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At least 307 records · Page 17Linked to original sources
PubMed2000

Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.

Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.

Benzamides↗
PubMed2001

Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death.

Excessive activation of poly(ADP-ribose) polymerase 1 (PARP1) leads to NAD(+) depletion and cell death during ischemia and other conditions that generate extensive DNA damage. When activated by DNA strand breaks, PARP1 uses NAD(+) as substrate to form ADP-ribose polymers on specific acceptor proteins. These polymers are in turn rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG), a ubiquitously expressed exo- and endoglycohydrolase. In this study, we examined the role of PARG in the PARP1-mediated cell death pathway. Mouse neuron and astrocyte cultures were exposed to hydrogen peroxide, N-methyl-d-aspartate (NMDA), or the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Cell death in each condition was markedly reduced by the PARP1 inhibitor benzamide and equally reduced by the PARG inhibitors gallotannin and nobotanin B. The PARP1 inhibitor benzamide and the PARG inhibitor gallotannin both prevented the NAD(+) depletion that otherwise results from PARP1 activation by MNNG or H(2)O(2). However, these agents had opposite effects on protein poly(ADP-ribosyl)ation. Immunostaining for poly(ADP-ribose) on Western blots and neuron cultures showed benzamide to decrease and gallotannin to increase poly(ADP-ribose) accumulation during MNNG exposure. These results suggest that PARG inhibitors do not inhibit PARP1 directly, but instead prevent PARP1-mediated cell death by slowing the turnover of poly(ADP-ribose) and thus slowing NAD(+) consumption. PARG appears to be a necessary component of the PARP-mediated cell death pathway, and PARG inhibitors may have promise as neuroprotective agents.

Animals↗
PubMed1979

Structure of poly(adenosine diphosphate ribose): identification of 2'-[1''-ribosyl-2''-(or 3''-)(1'''-ribosyl)]adenosine-5',5'',5'''-tris(phosphate) as a branch linkage.

Poly([14C]adenosine diphosphate ribose) was synthesized from [14C]NAD+ with calf thymus nuclei. The fraction containing poly(adenosine diphosphate ribose) eluted with 0.22--0.40 M phosphate buffer (pH 6.8) from a hydroxylapatite column, was completely hydrolyzed with venom phosphodiesterase, and was separated by DEAE-Sephadex A-25 column chromatography in 7 M urea. A new compound, which constituted 2% of the products from poly(adenosine diphosphate ribose), was found in addition to the expected products--i.e., 5'-AMP, 2'-(1''-ribosyl)adenosine-5',5''-bis(phosphate), and its derivatives. This compound was identified as 2'-[1''-ribosyl 2''-(or 3''-)(1'''-ribosyl)]adenosine-5',5'',5'''-tris(phosphate). The existence of this compound is evidence of a branching structure of poly(adenosine diphosphate ribose), which was previously thought to be a linear molecule. The content of this compound suggests that the frequency of branching is about 1 per 20--30 adenosine diphosphate ribose residues of high molecular weight poly(adenosine diphosphate ribose).

Chemical Phenomena↗
PubMed1984

Induction of murine teratocarcinoma cell differentiation by suppression of poly(ADP-ribose) synthesis.

Poly(ADP-ribose) synthesizing activity in mouse teratocarcinoma EC-A1 cells decreased markedly during differentiation induced by retinoic acid; the activities assayed in permeabilized cells decreased to 25% and 10% of the activity of control (uninduced cells) 2 and 3 days, respectively, after the addition of 0.1 microM retinoic acid to the culture medium. This change preceded changes in morphology and DNA synthesis, which became prominent after 4 days. The decrease in poly(ADP-ribose) synthesizing activity appeared to be caused by a diminution of the synthetase protein and not by a decrease in its catalytic activity, because the full activity disclosed by DNase I treatment decreased in parallel, albeit at about 20 times higher levels. When 8 mM 3-aminobenzamide or 10 mM nicotinamide, specific inhibitors of poly(ADP-ribose) synthetase, was added to the culture medium, the cells underwent differentiation after 7-9 days. An analogue, 3-aminobenzoic acid, which is not inhibitory to the synthetase, induced differentiation much less efficiently than did 3-aminobenzamide, and the effect of 3-aminobenzoic acid appeared to be ascribable to its potent cytotoxicity. Immunohistochemical analysis using anti-poly(ADP-ribose) antibody confirmed the marked reduction in poly(ADP-ribose) synthesizing activity in nuclei of the cells treated with retinoic acid or 3-aminobenzamide but not with 3-aminobenzoic acid. These results suggest that a decrease in poly(ADP-ribose) synthesis triggers differentiation of teratocarcinoma cells.

