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:2.6.1.44 (AGT)
770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new simple low ionic strength antiglobulin test (LIS-AGT) is presented for use in the antibody screening phase of pretransfusion tests. The ionic strength during the incubation phase of LIS-AGT is held between 15-17% of that of indirect AGT, and 8 mM EDTA is added to serum to inhibit false-positive tests. The prevalence of false-positive LIS-AGT was determined to be approximately two times higher than that observed with the indirect AGT. The new test was superior to the indirect AGT in detecting antibodies specific to Rh, Duffy, Kidd, and MNSs antigens, while the indirect AGT was superior in detecting antibodies specific to K and Lewis antigens. On the basis of three 51Cr red blood cell (RBC) survival studies, it was shown that antibodies reactive with LIS-AGT only decreased the long-term survival of incompatible erythrocytes, although the one-hour recovery was not affected. It appeared that antibodies reactive by LIS-AGT only can cause delayed rather than acute hemolytic transfusion reactions. The data shown indicate that the LIS-AGT is a simple and valuable addition to the pre-transfusion antibody screening test.
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PMID:A new low ionic strength test for assessment of pretransfusion compatibility. Studies in vitro and in vivo. 685 63

The kinetics of accumulation of the premutagenic DNA adduct O6-methylguanine (O6-meG) in the liver, blood leukocytes, lymph nodes and bone marrow of rats was examined and compared after single or multiple doses of procarbazine, a methylating cytostatic drug employed in the treatment of Hodgkin's lymphoma patients, and methylnitrosourea (MNU), an experimental methylating agent and carcinogen. Maximal O6-meG levels occurred 1-2 h after administration of single doses of procarbazine (10 mg/kg) or MNU (1 mg/kg), thereafter decreasing with half-lives of approximately 20-45 h, depending on the tissue. A relatively uniform tissue distribution was observed with both agents, with the liver generally showing highest adduct levels, followed by the lymph nodes, bone marrow and blood leukocytes which contained broadly similar amounts of O6-meG. During daily, oral administration to rats of procarbazine for 10 days at dose rates of 2.5, 5, 10 or 20 mg/kg/day (treatment analogous to that of the MOOP chemotherapy protocol for Hodgkin's lymphoma) followed by animal death on different days (in each case 24 h after the last treatment), a biphasic mode of O6-meG induction was observed: an initially steep build-up during the first 3-4 days was followed by a transient decline in the rate of accumulation, in turn followed by a second wave of accumulation and then a further slow-down. During the same treatment, liver O6-methylguanine-DNA alkyltransferase (AGT) declined in a dose-related manner. AGT recovery after the end of treatment was slow, taking nearly 20 days after the end of the high-dose treatment to return to control levels, despite the fact that all detectable adducts had been lost from DNA within 3 days after the end of treatment. A similar depletion and slow recovery of AGT in the liver, blood lymphocytes, bone marrow and lymph nodes was observed after treatment with a single dose of 100 mg/kg procarbazine. In contrast to these observations, O6-meG accumulated smoothly during a 10 day administration of MNU (1 or 10 mg/kg/day) to reach a steady-state within 5-6 days, while liver AGT was partially depleted after the high dose and recovered fully within 72 h of cessation of treatment. Similarly, a single dose of MNU (35 mg/kg) resulted in AGT depletion followed by rapid recovery in all four tissues examined. It is concluded that procarbazine (but not MNU) causes a decrease in cellular AGT concentrations by a mechanism additional to suicide repair of O6-meG.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential effects of procarbazine and methylnitrosourea on the accumulation of O6-methylguanine and the depletion and recovery of O6-alkylguanine-DNA alkyltransferase in rat tissues. 751 72

It is shown by fluorescence spectroscopy that the post-activated form of neocarzinostatin chromophore (NCSi-glu) can form stable complexes with single-site oligonucleotides (SSOs) featuring sequences known to be involved in double stranded (AGC.GCT, AGT.ACT, AGA.TCT, ACA.TGT) or single stranded (AGG.CCT) cleavage (attacked residues in bold). Furthermore, the same SSOs form cleavage productive complexes with native neocarzinostatin chromophore (NCS chrom) over a similar concentration range. The productive complexes yield damage similar to that observed if the same sequence is part of a longer DNA piece. Previously identified double stranded site sequences ATT.AAT and TAT.ATA are shown to contain overlapping attack sites. Binding order preference derived from fluorescence quenching experiments for NCSi-glu is consistent with constants derived by quantitative cleavage affinity binding experiments with NCS chrom. This confirms the similarity in interactions between the NCSi-glu and NCS chrom and justifies the use of NCSi-glu as a stable analog of NCS chrom.
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PMID:Binding and cleavage characteristics of the complexes formed between the neocarzinostatin chromophore and single site containing oligonucleotides. 758 49

