Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fibroblast cell line L929 contains a constitutively expressed NO synthase (EC 1.14.29.-) activity, which can be increased about 10-fold by tumour-necrosis factor alpha (TNF-alpha). Activities of the constitutive and the inducible enzymes are tetrahydrobiopterin-independent and can be inhibited by L-NG-nitroarginine. Induction of NO synthase by TNF-alpha was prevented by inhibitors of poly(ADP-ribose) polymerase, namely nicotinamide, 3-methoxybenzamide and 3-aminobenzamide. TNF-alpha did not lead to an increase in ADP-ribosyltransferase activity nor to a change in the pattern of ADP-ribosylated proteins. The inhibitors were only active during the first 4-5 h after exposure to TNF-alpha and they were found to suppress synthesis of protein, DNA and RNA. These data suggest that the inhibitors prevent induction of NO synthase by interference with RNA and protein synthesis. It is not yet known which reactions of these biosynthetic processes are affected by the inhibitors.
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PMID:Induction of nitric oxide synthase in L929 cells by tumour-necrosis factor alpha is prevented by inhibitors of poly(ADP-ribose) polymerase. 128 Jan 12

Constitutive expression of human nuclear NAD+: protein ADP-ribosyltransferase (polymerizing) [pADPRT; poly(ADP-ribose)polymerase; EC 2.4.2.30] as an active enzyme in Saccharomyces cerevisiae, under the control of the alcohol dehydrogenase promoter, was only possible with simultaneous inhibition of ADP-ribosylation by 3-methoxybenzamide. Induction of fully active pADPRT from the inducible galactose epimerase promoter resulted in inhibition of cell division and morphological changes reminiscent of cell cycle mutants. Expression of a pADPRT cDNA truncated at its 5' end had no influence on cell proliferation at all. Obviously the amino-terminal part of the DNA binding domain containing the first "zinc finger", which is essential for inducibility of pADPRT activity by DNA breaks, is also required for inhibition of cell growth on expression in yeast. Full-length as well as truncated pADPRT molecules were directed to the cell nucleus where the fully active enzyme produced large amounts of poly(ADP-ribose) by automodification. Since pADPRT turned out to be the only target for ADP-ribosylation in these cells, elevated levels of poly(ADP-ribose) were the most likely cause of inhibition of cell division, presumably resulting from interaction with chromosomal proteins.
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PMID:Inhibition of cell proliferation in Saccharomyces cerevisiae by expression of human NAD+ ADP-ribosyltransferase requires the DNA binding domain ("zinc fingers"). 155 29

Stimulating bone marrow derived macrophages with LPS results in the induction of NO-synthase as measured by NO2- formation. Inhibitors of poly(ADP-ribose)polymerase, namely nicotinamide, 3-aminobenzamide and 3-methoxybenzamide, prevented NO2- formation in a dose dependent manner. Inhibition was most effective if the inhibitors were added at the same time as LPS. When added 10 h after exposure to LPS, a time at which expression of the enzyme had reached its maximum, no inhibition was observed. The inhibitors also blocked early events in activation such as protein and RNA-synthesis as well as DNA-synthesis. Thus prevention of NO2- formation may be related to inhibition of these events. Activation of macrophages by LPS was not accompanied by an increase but rather by a small decrease in ADP-ribosyltransferase activity. Whether this decrease plays a physiological role in activation needs further exploration.
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PMID:Inhibitors of poly (ADP-ribose) polymerase suppress lipopolysaccharide-induced nitrite formation in macrophages. 171 89