Aminobenzoates↗
PubMed2000

Nitric oxide inhibits Ca(2+) mobilization through cADP-ribose signaling in coronary arterial smooth muscle cells.

The present study was designed to determine whether the cADP-ribose-mediated Ca(2+) signaling is involved in the inhibitory effect of nitric oxide (NO) on intracellular Ca(2+) mobilization. With the use of fluorescent microscopic spectrometry, cADP-ribose-induced Ca(2+) release from sarcoplasmic reticulum (SR) of bovine coronary arterial smooth muscle cells (CASMCs) was determined. In the alpha-toxin-permeabilized primary cultures of CASMCs, cADP-ribose (5 microM) produced a rapid Ca(2+) release, which was completely blocked by pretreatment of cells with the cADP-ribose antagonist 8-bromo-cADP-ribose (8-Br-cADPR). In intact fura 2-loaded CASMCs, 80 mM KCl was added to depolarize the cells and increase intracellular Ca(2+) concentration ([Ca(2+)](i)). Sodium nitroprusside (SNP), an NO donor, produced a concentration-dependent inhibition of the KCl-induced increase in [Ca(2+)](i), but it had no effect on the U-46619-induced increase in [Ca(2+)](i). In the presence of 8-Br-cADPR (100 microM) and ryanodine (10 microM), the inhibitory effect of SNP was markedly attenuated. HPLC analyses showed that CASMCs expressed the ADP-ribosyl cyclase activity, and SNP (1-100 microM) significantly reduced the ADP-ribosyl cyclase activity in a concentration-dependent manner. The effect of SNP was completely blocked by addition of 10 microM oxygenated hemoglobin. We conclude that ADP-ribosyl cyclase is present in CASMCs, and NO may decrease [Ca(2+)](i) by inhibition of cADP-ribose-induced Ca(2+) mobilization.

ADP-ribosyl Cyclase↗
PubMed1992

Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase.

Two classes of enzymes, poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferases, catalyze covalent attachment of multiple or single residues, respectively, of the ADP-ribose moiety of NAD+ to various proteins. In order to find good inhibitors of poly(ADP-ribose) synthetase free of side actions and applicable to in vivo studies, we made a large scale survey using an in vitro assay system, and found many potent inhibitors. The four strongest were 4-amino-1,8-naphthalimide, 6(5H)- and 2-nitro-6(5H)-phenanthridinones, and 1,5-dihydroxyisoquinoline. Their 50% inhibitory concentrations, 0.18-0.39 microM, were about two orders of magnitude lower than that of 3-aminobenzamide that is currently most popularly used. A common structural feature among all potent inhibitors, including 1-hydroxyisoquinoline, chlorthenoxazin, 3-hydroxybenzamide, and 4-hydroxyquinazoline, in addition to the four mentioned above, was the presence of a carbonyl group built in a polyaromatic heterocyclic skeleton or a carbamoyl group attached to an aromatic ring. Most of the inhibitors exhibited mixed-type inhibition with respect to NAD+. Comparative studies of the effects on poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase from hen heterophils revealed high specificity of most of the potent inhibitors for poly(ADP-ribose) synthetase. On the other hand, unsaturated long-chain fatty acids inhibited both enzymes, and saturated long-chain fatty acids and vitamin K1 acted selectively on mono(ADP-ribosyl)transferase. The finding of many inhibitors of ADP-ribosyltransferases, especially poly(ADP-ribose) synthetase, supports the view that ADP-ribosylation of proteins may be regulated by a variety of metabolites or structural constituents in the cell.

