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)

Bleomycin (BLM), a DNA-cleaving, antitumor antibiotic, causes pulmonary fibrosis. It also causes cell injury and activates the nuclear enzyme poly(ADP-ribose) polymerase (PAP; EC 2.4.2.30) in lung slices exposed to the drug in vitro. 3-Aminobenzamide (3-AB), a PAP inhibitor, prevents enzyme activation and cell injury. We have examined the potential role of ATP and NAD depletion in injury of BLM-sensitive C57B1/6N and -resistant BALB/cN murine lung slices treated with BLM or deprived of glucose, the major metabolic substrate of lung. Lung slices either were treated for 45 min with injurious concentrations of BLM (10-500 micrograms/mL) or were incubated without glucose, in the presence or absence of 2.5 mM 3-AB. Only the highest concentration of BLM, 500 micrograms/mL, caused any ATP depletion, and this 35% decrease was transient, occurring at 220 min in C57B1/6N slices. In contrast, glucose deprivation caused 50-70% ATP depletion in slices from both strains. BLM alone at 100 and 500 micrograms/mL caused a sustained 30-70% NAD depletion from 75 min through 400 min in C57B1/6N mouse lung slices. In the resistant BALB/cN lung slices, NAD depletion by BLM was only seen at 400 min. 3-AB almost completely antagonized NAD depletion in slices from both strains. In contrast to BLM, glucose deprivation did not decrease NAD levels unless 3-AB was present in C57B1/6N slices. Thus, ATP depletion may play a role in the injurious effects of glucose deprivation, but does not appear to be a major factor in pneumocyte injury caused by BLM. NAD depletion or other effects of PAP activation appear to account for the strain-selective, injurious effect of BLM on lung tissue.
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PMID:NAD depletion after in vitro exposure of murine lung slices to bleomycin. 750 88

A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.
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PMID:Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation. 757 30

Exposure to hydrogen peroxide (H2O2) decreases phosphatidylcholine (PC) synthesis in rabbit type II pneumocytes. Activation of poly(ADP-ribose) polymerase (PARP) may play a role in this process. Exposure of type II pneumocytes to H2O2 resulted in a 53% decrease in the rate of incorporation of [3H]choline into PC (P < 0.001). Cell NAD and ATP levels were decreased by 52% (P < 0.001) and 39% (P < 0.01), respectively, without significant changes in cell viability. Exposure to H2O2 also resulted in a 52% (P < 0.05) increase in the activity of PARP. Preincubation of type II cells with inhibitors of PARP (nicotinamide; 3-aminobenzamide) before H2O2 exposure prevented the increase in PARP activity, and blocked the decreases in ATP, NAD, and rate of PC synthesis. These results suggest that the energy depletion associated with activation of PARP contributes to the effects of oxidant stress on type II cell metabolic function and may be ameliorated by pharmacological agents in vitro.
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PMID:Inhibition of poly(ADP-ribose) polymerase preserves surfactant synthesis after hydrogen peroxide exposure. 763 15

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is an early response of cells exposed to DNA-damaging compounds such as nitric oxide (NO) or reactive oxygen intermediates (ROI). Excessive poly-(ADP-ribose) formation by PARP has been assumed to deplete cellular NAD+ pools and to induce the death of several cell types, including the loss of insulin-producing islet cells in type I diabetes. In the present study we used cells from mice with a disrupted and thus inactivated PARP gene to provide direct evidence for a causal relationship between PARP activation, NAD+ depletion, and cell death. We found that mutant islet cells do not show NAD+ depletion after exposure to DNA-damaging radicals and are more resistant to the toxicity of both NO and ROI. These findings directly prove that PARP activation is responsible for most of the loss of NAD+ following such treatment. The ADP-ribosylation inhibitor 3-aminobenzamide partially protected islet cells with intact PARP gene but not mutant cells from lysis following either NO or ROI treatment. Hence the protective action of 3-aminobenzamide must be due to inhibition of PARP and does not result from its other pharmacological properties such as oxygen radical scavenging. Finally, the use of mutant cells an alternative pathway of cell death was discovered which does not require PARP activation and NAD+ depletion. In conclusion, the data prove the causal relationship of PARP activation and subsequent islet cell death and demonstrate the existence of an alternative pathway of cell death independent of PARP activation and NAD+ depletion.
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PMID:Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells. 774 49

