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)

Activation of poly(ADP-ribose) polymerase (PARP) by DNA breaks catalyzes poly(ADP-ribosyl)ation and results in depletion of NAD+ and ATP, which is thought to induce necrosis. Proteolytic cleavage of PARP by caspases is a hallmark of apoptosis. To investigate whether PARP cleavage plays a role in apoptosis and in the decision of cells to undergo apoptosis or necrosis, we introduced a point mutation into the cleavage site (DEVD) of PARP that renders the protein resistant to caspase cleavage in vitro and in vivo. Here, we show that after treatment with tumor necrosis factor alpha, fibroblasts expressing this caspase-resistant PARP exhibited an accelerated cell death. This enhanced cell death is attributable to the induction of necrosis and an increased apoptosis and was coupled with depletion of NAD+ and ATP that occurred only in cells expressing caspase-resistant PARP. The PARP inhibitor 3-aminobenzamide prevented the NAD+ drop and concomitantly inhibited necrosis and the elevated apoptosis. These data indicate that this accelerated cell death is due to NAD+ depletion, a mechanism known to kill various cell types, caused by activation of uncleaved PARP after DNA fragmentation. The present study demonstrates that PARP cleavage prevents induction of necrosis during apoptosis and ensures appropriate execution of caspase-mediated programmed cell death.
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PMID:Failure of poly(ADP-ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis. 1037 61

The activation of poly(ADP-ribose) polymerase (PARP) by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The purpose of the present study was to examine the neuroprotective effects of a PARP inhibitor, 3-aminobenzamide (3-ABA), which was administered either prior to or following reperfusion, to determine the importance of PARP inhibition prior to reperfusion. 3-ABA was injected i.p. either 15 min before or 15 min following reperfusion in a transient focal ischemia model in the rat. Treatment prior to the reperfusion led to a significant decrease in the volume of damaged tissue at 24 h (118.7 +/- 18.8 mm3, mean +/- s.d., p < 0.01), compared with the control (176.1 +/- 22.8 mm3). However, treatment after the reperfusion failed to produce a reduction in the damaged volume (171.9 +/- 27.6 mm3). These findings suggest that PARP activation sufficient to produce cellular damage occurs immediately after the reperfusion following cerebral ischemia.
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PMID:The effect of reperfusion on neuroprotection using an inhibitor of poly(ADP-ribose) polymerase. 1042 67

The role of endogenous ADP-ribosylation in mediating the activation of the Ca(2+)-activated K(+) channels was determined in bovine coronary arteries. Endogenous ADP-ribosylation was examined by incubating coronary arterial homogenates or lysates of cultured coronary arterial smooth muscle cells with [adenylate-(32)P]NAD. Four (32)P-labeled proteins were observed at 51, 52, 80, and 124 kDa in the homogenates and lysates. This reaction was enhanced by the addition of 11,12-epoxyeicosatrienoic acid (11,12-EET), a cytochrome P450-derived eicosanoid, and GTP to the incubation. By Western blot analysis, 42- and 70-kDa proteins were recognized by specific antibodies against ADP-ribosyltransferase in the coronary arterial homogenates and smooth muscle cell lysate but not in the lysate of endothelial cells. The 52-kDa acceptor protein of endogenous ADP-ribosylation comigrated with a protein ADP-ribosylated by cholera toxin and was recognized and immunoprecipitated by an anti-G(S)alpha antibody. These results suggest that G(S)alpha is one of several acceptors of the ADP-ribose moiety. As shown by the patch-clamp technique, 11,12-EET stimulated the activation of the K(+) channels in the smooth muscle cells, and this activation was completely blocked by novobiocin, vitamin K(1), 3-aminobenzamide, and m-iodobenzylguanidine, inhibitors of endogenous mono-ADP-ribosyltransferases. We conclude that endogenous mono-ADP-ribosyltransferases are present in smooth muscle from bovine coronary arteries. These enzymes transfer ADP-ribose to the cellular proteins such as G(S)alpha and may mediate intracellular signal transduction in coronary vascular smooth muscle. In the coronary circulation, the ADP-ribosylation signaling pathway may play an important role in mediating the activation of the K(+) channels induced by 11,12-EET.
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PMID:11,12-Epoxyeicosatrienoic acid stimulates endogenous mono-ADP-ribosylation in bovine coronary arterial smooth muscle. 1045 63