ADP Ribose Transferases↗
PubMed1986

Modulation of chromatin superstructure induced by poly(ADP-ribose) synthesis and degradation.

It has been demonstrated recently by Poirier et al. (Poirier, G. G., de Murcia, G., Jongstra-Bilen, J., Niedergang, C., and Mandel, P. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 3423-3427) that poly(ADP-ribosyl)ation of pancreatic nucleosomes causes relaxation of the chromatin superstructure through H1 modification. The in vitro effect of poly(ADP-ribose) synthesis and degradation on calf thymus chromatin was investigated by the time course incorporation of ADP-ribose, electron microscopy, analytical ultracentrifugation, and autoradiography of the protein acceptors. Purified calf thymus poly(ADP-ribose) polymerase and partially purified bull testis poly(ADP-ribose) glycohydrolase were used. Degradation of ADP-ribose units on hyper(ADP-ribosyl)ated H1 by poly(ADP-ribose) glycohydrolase restores the native condensed chromatin superstructure. This reversible conformational change induced by poly(ADP-ribosyl)ation on nucleosomal arrangement could be one of the mechanisms by which the accessibility of DNA polymerases and/or excision-repair enzymes is favored, the native structure being fully restorable.

Animals↗
PubMed1989

Differentiation of 3T3-L1 pre-adipocytes induced by inhibitors of poly(ADP-ribose) polymerase and by related noninhibitory acids.

To analyze a possible involvement of ADP-ribosylation reactions in 3T3-L1 pre-adipocyte differentiation. ADP-ribosyltransferase activities is permeabilized cells as well as endogenous amounts of protein-bound mono- and poly(ADP-ribose) residues were determined. Also, in vivo labeling with [3H]adenosine of ADP-ribose residues linked to high-mobility-group (HMG) proteins was performed. As an additional probe, the effects of ADP-ribosylation inhibitors and non-inhibitory analogs were studied. Basal and total poly(ADP-ribose) polymerase activities markedly increased prior to the appearance of the differentiation marker glycerol-3-phosphate dehydrogenase. Despite these apparent changes in activity, however, neither protein-bound poly(ADP-ribose) residue nor mono(ADP-ribosyl) groups in histones, nor the NAD content, changed significantly under these conditions. Furthermore, although HMG protein-associated [3H]ADP-ribose was reduced in differentiating [3H]adenosine-labeled cells, the data suggest altered precursor pool labeling rather than a specific decrease in ADP-ribosylated HMG proteins. Non-participation of ADP-ribosylation reactions in 3T3-L1 differentiation is further supported by experiments with inhibitors and non-inhibitory analogs. Benzamide at 0.3-3 mM per se without effect on differentiation, was able to induce specific gene expression when combined with insulin (10(-12)-10(-7) M). Similar effects were seen with benzoate as well as with nicotinamide, 3-aminobenzamide and their corresponding acids. The data indicate that benzamide and analogs have profound effects on chromatin functions that are not mediated by ADP-ribosylation reactions.

ADP Ribose Transferases↗
PubMed2006

Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity.

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.

Catechol O-Methyltransferase↗
PubMed1997

ADP-ribose in glycation and glycoxidation reactions.

Glycation is initiated by reaction of a reducing sugar with a protein amino group to generate a Schiff base adduct. Following an Amadori rearrangement to form a ketoamine adduct, a complex chemistry involving oxidation often leads to protein glycoxidation products referred to as advanced glycosylation end products (AGE). The AGE include protein carboxymethyllysine (CML) residues and a heterogeneous group of complex modifications characterized by high fluorescence and protein-protein cross links. The sugar sources for the glycoxidation of intracellular proteins are not well defined but pentoses have been implicated because they are efficient precursors for the formation of the fluorescent AGE, pentosidine. ADP-ribose, generated from NAD by ADP-ribose transfer reactions, is a likely intracellular source of a reducing pentose moiety. Incubation of ADP-ribose with histones results in the formation of ketoamine glycation conjugates and also leads to the rapid formation of protein CML residues, histone H1 dimers, and highly fluorescent products with properties similar to the AGE. ADP-ribose is much more efficient than other possible pentose donors for glycation and glycoxidation of protein amino groups. Recently developed methods that differentiate nonenzymic modifications of proteins by ADP-ribose from enzymic modifications now allow investigations to establish whether some protein modifications by monomers of ADP-ribose in vivo represent glycation and glycoxidation.