The effect of inhibition of poly(ADP-ribose) polymerase (PARP) on the growth arrest and cell killing induced by N-methyl-N-nitrosourea (MNU) was studied in L929 fibroblasts. Depletion of NAD and ATP preceded the cell killing by a 1-h exposure to 10 or 15 mM MNU. 3-Aminobenzamide (ABA), an inhibitor of PARP, spared the depletion of NAD and ATP and prevented the cell killing. With 5 mM MNU, a depletion of NAD was promptly reversed, and there was no loss of ATP and no cell death. Aphidicolin, a DNA polymerase inhibitor, prevented the restoration of NAD, with resulting depletion of ATP and death of the cells, effects that were prevented by ABA. Azide together with 2-deoxyglucose depleted ATP, followed by a loss of NAD and cell death, changes that occurred in the absence of DNA single strand breaks (DNA SSB). ABA prevented the depletion of NAD, but not that of ATP, nor the cell killing. MNU (2.5 mM) inhibited cell growth without effect on the viability of the cells. ABA potentiated the cell growth inhibition. Thus, inhibition of PARP potentiates cell growth inhibition by limiting DNA repair mechanisms. Alternatively, inhibition of the DNA repair response to more extensive DNA damage prevents cell killing. The ATP depletion caused by poly(ADP-ribosyl)ation, rather than DNA SSB and the loss of NAD, is the more critical event in the cell killing.
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PMID:Growth inhibition and cell killing by N-methyl-N-nitrosourea: metabolic alterations that accompany poly(ADP-ribosyl)ation. 778 36

Low-dose gamma-irradiation of mouse embryonic fibroblast C3D2F1 3T3-a cells caused G1 arrest along with G2 arrest and inhibition of replicative DNA synthesis. When the cells were cultured in the presence of inhibitors of poly(ADP-ribose) polymerase [EC 2.4.2.30], such as 3-aminobenzamide, benzamide and luminol, G1 arrest of C3D2F1 3T3-a cells was suppressed and enhancement of G2 arrest was observed. In contrast, 3-aminobenzoic acid, a non-inhibitory analog of 3-aminobenzamide, did not suppress G1 arrest following gamma-irradiation. These results suggest that the poly(ADP-ribosyl)ation reaction is critical for the pathway of G1 arrest and is also involved in the pathway of G2 arrest.
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PMID:Suppression of G1 arrest and enhancement of G2 arrest by inhibitors of poly(ADP-ribose) polymerase: possible involvement of poly(ADP-ribosyl)ation in cell cycle arrest following gamma-irradiation. 782 93

Poly (ADP-ribose) polymerase (PARP) participates in the immediate response in mammalian cells exposed to DNA-damaging agents. Recombinant baculovirus harboring the cDNA of the chicken PARP catalytic domain (40 kDa) have been used to infect Spodoptera frugiperda (Sf9) insect cells. The recombinant polypeptide (30 mg per 1 x 10(9) cells) was purified to homogeneity by 3-aminobenzamide affinity chromatography. The enzymatic properties of the recombinant domain were similar to those of the native fragment. Crystals of the purified recombinant catalytic domain were grown by vapor diffusion. The crystals belong to space group P2(1)2(1)2(1) with unit cell dimensions of a = 59.2 A, b = 65.0 A, c = 96.9 A. They are suitable for X-ray analysis and diffract to 2.0 A.
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PMID:Crystallization and X-ray crystallographic analysis of recombinant chicken poly(ADP-ribose) polymerase catalytic domain produced in Sf9 insect cells. 796 15

