 to 250 in human fibroblasts does not correlate with mutations observed in the DNA from non-melanoma skin cancer. This lack of correlation suggests that the mutability of this p53 sequence at the DNA level plays only a minor role in the pathogenesis of non-melanoma skin cancer in humans.
Mol Carcinog 1994 Aug
PMID:Ultraviolet B light-induced mutagenesis of p53 hotspot codons 248 and 249 in human skin fibroblasts. 806 78

Major non-coding region of human mitochondrial DNA (mtDNA) (1122 bp) was assessed using the method of complexity analysis of genomes. The ACT, TCA, AGT and TGA motifs (AST-repeats) were shown to form short repeats as well as more complex block structures. These motifs are intrinsic for regulatory sequences of DNA of procaryotic and eucaryotic genes. ACT-repeats based blocks happen to be the most variable parts of the region studied too. Each inherited type of mtDNA is proposed to be a pattern of short repeats arranged with the regard to their symmetry, complementarity and alternativeness thus forming block DNA structures. The existence of similar structures may be possible due to the variability of nucleotide sequences more pronounced in the blocks of repeats of major non-coding region of human mtDNA.
Mol Biol (Mosk)
PMID:[Short repeats and variability in the smooth noncoding area of human mitochondrial DNA]. 824 30

The trypanosomatid mitochondrial genome does not encode tRNA genes at all and experimental evidence obtained with Leishmania tarentolae shows that tRNAs in mitochondria represent a selected set of imported nuclear-encoded tRNAs. In this paper we present the data showing that tRNAs derived from the clustered genomic tRNA genes are invariably imported into mitochondria, while tRNA from the solitary gene is not. By sequencing a cosmid DNA clone of L. tarentolae genomic DNA, we have identified a 1.5-kb subclone encoding a duplicate set of the closely linked tRNA(Tyr) (GTA) and tRNA(Thr) (AGT) genes. Northern analysis shows that these tRNAs are imported into mitochondria. In contrast, when the tRNA gene [tRNA(Gln) (CUG)] located alone in a 40-kb DNA fragment was examined, the corresponding tRNA was not detected in the mitochondrion. This "loner" tRNA gene is highly unusual since the 3'-flanking putative RNA polymerase III transcription termination signal sequence is characterized by a long string of 8 Ts followed by an A and a stretch of 7 Cs, while all other trypanosomatid tRNA genes whose tRNA transcripts are imported are terminated by a possible transcription termination signal of only 4-6 Ts. Whether the correlation found between the gene organization and tRNA-import characteristics is of general significance needs to be investigated further. A simple computer analysis presented in this paper rules out the possibility that tRNAs found in the trypanosomatid mitochondrion are the products of the U-addition type 'RNA editing' of maxicircle DNA.
Mol Biochem Parasitol 1993 Apr
PMID:Selective import of nuclear-encoded tRNAs into mitochondria of the protozoan Leishmania tarentolae. 847 48

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

The Keewatin Inuit of the Northwest Territories of Canada have a very low age-adjusted mortality rate from coronary heart disease. We hypothesized that this apparent protection from disease has a genetic basis. We determined the prevalence of the disease-associated alleles of five candidate genes for atherosclerosis-related phenotypes. Surprisingly, four of the five alleles studied, namely AGT T235, FABP2 T54, PON R192 and APOE E4, were significantly more frequent in a sample of 175 Keewatin Inuit than among a representative control sample of whites living in the region. The high frequencies of these disease-associated alleles suggests either that they have no relationship with disease susceptibility in the Inuit, or that some unmeasured genetic and/or environmental factors mitigate disease susceptibility that is associated with these alleles. This highlights the difficulty in extrapolating findings from one population to another. Also, very modest genotype-phenotype associations were observed between APOE genotype (P = 0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial, glucose concentration (P = 0.048). The relationship between APOE alleles and plasma low-density lipoprotein cholesterol was the same as has been previously reported in many study samples. However, the relationship between FABP2 alleles and plasma 2-h postprandial glucose concentrations was the opposite to that reported in other studies. This suggests that differences in environment, such as the type of fatty acid consumed, interacts with functional differences in gene products involved in candidate metabolic pathways to produce phenotypic differences.
J Mol Med (Berl) 1997 May
PMID:Are Canadian Inuit at increased genetic risk for coronary heart disease? 918 78

According to the "thrifty-genotype" hypothesis proposed by Neel, diseases of civilization such as non-insulin-dependent diabetes mellitus and hypertension result from a discordance between certain features of our present-day environment and our genetic make-up which evolved to fit the life of Paleolithic humans. This concept implies that while "affected" individuals harbor the "original" ancestral version of the relevant genes, healthy or "unaffected" individuals have picked up recent mutations leading to a "loss of thriftiness" of these genes. Support for this concept now comes from recent studies of the angiotensinogen gene, where an ancestral variant of the gene (AGT 235T), also present in primates, has now been associated with hypertension whereas a neomorphic variant (AGT 235M) apparently reduces the risk of high blood pressure. The implications of these findings for our understanding and approach to the study of complex genetic diseases is discussed.
J Mol Med (Berl) 1998 Jul
PMID:The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man. 969 33


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