Adenosine Diphosphate Ribose↗
PubMed1994

Poly(ADP-ribose): historical perspective.

The early historical background of the discovery of poly(ADP-ribose) and the following development of science on poly(ADP-ribose) are reviewed. Fundamental knowledge on the natures of poly(ADP-ribose), poly(ADP-ribose) polymerase and enzymes degrading poly(ADP-ribose) are summarized with brief description on the methodology for their purification and characterization. Future prospect of research on biological significance of poly(ADP-ribose) has also been discussed briefly.

History, 20th Century↗
PubMed1994

Poly(ADP-ribose) catabolism in mammalian cells.

Poly(ADP-ribose) catabolism is a complex situation involving many proteins and DNA. We have developed an in vitro turnover system where poly(ADP-ribose) metabolism is monitored in presence of different relative amounts of two principal enzymes poly(ADP-ribose) transferase and poly(ADP-ribose) glycohydrolase along with other proteins and DNA. Our current results reviewed here show that the quality of polymer, i.e. chain length and complexity, as well as preference for the nuclear substrate varies depending upon the availability of poly(ADP-ribose) glycohydrolase. These results are interpreted in the light of the recent data implicating poly(ADP-ribose) metabolism in DNA-repair.

DNA Polymerase II↗
PubMed1991

Direct stimulation of poly(ADP ribose) polymerase in permeabilized cells by double-stranded DNA oligomers.

Poly(ADP ribosyl)ation, a post-translational modification of nuclear proteins catalyzed by poly (ADP ribose) polymerase, is an immediate response of most eukaryotic cells to DNA strand breaks and has been implicated in DNA repair and other cellular phenomena associated with DNA strand breakage. Poly(ADP ribose) polymerase activity levels have been frequently assayed by incubating permeabilized cells with radioactively labeled NAD+ as substrate. In such assays enzyme activation has routinely been achieved indirectly by prior exposure of living cells to carcinogens or by adding DNase I to permeabilized cells, thereby introducing strand breaks in chromosomal DNA. Here we show that, as an alternative method, the direct activation of purified poly(ADP ribose) polymerase by double-stranded oligonucleotides (N. A. Berger and S. I. Petzold, 1985, Biochemistry 24, 4352-4355) can be adopted for permeabilized cell systems. The inclusion of a palindromic decameric deoxynucleotide in the reaction buffer stimulated the enzyme activity in permeabilized Molt-3 human lymphoma cells up to 30-fold (at 50 micrograms/ml [corrected] oligonucleotide concentration) in a concentration-dependent manner. The activating effect of oligonucleotides was also evident when ethanol-fixed HeLa cells were postincubated with NAD+ to allow poly(ADP ribose) synthesis to occur in situ, which was detected as specific anti-poly (ADP ribose) immunofluorescence. We conclude that double-stranded oligonucleotides can be conveniently used as chemically and stoichiometrically well-defined poly (ADP ribose) polymerase activators in permeabilized or ethanol-fixed mammalian cells.

Base Sequence↗
PubMed1990

Regulation of poly(ADP-ribose) polymerase mRNA levels during compensatory and mitogen-induced growth of rat liver.

Poly(ADP-ribose) polymerase mRNA levels were studied in hepatic regeneration following partial hepatectomy, and in hyperplasia induced by the mitogen lead nitrate. A significant increase in the level of poly(ADP-ribose) polymerase mRNA was found 8 h after partial hepatectomy when no detectable increase of DNA synthesis could be observed; the level of poly(ADP-ribose) polymerase transcripts increased up to six-fold within 1-2 days. A similar increase of the level of poly(ADP-ribose) polymerase mRNA was found 24 h after treatment with lead nitrate. A twofold increase in poly(ADP-ribose) polymerase activity was observed 2 days after (a) partial hepatectomy and (b) lead nitrate treatment. From these results an important role of poly(ADP-ribose) polymerase in cell proliferation could be suggested.