Vascular pathologies induced by ischemia/reperfusion involve the production of reactive oxygen species (ROS) that in part cause tissue injury. The production of ROS that occurs upon reperfusion activates specific second messenger pathways. In diabetic retinopathy there is a characteristic loss of the microvascular pericyte. Pericytes are more sensitive than endothelial cells to low concentrations of ROS, such as hydrogen peroxide (H(2)O(2)) when tested in vitro. Whether the pericyte loss is due to toxic cell death triggered by the noxious H(2)O(2) or apoptosis, due to activation of specific second messenger pathways, is unknown. During apoptosis, a cell's nucleus and cytoplasm condense, the cell becomes fragmented, and ultimately forms apoptotic bodies. It is generally assumed that apoptosis depends on nuclear signaling, but cytoplasmic morphological processes are not well described. We find that exposing cultured retinal pericytes to 100 microM H(2)O(2) for 30 min leads to myosin heavy chain translocation from the cytosol to the cytoskeleton and a significant decrease in cell surface area. Pericyte death follows within 60-120 min. Exposing cells to 150 mJ/cm(2) ultraviolet radiation, an alternate free radical generating system, also causes pericyte myosin translocation and apoptosis. Proteolytic cleavage of actin is not observed in pericyte apoptosis. 3-aminobenzamide, a pharmacological inhibitor of the cleavage and activation of the DNA-repairing enzyme poly (ADP-ribose) polymerase (PARP) inhibits pericyte apoptosis, and prevents myosin translocation. Deferoxamine, an iron chelator known to interfere with free radical generation, also inhibits pericyte myosin translocation, contractility, and cell death. Myosin translocation to the cytoskeleton may be an early step in assembly of a competent contractile apparatus, which is involved in apoptotic cell condensation. These results suggest that pericyte loss associated with increased free radical production in diabetic retina may be by an apoptotic phenomenon.
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PMID:Myosin translocation in retinal pericytes during free-radical induced apoptosis. 1046 10

Endothelial cells (EC) are subject to oxidative-induced cell death. Activation of poly(ADP-ribose) polymerase (PARP) occurs early in oxidant-induced EC injury and putatively mediates cell death by depleting its substrate, NAD(+). In this study, the role of PARP in H(2)O(2)-induced EC death was investigated. EC were exposed to oxidant stress and viability continuously monitored using fluorescent dye exclusion. Inhibition of PARP with 1, 5-dihydroxyisoquinoline (DIQ) delayed the time course of oxidant-induced EC death. Concurrent addition of the protein synthesis inhibitor, cycloheximide, or the endonuclease inhibitor, aurintricarboxylic acid, to PARP-inhibited cells further delayed the onset and attenuated the extent of H(2)O(2)-induced cell lysis, consistent with an active mode of cell death. Caspase-3-like activity, a hallmark of apoptosis, was negligible in oxidant-treated EC alone, however, inhibition of PARP by 3-aminobenzamide or DIQ dramatically increased caspase-3-like activity. Morphological assessment confirmed that the primary mode of death in oxidant-stressed EC was oncosis. However, following PARP inhibition, the cells switched to apoptosis. Since inflammation is associated with oncosis and not apoptosis, the results presented here could explain the beneficial effects seen with PARP inhibition in various in vivo models of oxidant injury and provide a mechanism to manipulate this injury into a state of cell death that could ultimately be controlled.
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PMID:Poly(ADP-ribose) polymerase inhibition in oxidant-stressed endothelial cells prevents oncosis and permits caspase activation and apoptosis. 1047 25

Oxidant-induced cell injury has been implicated in the pathogenesis of several forms of acute renal failure. The present studies examined whether activation of poly(ADP-ribose)polymerase (PARP) by oxidant-induced DNA damage contributes to oxidant injury of renal epithelial cells. H2O2 exposure resulted in an increase in PARP activity and decreases in cell ATP and NAD content. These changes were significantly inhibited by 10 mM 3-aminobenzamide (3-ABA), a PARP inhibitor. In contrast, H2O2-induced DNA damage was not prevented by 3-ABA. Exposure of LLC-PK(1) cells to 1 mM H2O2 for 2 h induced necrotic cell death as measured by increased lactate dehydrogenase (LDH) release. 3-ABA completely prevented the H2O2-induced LDH release. Live/dead fluorescent staining confirmed the protection by 3-ABA. These results are consistent with the view that oxidant-induced DNA damage activates PARP and that the subsequent ATP and NAD depletion contribute to necrotic cell death. Of note, although protected from necrosis, cells treated with H2O2 and 3-ABA underwent apoptosis as evidenced by DNA fragmentation and bis-benzimide staining. In conclusion, activation of PARP contributes to oxidant-induced ATP depletion and necrosis in LLC-PK1 cells. However, PARP inhibition may target cells toward an apoptotic form of cell death.
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PMID:Inhibition of PARP prevents oxidant-induced necrosis but not apoptosis in LLC-PK1 cells. 1048 26