Nucleotide sequence features of the human interferon-inducible gene 6-16 are described and include, within a CpG island, a partially expressed minisatellite consisting of 26 tandemly repeated dodecanucleotides. The repeat unit consensus sequence (CAGGTAAGGGTG) is similar to the mammalian splice donor consensus sequence [(A/C)AGGT(A/G)AGT]. The splice donor site of exon 2, as determined previously, forms part of the most upstream of the repeat units. We show that the two neighbouring repeat units also provide functional splice donor sites effectively extending exon 2 by 12 or 24 nt and inserting four or eight amino acids respectively into the predicted gene product. A similar pattern of differently spliced transcripts is detected in several human cell types. Both the number of repeat units per allele and the nucleotide sequence itself show limited polymorphism within the human population. Similar minisatellites from nonhuman primates are described and also appear to modulate splicing of a 6-16 transcript. The 6-16 minisatellite is therefore an example of tandemly repeated DNA that has a role in gene expression and may provide a useful in vivo system for the analysis of 5' splice site choice and minisatellite biology.
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PMID:Characterisation of a novel minisatellite that provides multiple splice donor sites in an interferon-induced transcript. 759 9

We demonstrated a germline p53 replication error in two generations of a Li-Fraumeni family affected with liposarcoma, adrenocortical carcinoma, and osteosarcoma. The trinucleotide repeat mutation changed 5'-AGT GTG GTG GTG-3' at codons 215-218 to 5'-AGT TGG TTG GTG GTG-3'. The predicted protein would be elongated by one amino acid (val216-->trp leu) without a change in charge. Detection of p53 in the adrenal tumor by immunostaining suggested that the mutant protein was expressed. Persistence of the mutation in the germline may suggest a defect in DNA repair in the family member first affected. This is the first report where germline transmission of replication-damaged p53 trinucleotide repeats is associated with the Li-Fraumeni syndrome.
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PMID:Complex replication error causes p53 mutation in a Li-Fraumeni family. 761 54

Expansion of trinucleotide repeats (CAG)n and (CGG)n is found in genes responsible for certain human hereditary neurodegenerative diseases. By gel-mobility shift assay, we detected a single-stranded (AGC)n repeat-binding activity primarily in mouse brain extracts and very low or undetectable activity in other tissue extracts. Two (AGC)n-repeat binding proteins, with apparent molecular weights of 44 and 40 kDa, have been purified from mouse adult brain by a DNA affinity column and fast protein liquid chromatography. UV-cross linking of radiolabeled (AGC)n repeats with crude brain extracts and with purified two proteins of 44 and 40 kDa produced identical doublet bands, indicating that these proteins are in fact responsible for the (AGC)n-binding activity in brain extracts. We designated these two proteins TRIP-1 for the 44 kDa protein and TRIP-2 for the 40 kDa protein, where TRIP represents trinucleotide repeat-binding protein. TRIP-1 and TRIP-2 bind to a specific subset of trinucleotide repeat sequences including (AGC)n, (AGT)n, (GGC)n, and (GGT)n repeats but not to various other trinucleotide repeats. A minimum of eight (AGC) trinucleotide repeating units is required for TRIP-1 and -2 recognition and binding. The (AGC)n repeat-binding activity increases in the brain after birth and reaches a plateau within 3 weeks. In the brain, TRIP-1 and TRIP-2 may alter the function of the genes containing the expanded-trinucleotide repeats.
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PMID:Single-stranded DNA binding proteins isolated from mouse brain recognize specific trinucleotide repeat sequences in vitro. 765 26