Animals↗
PubMed1975

Stimulation of nuclear poly (adenosine diphosphate-ribose) polymerase activity from HeLa cells by endonucleases.

Isolated nuclei from HeLa cells can incorporate labeled ADP-ribose from NAD into an acid-precipitable product, poly(ADP-ribose). This reaction is stimulated by 4-6-fold by the addition of deoxyribonuclease I to the complete reaction mixture. If the nuclei are treated first with deoxyribonuclease I, no effect is seen; the stimulation is only apparent when the two enzymes deoxyribonuclease I and poly(ADP-ribose) polymerase, are operating at the same time. After making several minor modifications in the assay mixture, it was found that another endonuclease, micrococcal nuclease, can also stimulate the poly(ADP-ribose) polymerase activity of HeLa nuclei. A comparison of the two stimulatory effects indicated that the two endonucleases activated to the poly(ADP-ribose) polymerase activity of HeLa nuclei in the same way. Overall this evidence suggests that poly(ADP-ribose) polymerase may have a functional role in the process of DNA repair.

Cell Nucleus↗
PubMed1989

Expression of human poly(ADP-ribose) polymerase with DNA-dependent enzymatic activity in Escherichia coli.

A cDNA for human poly(ADP-ribose) polymerase was inserted into a plasmid, transfected and expressed in E. coli. A lysate of the E. coli cells containing the expression plasmid reacted with antibody against human poly(ADP-ribose) polymerase and synthesized poly(ADP-ribose). The partially purified poly(ADP-ribose) polymerase expressed in E. coli had the same molecular weight and enzymological properties as human placental poly(ADP-ribose) polymerase, including affinity for NAD, turnover number and DNA-dependency for activity. This expression system should be useful for structure-function analysis of poly(ADP-ribose) polymerase.

Blotting, Western↗
PubMed1992

The alpha-glycosidic bonds of poly(ADP-ribose) are acid-labile.

The poly(ADP-ribosyl)ation system of higher eukaryotes produces multiple ADP-ribose polymers of distinct sizes which exhibit different binding affinities for histones. Although precipitation with trichloroacetic acid (TCA) is the standard procedure for isolation of poly(ADP-ribose) from biological material, we show here that poly(ADP-ribose) is not stable under acidic conditions. Storage of poly(ADP-ribose) as TCA pellets results in acid hydrolysis of polymers, the extent of which is dependent on storage time and temperature. The alpha-glycosidic, inter-residue bonds are the preferred sites of attack, thus reducing polymer sizes by integral numbers of ADP-ribose to yield artefactually more and smaller polymers than originally present. Therefore, poly(ADP-ribosyl)ation studies involving TCA precipitation, histone extraction with acids, or acidic incubations of ADP-ribose polymers must account for the impact of acids on resulting polymer populations.

Chromatography, High Pressure Liquid↗
PubMed1987

Strategy for selection of cell variants deficient in poly(ADP-ribose) polymerase.

A selection strategy to obtain cells deficient in poly(ADP-ribose) polymerase was developed based on the fact that treatment with high levels of N-methyl-N'-nitro-N-nitrosoguanidine results in sufficient activation of poly(ADP-ribose) polymerase to cause NAD and ATP depletion leading to cessation of all energy-dependent processes and rapid cell death. In contrast, cells with low levels of poly(ADP-ribose) polymerase should not consume their NAD and might therefore be more likely to survive the DNA damage. Using this approach, we have cloned a number of cell lines containing 37-82% enzyme activity. The apparent decrease in poly(ADP-ribose) polymerase activity is not due to increases in NAD glycohydrolase, poly(ADP-ribose) glycohydrolase, or phosphodiesterase activities. Further characterization of the poly(ADP-ribose) polymerase-deficient cells indicates that they have prolonged generation times and increased rates of spontaneous sister chromatid exchanges.

Adenosine Triphosphate↗