Cyclophosphamide (CYC) is a metabolically activated, DNA-alkylating, antitumor agent that causes pulmonary fibrosis. BALB/cN (B) mice are sensitive and C57Bl/6N (C) mice are resistant to CYC-induced fibrosis. Pulmonary bioactivation may contribute to strain sensitivity. Therefore, we tested the intrinsic susceptibility of murine lung slices to cell injury by direct exposure to CYC for 2-8 hr. Injury was measured by release of lactate dehydrogenase (LDH). DNA damage activates the nuclear enzyme poly(ADP-ribose) polymerase (PAP, EC 2.4.2.30), causing depletion of its substrate, NAD. NAD can also be decreased by phosphorylation to NADP, as seen with oxidative stress. Depletion of NAD can lead to loss of ATP. Thus, we measured LDH release, PAP activation, NAD, NADP and ATP in slices incubated with or without the PAP-inhibitor, 3-aminobenzamide (3-AB). CYC (0.1 to 1.0 mg/mL for 4-8 hr) caused LDH release in slices from both murine strains, but LDH release was significantly greater in B lung slices than in C slices. After an 8-hr incubation 63.9 +/- 3.7% (mean +/- SEM) of total LDH was released from B lung slices with 1.0 mg CYC/mL, whereas only 45.8 +/- 2.6% was released from C lung slices (P < 0.05). 3-AB reduced LDH release to 44.7 +/- 2.4% in B slices and 28.1 +/- 2.0% in C slices (P < 0.05 vs CYC only). PAP activity in nuclei isolated from CYC-treated B lung slices was increased 2- to 4-fold after 2 hr of incubation with 0.5 and 1.0 mg CYC/mL. PAP activation was delayed and reduced with incubation in 3-AB. PAP was activated 2-fold in nuclei from C slices treated with 0.5 mg CYC/mL for 2 hr. NAD was decreased at 2 and 4 hr in B slices treated with 0.5 and 1.0 mg CYC/mL, and at 4 hr with 0.1 mg CYC/mL. NAD depletion occurred only at 4 hr in the resistant C slices treated with 1.0 mg CYC/mL. CYC increased NADP by a similar extent in B and C lung slices. In B slices, NAD losses were approximately 4 times the increases in NADP. CYC did not decrease ATP in B slices and ATP dropped 25% only after 4 hr in the resistant C slices. We conclude that CYC is directly toxic to lung tissue and observe that strain sensitivity in vitro mirrors the sensitivity to fibrosis in vivo. PAP activation and oxidative stress may contribute to this toxicity.
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PMID:Acute pneumocyte injury, poly(ADP-ribose) polymerase activity, and pyridine nucleotide levels after in vitro exposure of murine lung slices to cyclophosphamide. 798 Jun 45

The mechanism by which NAD stimulates cardiac adenylate cyclase was investigated. In highly purified canine cardiac sarcolemma, NAD stimulated adenylate cyclase activity in the presence of agents which activate Gs (i.e. 5 mM AlF4-, 10 microM GTP gamma S, 10 microM GppNHp or isoproterenol plus 2 nM GTP gamma S). Furthermore, the EC50 of isoproterenol to stimulate adenylate cyclase was reduced in the presence of NAD. In membranes incubated with [32P]-NAD, AlF4-, 10 microM GTP gamma S or isoproterenol plus 2 nM GTP gamma S produced a selective increase in the radiolabeling of a single 45-kDa protein which was identified as Gs alpha by immunoprecipitation. Cholera toxin catalysed radiolabeling of the same protein. Neutral hydroxylamine released [32P]-ADP-ribose from Gs alpha prelabeled in the presence of AlF4- and [32P]-NAD indicating that an arginine residue on Gs alpha was modified by an endogenous ADP-ribosyltransferase. ADP-ribosyltransferase inhibitors, novobiocin, vitamin K1 or 3-aminobenzamide, inhibited AlF4- stimulated ADP-ribosylation of Gs alpha and NAD potentiation of adenylate cyclase with similar efficacies. The activity responsible for NAD potentiation of adenylate cyclase and ADP-ribosylation of Gs alpha was not removed under hypotonic or hypertonic conditions and therefore appears to be tightly membrane bound. Collectively, these observations indicate that canine cardiac sarcolemma possess an ADP-ribosyltransferase which may constitutively catalyse transfer of an ADP-ribose to activated Gs alpha.
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PMID:Modification of cardiac membrane adenylate cyclase activity and Gs alpha by NAD and endogenous ADP-ribosyltransferase. 800 86

It has been recently shown that in developing chicken embryonic nuclear extracts there is a 5-methyldeoxycytidine excision repair activity (Jost, J. P. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4684-4688). We show that in differentiating mouse myoblasts, a similar enzymatic reaction may be responsible for the genome-wide DNA demethylation (up to 50% of all CmCGG) occurring between the 3rd and 5th days of differentiation. Furthermore, in differentiating myoblasts, there is first a 50% transient decrease in DNA methyltransferase activity and a 90% drop in the rate of DNA synthesis, followed by an increase in 5-methyl-CpG endonuclease and 5-methyldeoxycytidine excision repair activities. As tested in vitro, the maximal activity of the 5-methyldeoxycytidine excision repair coincides with the maximal in vivo genome-wide DNA demethylation. We also find that 3-aminobenzamide, a potent inhibitor of ADP-ribosyltransferase, blocks the differentiation of myoblasts, the 5-methyldeoxycytidine excision repair activity, and the genome-wide demethylation.
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PMID:Transient DNA demethylation in differentiating mouse myoblasts correlates with higher activity of 5-methyldeoxycytidine excision repair. 814 2


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