Experiments were done to show whether a G to T mis-sense mutation at the third base of codon 249 of the p53 tumour suppressor gene is a 'hot spot' of aflatoxin attack as suggested by the results of epidemiological studies. Liver tissue from liver cancer patients in Taiwan and Japan was analysed for the presence of aflatoxin-DNA adducts (ADA) as a marker for aflatoxin exposure and an AGG to AGT transversion at codon 249 of the p53 gene. Ten per cent of samples containing ADA, indicating definite exposure of the subjects to aflatoxin, was found to harbour the codon 249 mutation, whereas 18% of the samples with no detectable adducts also contained the mutation. Our data do not support the hypothesis that codon 249 of the p53 gene DNA is a hot spot for aflatoxin mutagenesis as a 'late stage event' in human hepatocellular carcinogenesis.
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PMID:Recent aflatoxin exposure and mutation at codon 249 of the human p53 gene: lack of association. 766 37

We have selected an HXB2 variant which can replicate in the presence of a neutralizing human serum. Sequencing of the gp120 region of the env gene from the variant and parental viruses identified a single amino acid substitution in the third conserved region of gp120 at residue 375 (AGT-->AAT, Ser-->Asn; designated 375 S/N). The escape mutant was found to be resistant to neutralization by soluble CD4 (sCD4) and four monoclonal antibodies (MAbs), 39.13g, 1.5e, G13, and 448, binding to epitopes overlapping that of the CD4 binding site (CD4 b.s.). Introduction of the 375 S/N mutation into HXB2 by site-directed mutagenesis confirmed that this mutation is responsible for the neutralization-resistant phenotype. Both sCD4 and three of the CD4 b.s. MAbs (39.13g, 1.5e, and G13) demonstrated reduced binding to the native 375 S/N mutant gp120. The ability to select for an escape variant resistant to multiple independent CD4 b.s. MAbs by a human serum confirms the reports that antibodies to the discontinuous CD4 b.s. are a major component of the group-specific neutralizing activity in human sera.
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PMID:Resistance of a human serum-selected human immunodeficiency virus type 1 escape mutant to neutralization by CD4 binding site monoclonal antibodies is conferred by a single amino acid change in gp120. 768 20

In nine human colon tumour cell lines the relationship between O6-alkylguanine-DNA alkyltransferase (O6-AGT) activity and carmustine resistance was investigated. Three lines with O6-AGT activity below 25 fmol/mg protein had carmustine ED50 values ranging from 5.0 microM to 11.9 microM; six lines displaying an O6-AGT activity above 240 fmol/mg protein had ED50 values ranging from 28.9 microM to 69.5 microM. In lines with low O6-AGT activity, depletion of the repair protein by O6-benzylguanine resulted in a marginal increase of carmustine cytotoxicity (sensitization factors less than 2). In the majority of cell lines with high O6-AGT activity, pretreatment with O6-benzylguanine resulted in a pronounced sensitization to carmustine. In one line, an optimal time schedule for sensitization of colon tumour cells by O6-benzylguanine was assessed; continuous exposure to O6-benzylguanine > or = 16 h after carmustine exposure) was superior to short-term exposure limited to a period before carmustine treatment.
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PMID:Sensitization of human colon tumour cell lines to carmustine by depletion of O6-alkylguanine-DNA alkyltransferase. 775 21

O6-Alkylguanine-DNA alkyltransferase (O6-AGT) activity in rat ovarian tumor lines O-342 and O 342/DDP was 103.4 +/- 18.4 and 240.9 +/- 40.2 fmol/mg protein, respectively; thus, cisplatin (DDP) resistance was paralleled by an increase in O6-AGT activity by a factor of approximately 2.3. The DDP-resistant line expressed a collateral resistance to BCNU. Both lines could be sensitized to BCNU by O6-BG, with sensitization factors of 6.0 and 2.1, respectively. In neither line did depletion of O6-AGT have any sensitizing effect towards DDP. In the human ovarian cancer lines SK-OV-3 and OAW 42, O6-AGT activity was 337.6 +/- 18.2 and 180.0 +/- 39.9 fmol/mg protein, respectively; in these lines depletion of O6-AGT activity by O6-BG treatment resulted in sensitization factors of 3.0 and 4.1, respectively. The increase in sensitivity of ovarian tumor cell lines against a chloroethylating agent by O6-AGT depletion and possible pharmacological advantages of regional (i.p.) administration of this combination might be beneficial in advanced ovarian cancer.
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PMID:Inhibition of O6-alkylguanine-DNA alkyltransferase in animal and human ovarian tumor cell lines by O6-benzylguanine and sensitization to BCNU. 780 87


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