The gene for human nuclear NAD+ ADP-ribosyltransferase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosetransferase, EC 2.4.2.30; pADPRT] was localized to chromosome 1 at q41-q42 by in situ hybridization with a pADPRT-specific cDNA probe. Expression of a pADPRT cDNA under control of the lac promoter in Escherichia coli induces the synthesis of a group of related proteins that were immunoreactive with pADPRT antibody and that had catalytic properties very similar to those of the human enzyme. Purification of this enzymatic activity was performed essentially as described for the human enzyme. The Km, pH optimum, optimal reaction temperature, and inhibition by 3-aminobenzamide and 3-methoxybenzamide were found to be similar for the recombinant and the human enzymes. The purified recombinant enzyme consists of two major proteins of Mr 99,000 and Mr 89,000. Both proteins show pADPRT activity in activity gel analysis with [32P]NAD+ as substrate. Microsequencing of these two proteins isolated by denaturing gel electrophoresis and deletion mutagenesis of the pADPRT expression plasmid shows that the Mr 99,000 and Mr 89,000 proteins derive from initiation of translation at internal translational start signals located within the pADPRT cDNA.
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PMID:Human nuclear NAD+ ADP-ribosyltransferase: localization of the gene on chromosome 1q41-q42 and expression of an active human enzyme in Escherichia coli. 249 72

Simple competitive inhibitors of the nuclear enzyme ADP-ribosyltransferase, such as 3-methoxybenzamide (3MB), are known to block mitogen-induced activation of lymphocytes by inhibiting an early event. We now report that 3MB affects neither the generation of inositol phosphates nor the increase in cytoplasmic calcium in human T lymphocytes stimulated with phytohaemagglutinin (PHA), indicating that it acts on later or parallel events. The proliferative response to the phorbol ester 12-o-tetradecanoylphorbol-13-acetate (TPA) was much less sensitive to 3MB than was the response to PHA. Similarly, the TPA-induced increases in the expression of the c-myc proto-oncogene and of the Tac polypeptide of the interleukin-2 receptor were not affected by 3MB, whereas the same responses to either PHA or the calcium ionophore A23187 were inhibited by 3MB. The data suggest that 3MB affects the calcium-mediated signal for T-lymphocyte activation, acting after the increase in cytoplasmic calcium, and possibly also affects other signal transduction pathways distinct from the hydrolysis of polyphosphoinositides. There are some similarities between the actions of 3MB and cyclosporin.
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PMID:Differential role for ADP-ribosylation in gene expression during the activation of T lymphocytes by various stimuli. 250 98

The level of mRNA encoding the nuclear enzyme poly(ADP-ribose) polymerase (ADP-ribosyltransferase, EC 2.4.2.30) was found to be very low in quiescent human lymphocytes and to increase at least 10-fold between 1 and 2 dyas after stimulation with the mitogen phytohaemagglutinin, staying high for several days thereafter. This increase was inhibited by 3-methoxybenzamide (a competitive inhibitor of poly(ADP-ribose) polymerase) but was not affected significantly by aphidicolin. Incubation of activated cells with cycloheximide for 2 h increased the expression slightly. These data demonstrate that, during lymphocyte activation, the level of mRNA of the poly(ADP-ribose) polymerase gene correlates with, and hence is presumably responsible for, the increase in poly(ADP-ribose) polymerase protein detectable by enzyme assay or immunochemistry.
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PMID:Changes in mRNA levels of poly(ADP-ribose) polymerase during activation of human lymphocytes. 250 50

An affinity adsorbent for ADP-ribosyltransferase (EC 2.4.2.30) has been synthesized by coupling 3-aminobenzamide to Sepharose 4B. Using this material, ADP-ribosyltransferase from human placenta has been purified from crude extract to homogeneity within a few hours. The enzyme has an apparent Km for NAD+ of 52 microM. Its molecular mass is 115,000 as determined by gel electrophoresis. The enzyme is DNA dependent and stimulated by histone, its temperature optimum is at 25 degrees C, and its pH optimum is around pH 9. alpha-NAD+, thymidine, caffeine, theophylline, theobromine, 3-methoxybenzamide, and nicotinamide inhibit the enzyme. Purification of ADP-ribosyltransferases from horse, rat, and chicken liver was also achieved with the method described.
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PMID:Isolation of ADP-ribosyltransferase by affinity chromatography. 300 87