Poly (ADP-ribose) polymerase (PARP) is activated following binding to DNA strand breaks and is cleaved in cells undergoing apoptosis. Work predominantly in murine systems has suggested that inhibitors of PARP might potentiate the effects of chemotherapeutic agents and be used as adjuncts to cancer therapy. Therefore, we studied the role of PARP in drug-induced apoptosis in HL-60, myeloid leukaemia cells and found that pre-treatment with 3-aminobenzamide (3AB) or 6(5H)-phenanthridinone, inhibitors of PARP, resulted in resistance to, rather than potentiation of apoptotic death induced by DNA-damaging agents, idarubicin, etoposide and fludarabine, as determined by flow cytometry, following propidium iodide staining. 3AB treated CEM/VLB100, mdr-expressing human lymphoblastic leukaemia cells were also found to be more resistant to idarubicin compared to cells treated with idarubicin alone, however, apoptosis was not reduced in parental CCRF-CEM cells under the same conditions. Similar results were obtained using agents with primary modes of action which do not involve DNA damage, vinblastine and a fas-ligating antibody (CH11). The precise role of PARP has yet to be defined but might involve effects on cell cycle progression. We conclude that PARP activation appears to be involved in apoptosis in certain leukaemic cell lines and that these effects are independent of lineage or p-glycoprotein. Constitutive failure to activate PARP might be responsible for conferring resistance to apoptosis.
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PMID:Effects of PARP inhibition on drug and Fas-induced apoptosis in leukaemic cells. 1050 Aug 2

Human fibroblasts and keratinocytes possess nitric oxide synthases (NOS), which metabolize L-arginine (L-Arg) for producing nitric oxide (NO*). This report delineates the relations between NO* and UVA in the human keratinocyte cell line HaCaT. NOS activity was stimulated by exposure of cells to L-Arg just after irradiation. L-Arg (5 mM) supply led to an increase in UVA (25.3 J/cm(2)) cytotoxicity (% of viability 18 +/- 3%) whereas neither L-Arg itself nor UVA irradiation induced cell death at the doses used in this study. Cells were also treated either with L-thiocitrulline (L-Thio), an irreversible inhibitor of NOS, or with exogenous superoxide dismutase (SOD) and catalase. L-Thio and SOD prevented L-Arg-mediated deleterious effects in irradiated cells, whereas catalase was ineffective. Intracellular antioxidant enzyme activities were also determined. UVA/L-Arg stress altered catalase (66% decrease) and glutathione peroxidase (83% decrease). DNA damage was evaluated using the 'comet assay' and quantified using the 'tail moment'. UVA alone was genotoxic (mean tail moment: 25.43 +/- 1.23, P<0.001 compared control cells). The addition of L-Arg potentiated DNA damage (mean tail moment: 41.05+/-3.9) whereas L-Thio prevented them (mean tail moment 9.86 +/- 0.98). We attempted to assess the effect of poly(ADP-ribose) polymerase (PARP) inhibition on cell death. Using the PARP inhibitor 3-aminobenzamide, we established that PARP determines both cell lysis and DNA damage induced by UVA and/or L-Arg. Our findings demonstrated that L-Arg was able to increase UVA-mediated deleterious effects in keratinocytes (both DNA damage and cytotoxicity) and that the ratio NO*/O2*- plays a key role in these processes.
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PMID:L-arginine increases UVA cytotoxicity in irradiated human keratinocyte cell line: potential role of nitric oxide. 1050 85

Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats received intraperitoneal saline or Etx (Salmonella typhimurium; 20 mg/kg) and one of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamide (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothelium-dependent (response to ACh and calcium ionophore) and -independent (sodium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Etx-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung myeloperoxidase activity and edema. Lung ATP decreased after Etx but was maintained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefold after Etx, which 3-AB and Nic prevented. The beneficial effects were not observed with benzoic acid, a structural analog of 3-AB that does not inhibit PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injury.
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PMID:Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation. 1051 18

Glucocorticoids and fludarabine are able to induce typical features of apoptosis in CLL lymphocytes. Cysteinyl aspartate specific proteases (caspases) play a key biochemical role in the apoptotic pathway. Caspase activation following cytotoxic stimuli leads to highly specific proteolytic cleavage of functionally important cellular enzymes. One of them is poly ADP-ribose) polymerase (PARP). To some extent caspase activation seems to be under the control of the Bcl-2 family of interacting proteins. We determined the role of Bcl-2-family proteins Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), activation of caspase-3 (CPP32/Yama) and activation of PARP in CLL apoptosis. All 21 analyzed CLL samples expressed Bcl-2 and Bax. Four of 13 (31%) samples with a low Bcl-2/Bax ratio exhibited in vitro prednisolone resistance, whereas eight of nine (88%) samples with a high Bcl-2/Bax ratio were in vitro resistant (</=0.025). There was no significant correlation between clinical pre-treatment status and Bcl-2/Bax ratio. Caspase-3/CPP32 activity increase was registered after dexamethasone as well as after fludarabine treatment in CLL lymphocytes in vitro. Caspase inhibitor Z-VAD.fmk was only able to partially block dexamethasone-induced and spontaneous apoptosis but not fludarabine-induced apoptosis in CLL lymphocytes. PARP activity decreased after dexamethasone and fludarabine treatment. PARP inhibitor 3-aminobenzamide (3-AB) was able to partially inhibit dexamethasone-induced apoptosis but not fludarabine-induced and spontaneous apoptosis.
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PMID:Drug-induced apoptosis in chronic lymphocytic leukemia. 1055 65


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