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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NAD+ glycohydrolase (NADase) and non-enzymic ADP-ribosylation have been thought to be involved in the regulation of mitochondrial Ca2+ fluxes. In this study it was found that several conditions (5 mM nicotinamide, 5 mM 3-aminobenzamide, 2 mM EDTA, 1 mM ATP, 10 mM dithiothreitol) known to strongly inhibit the NADase decreased ADP-ribosylation in bovine liver mitochondrial membranes with [32P]NAD+ as substrate to only a limited extent, if at all. The reaction led to the specific modification of two proteins with apparent molecular masses of approx. 26 and 53 kDa. An excess of added free ADP-ribose diminished the incorporation of label from [32P]NAD+ only slightly. Dithiothreitol inactivated the NADase, whereas ADP-ribosylation was unaffected. At low concentrations (25 microM) ADP-ribosylation was efficient with NAD+, but not ADP-ribose, as substrate. Under these conditions mitochondrial ADP-ribosylation seems to occur as an enzymic reaction rather than a non-enzymic transfer of ADP-ribose previously liberated from NAD+ by NAD+ glycohydrolase. The chemical stability of the protein-ADP-ribose bonds in the mitochondrial membranes indicated that cysteine residues are the predominant acceptors. Moreover, yeast aldehyde dehydrogenase, known to be a substrate for thiol-associated ADP-ribosylation, was efficiently ADP-ribosylated by using the mitochondrial activity and NAD+ as substrate. The modification of a cysteine residue in the aldehyde dehydrogenase was verified by the observation that pretreatment of this acceptor protein with N-ethylmaleimide substantially decreased its modification. It is therefore concluded that bovine liver mitochondria contain a cysteine-specific ADP-ribosyltransferase.
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PMID:Enzymic, cysteine-specific ADP-ribosylation in bovine liver mitochondria. 957 67

We have presently determined the effect of inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) on the occurrence of apoptosis in insulin-producing cells. The ADP-ribosylation activities of intact cells were decreased by incubation of RINm5F cells for 16 h with the PARP inhibitors nicotinamide (NA) (20-50 mM) or 3-aminobenzamide (3-ABA) (10 mM). Exposure to 20-50 mM NA or 10 mM 3-ABA both resulted in massive apoptosis in RINm5F cells. A 24 h exposure to 50 mM nicotinamide induced apoptosis in fetal but not adult rat islet cells. In addition, exposure of RINm5F cells to 50 mM NA for 12-24 h induced the appearance of the 85 kDa proteolytic PARP fragment, indicating activation of the ICE-like protease caspase-3. Incubation with 20-50 mM NA did not induce any consistent effects upon transcription factor NF-kappaB activity, demonstrating that this pathway is not involved in induction of apoptosis by NA. It is concluded that in insulin-producing cells with a high mitotic rate, inhibition of ADP-ribosylation--and consequently of auto-modification and release of PARP bound to DNA strand breaks--leads to activation of programmed cell death.
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PMID:Nicotinamide-induced apoptosis in insulin producing cells is associated with cleavage of poly(ADP-ribose) polymerase. 970 78