Treatment of the Daudi Burkitt lymphoma-derived cell line with human interferon alpha, which inhibits cell proliferation in this system, induces differentiation of these B-lymphoid cells into cells with a plasmacytoid phenotype. This differentiation, quantified by the appearance of surface antigens characteristic of mature plasma cells, is impaired by addition to the culture medium of the ADP-ribosyltransferase (ADPRT; EC 2.4.2.30) inhibitors 3-methoxybenzamide or 3-aminobenzamide. These agents also protect the cells against the inhibition of proliferation induced by low doses of interferon alpha. In contrast, the large inhibition of thymidine incorporation into DNA caused by interferon treatment is not affected by the ADPRT inhibitors. The phorbol ester phorbol 12-tetradecanoate 13-acetate induces the same plasma cell surface antigens that are induced by interferon treatment, and this effect is also impaired by the ADPRT inhibitors. These results suggest that interferons and phorbol esters share a mechanism of action that requires ADPRT activity. Protection of the cells against the antiproliferative effect of interferons by the ADPRT inhibitors suggests that growth inhibition may be a consequence of cell differentiation. In contrast, the inhibition of thymidine incorporation alone is not sufficient for the cessation of cell proliferation and is not a true reflection of the rate of DNA synthesis.
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PMID:Induction of B-cell differentiation antigens in interferon- or phorbol ester-treated Daudi cells is impaired by inhibitors of ADP-ribosyltransferase. 311 50

ADP-ribosyltransferases from several higher eukaryotes have been purified and characterized, but little is known about ADP-ribosyltransferases in lower eukaryotes. We have purified an ADP-ribosyltransferase (EC 2.4.2.30) from Helix pomatia. The enzyme has an apparent Km of 26.7 microM. Optimal conditions for the enzyme reaction are 17.5 degrees C and pH 8. The time course is linear during the first 10 min of the reaction. The enzyme is capable of poly-ADP-ribosylation. The most highly purified preparation shows one major band at an Mr of 75,000 on electrophoresis in an SDS/polyacrylamide gel, with minor bands at Mr 115,000 and 155,000. Re-activation of SDS/polyacrylamide gels in situ shows the 75,000-Mr band to be enzymically active and additional active bands with Mr values of 115,000, 90,000 and 87,000 respectively. The 115,000-Mr and 75,000-Mr bands cross-react with a polyclonal affinity-purified antiserum against human ADP-ribosyltransferase. Like enzymes from higher eukaryotes, the activity from Helix pomatia is inhibited by thymidine, theophylline, theobromine nicotinamide, 3-methoxybenzamide and 3-aminobenzamide, and is dependent on histone and DNA.
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PMID:ADP-ribosyltransferase from Helix pomatia. Purification and characterization. 312 18

To investigate the origin of DNA repair in rat pleural mesothelial cells (RPMC) exposed to asbestos fibers, poly(ADP-ribose) polymerase (PARP) activity was measured in the asbestos-treated cells. As bleomycin has been shown to activate poly(ADP-ribose) synthesis in several cell systems, the response to bleomycin with regard to PARP assay was first investigated. Bleomycin produced a dose-dependent increase of poly(ADP-ribose) synthesis in RPMC. Likewise both chrysotile and crocidolite fibers produced a concentration-dependent PARP activation indicating that the formation of DNA strand breaks is one type of damage produced by asbestos in RPMC. Enhancement of DNA repair, assessed by the measurement of [3H] methylthymidine incorporation in growth arrested cells, was not detectable in the presence of 3-methoxybenzamide (3-MBA), a PARP inhibitor, confirming a relation between PARP activation and DNA repair. The participation of DNA breakage in asbestos toxicity on RPMC was determined by the colorimetric 3-4(5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was no relationship between DNA breakage and cytotoxicity since the use of PARP inhibitors did not change cell viability. These results indicate that asbestos produce DNA damage that is repaired in RPMC.
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PMID:Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture. 750 Sep 78


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