Nitric oxide from neuronal cells plays detrimental roles in glutamate neurotoxicity and in focal brain ischemia. Nitric oxide directly damages DNA, and breaks in the DNA strands activate poly(ADP-ribose) polymerase (PARP), which brings poly(ADP-ribosyl)ation of the nuclear proteins. The excessive activation of PARP is thought to cause depletion of ATP and the energy failure resulting in cell death. To clarify the involvement of poly(ADP-ribosyl)ation in ischemic insult, we examined poly(ADP ribosyl)ation by immunohistochemical methods and the protective effect of 3-aminobenzamide, which is a PARP inhibitor, on focal brain ischemia using an intraluminal permanent middle cerebral artery occlusion model in rats. Poly(ADP ribosyl)ation was widely and markedly detected 2 hours after the ischemic insult in the cerebral cortex and striatum in which infarction developed 24 hours later. The enhanced immunoreactivity of poly(ADP-ribose) gradually decreased, and 16 hours later, no immunoreactivity was detected. Intraventricular administration of 3-aminobenzamide (1 to 30 mg/kg) 30 minutes before the ischemic insult decreased infarction volume in a dose-dependent manner along with the immunohistochemical reduction of poly(ADP-ribosyl)ation. Pretreatment with 7-nitroindazole (25 mg/kg, intraperitoneally), a selective neuronal nitric oxide synthetase inhibitor, partially reduced poly(ADP-ribosyl)ation. These data suggest the involvement of poly(ADP-ribosyl)ation in the development of cerebral infarction.
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PMID:Enhanced poly(ADP-ribosyl)ation after focal ischemia in rat brain. 974 Jan 2

Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme responsible for DNA strand breaks, has been recently suggested to be crucial for apoptosis induced by a number chemotherapeutic drugs. In this study, we demonstrated that the PARP activity could be evidently elevated with a peak at 6 h when HL-60 cells were treated with a new anticancer drug GL331. Coincident with the peak of PARP activity, an apparent DNA fragmentation and apoptotic morphology were observed in cells treated with GL331. The subsequent apoptotic DNA fragmentation induced by GL331 could be completely blocked by transfecting cells with anti-sense PARP retroviral vector or by treating cells with PARP inhibitor, 3-aminobenzamide (3-AB). This blocking effect thus suggests that activation of PARP was critically involved in GL331-induced apoptosis. The fact that Bcl-2 has been found to antagonize cell death induced by a wide variety of agents, accounts for why we examined whether if Bcl-2 could antagonize GL331 effects. Interestingly, ectopic overexpression of Bcl-2 in either HL-60 or U937 cells caused in resistance towards GL331-elicited DNA fragmentation and cytotoxic effect. Additionally, Bcl-2 also attenuated the poly(ADP-ribosyl)ation of PARP itself as well as Histone H1 at the early period of drug treatment. However, Bcl-2 did not influence the extent of DNA strand breaks induced by GL331 in either control or Bcl-2-overexpressing cells. In addition, analysis of basal PARP activity in control and several Bcl-2 overexpressing clones revealed that Bcl-2 down-regulated PARP activity under the condition without DNA damages. Above findings suggest that poly(ADP-ribosyl)ation of nuclear targets is important for apoptosis induced by DNA-reactive anticancer drugs.
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PMID:Bcl-2 prevents topoisomerase II inhibitor GL331-induced apoptosis is mediated by down-regulation of poly(ADP-ribose)polymerase activity. 981 53

The objective of this investigation was to determine the role of poly(ADP-ribose) polymerase (PARP) in methylmercuric chloride (MeHgCl)-induced T-cell apoptosis. Following exposure of human T-cells to 2.5 microM MeHgCl, we observed PARP activation within 45 min. Maximal activation was observed at 90 min after MeHgCl treatment; thereafter, PARP activity declined. The loss in enzyme activity was coincidental with the cleavage of 116-kDa intact PARP protein to an 85-kDa fragment. To address the relationship between PARP activation and induction of apoptosis, we first examined the redox status of T cells treated with MeHgCl. We found that exposure of T cells to low concentrations of this toxicant resulted in decreased levels of reduced pyridine nucleotides and an increase in the relative amounts of oxidized flavoproteins. Thus, the possibility exists that activation of PARP leads to NAD+ depletion and thereby alters mitochondrial redox status. To determine if PARP activation is indeed part of the proapoptotic (destructive) response or a component of the antiapoptotic (protective) response, we employed two inhibitors: 3-aminobenzamide and nicotinamide. Pretreatment of T cells with these inhibitors protected cells from MeHgCl-induced apoptosis; this was seen as a reduction in the uptake of Hoechst 33258 and DNA fragmentation. Moreover, these inhibitors blocked MeHgCl-induced oxidative stress as evidenced by a reduction in reactive oxygen species (ROS) generation. These agents, however, failed to block MeHgCl-dependent decline in mitochondrial transmembrane potential (delta psi m). We conclude that PARP activation leads to proapoptotic events that contribute to MeHgCl-induced cell death.
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PMID:Inhibition of poly(ADP-ribose) polymerase rescues human T lymphocytes from methylmercury-induced apoptosis. 985 8

p53 and poly(ADP-ribose) polymerase (PARP) are both DNA damage recognition proteins and can be functionally activated by DNA strand breaks. To understand the functional interaction between these two proteins, the effects of a PARP inhibitor, 3-aminobenzamide (3AB), on the p53 pathway were investigated in human glioblastoma cells with different p53 status. Consistent with previous studies, irradiation with gamma-rays induced both p53 and WAF1 accumulation in A-172 cells (wtp53) but not in T98G cells (mp53). However, the presence of 3AB but not its analog suppressed radiation-induced accumulation of wtp53 and the expression of WAF1 and MDM2. Similar results were also obtained from U87MG, another human glioblastoma cell line with wtp53 status. Northern blotting analysis showed that 3AB inhibited the gamma-ray-induced WAF1 gene expression. Moreover, 3AB but not its analog inhibited irradiation-induced activation of sequence-specific DNA binding of wtp53 as detected using 32P-labeled or biotin-labeled p53 consensus sequence (p53CON). However, immunoblotting with an anti-poly(ADP-ribose) antibody showed that p53 proteins of the p53CON-bound fraction did not contain poly(ADP-ribose) (PAR). These findings suggested that poly(ADP-ribosyl)ation is required for rapid accumulation of p53, activation of p53 sequence-specific DNA binding and its transcriptional activity after DNA damage.
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PMID:Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. 987 88

The observation that 3-aminobenzamide, which inhibits a variety of ADP-ribose transferases, prolongs the gamma-irradiation-induced increase in intracellular p53 concentration suggested that one or more of such enzymes may determine the duration of the p53 response during G1 arrest. The role of poly(ADP-ribose) polymerase (PARP), an abundant nuclear enzyme activated by DNA strand breaks, in the p53 response to y-irradiation was investigated in Burkitt's lymphoma AG876 cells stably transfected with an inducible PARP antisense construct. Immunoblot analysis revealed that the cellular content of PARP was reduced to virtually undetectable levels after incubation of transfected cells for 72 h with the inducer dexamethasone. In noninduced antisense cells, the p53 concentration reached a maximum 2 h after exposure to 6.3 Gy of gamma-radiation and returned to control values by 4 h. In contrast, the p53 response in PARP-depleted antisense cells peaked at 4 h, with the levels of p53 remaining elevated for up to 12 h after y-irradiation. The maximal increase in p53 concentration was similar in both induced and noninduced cells. These results thus indicate that PARP activity, in part, determines the duration, but not the magnitude, of the p53 response to DNA damage.
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PMID:Prolongation of the p53 response to DNA strand breaks in cells depleted of PARP by antisense RNA expression. 991 21

The human colon carcinoma cell line Caco-2 was exposed to the oxidative stress-inducing agents menadione (MEN), 2,3-dimethoxy-1,4-naphthoquinone, and hydrogen peroxide. All three agents caused DNA damage which was assessed by alkaline unwinding. Further, all three agents induced intensive NAD+ depletion, followed by a decrease in intracellular ATP and viability. Inhibition of poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) by 3-aminobenzamide prevented the depletion of NAD+. These cells had a higher viability and ATP content. The most pronounced effect was observed with 25 microM of MEN, while at higher levels a partial preservation of NAD+ was observed with no effect on ATP or viability. The chelation of intracellular calcium by bis-(o-aminophenoxy)-ethane-N,N,N1,N1-tetraacidic acid/tetraacetoxymethyl) ester also prevented the dramatic loss of NAD+, demonstrating that Ca2+ is an activating factor in PARP-mediated cell killing.
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PMID:Prevention of oxidant-induced cell death in Caco-2 colon carcinoma cells after inhibition of poly(ADP-ribose) polymerase and Ca2+ chelation: involvement of a common mechanism. 992 Feb 81

Bile salts induce apoptosis and are implicated as promoters of colon cancer. The mechanisms by which bile salts produce these effects are poorly understood. We report that the cytotoxic bile salt, sodium deoxycholate (NaDOC), activates the key stress response proteins, NF-kappaB and poly(ADP-ribose) polymerase (PARP). The activation of NF-kappaB and PARP, respectively, indicates that bile salts induce oxidative stress and DNA damage. The pre-treatment of cells with specific inhibitors of these proteins [pyrrolidine dithiocarbamate (NF-kappaB inhibitor) and 3-aminobenzamide (PARP inhibitor)] sensitizes cells to the induction of apoptosis by NaDOC, indicating that these stress response pathways are protective in nature. Colon cancer risk has been reported to be associated with resistance to apoptosis. We found an increase in activated NF-kappaB at the base of human colon crypts that exhibit apoptosis resistance. This provides a link between an increased stress response and colon cancer risk. The implications of these findings with respect to apoptosis and to colon carcinogenesis are discussed.
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PMID:The stress-response proteins poly(ADP-ribose) polymerase and NF-kappaB protect against bile salt-induced apoptosis. 1020 May 17

Inhibitors of poly(ADP-ribose)polymerase (PARP) inhibit repair of damaged DNA and thus potentiate radiotherapy and chemotherapy of cancer. Treatment of 3-cyanothiophene with potassium nitrate and concentrated sulphuric acid gave 5-nitrothiophene-3-carboxamide. 4-Nitrothiophene-2-carboxamide and 5-nitrothiophene-2-carboxamide were formed similarly from 2-cyanothiophene. Reduction with tin(II) chloride gave the corresponding aminothiophenecarboxamide salts which were isolated via their N-Cbz derivatives. Lithiation of 3,4-dibromothiophene at -116 degrees C and quenching with alkyl chloroformates gave 4-bromothiophene-3-carboxylates, which were hydrolysed to 4-bromothiophene-3-carboxylic acid. Hurtley reactions with the enolates of pentane-2,4-dione and of 1-phenylbutane-1,3-dione, followed by acyl cleavage, led to 4-(2-oxopropyl)thiophene-3-carboxylic acid and 4-phenacylthiophene-3-carboxylic acid, respectively. Condensation with ammonia in acetic acid gave 6-methyl- and 6-phenylthieno[3,4-c]pyridin-4-ones, which were selectively nitrated at the 1- and 7-positions or were dinitrated. Ethyl 4-acetamido- and 4-benzamido-thiophene-3-carboxylates were cyclised to 2-methyl- and 2-phenyl-thieno[3,4-d][1,3]oxazin-4-ones, respectively. Ring-opening with ammonia and recyclisation led to 2-substituted thieno[3,4-d]pyrimidin-4-ones. The aminothiophenecarboxamides are analogues of 3-aminobenzamide, a selective inhibitor of poly(ADP-ribose)polymerase (PARP); the thienopyridinones and the thienopyrimidinones are analogues of isoquinolin-1-ones and quinazolin-4-ones, respectively, which inhibit this enzyme. In preliminary assays, several thienopyridinones and thienopyrimidinones showed potent inhibitory activity against PARP.
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PMID:Synthesis of thiophenecarboxamides, thieno[3,4-c]pyridin-4(5H)-ones and thieno[3,4-d]pyrimidin-4(3H)-ones and preliminary evaluation as inhibitors of poly(ADP-ribose)polymerase (PARP). 1021 21


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