Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:NAD depletion after in vitro exposure of murine lung slices to bleomycin. 750 88

Although specific proteinases play a critical role in the active phase of apoptosis, their substrates are largely unknown. We previously identified poly(ADP-ribose) polymerase (PARP) as an apoptosis-associated substrate for proteinase(s) related to interleukin 1 beta-converting enzyme (ICE). Now we have used a cell-free system to characterize proteinase(s) that cleave the nuclear lamins during apoptosis. Lamin cleavage during apoptosis requires the action of a second ICE-like enyzme, which exhibits kinetics of cleavage and a profile of sensitivity to specific inhibitors that is distinct from the PARP proteinase. Thus, multiple ICE-like enzymes are required for apoptotic events in these cell-free extracts. Inhibition of the lamin proteinase with tosyllysine "chloromethyl ketone" blocks nuclear apoptosis prior to the packaging of condensed chromatin into apoptotic bodies. Under these conditions, the nuclear DNA is fully cleaved to a nucleosomal ladder. Our studies reveal that the lamin proteinase and the fragmentation nuclease function in independent parallel pathways during the final stages of apoptotic execution. Neither pathway alone is sufficient for completion of nuclear apoptosis. Instead, the various activities cooperate to drive the disassembly of the nucleus.
 ...
PMID:Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution. 756 69

To study biological functions of poly(ADP-ribose) polymerase (PARP), low-molecular-mass inhibitors have been used extensively, and the experimental results obtained led to the view that PARP plays a role in DNA repair as well as in other cellular processes, eg DNA replication, cell proliferation, and differentiation. Accumulating evidence that these inhibitors have side effects on other metabolic pathways prompted us to develop two molecular genetic systems for the modulation of poly(ADP-ribosyl)ation in living cells: i) the first approach is centered on the DNA-binding domain (DBD) of PARP, which recognizes DNA strand breaks through its zinc fingers, leading to enzyme activation. We have established stable cell culture systems for either constitutive or inducible overexpression of the DBD. In these cells we observe a drastic trans-dominant inhibition of poly(ADP-ribosyl)ation which is associated with sensitization of cells to gamma-irradiation; and ii) in an attempt to specifically increase the poly(ADP-ribose) formation capacity in living cells, the hamster cell line CO60 was stably transfected to obtain constitutive overexpression of full-length human PARP. These molecular genetic systems may be useful for the elucidation of the precise role of poly(ADP-ribosyl)ation in the biological response to DNA damage.
 ...
PMID:Molecular genetic systems to study the role of poly(ADP-ribosyl)ation in the cellular response to DNA damage. 757 28

Dissection of the human poly(ADP-ribose) polymerase (PARP) molecule in terms of its structure-function relationship has proved to be an essential step towards understanding the biological role of poly(ADP-ribosylation) as a cellular response to DNA damage in eukaryotes. Current approaches aimed at elucidating the implication of this multifunctional enzyme in the maintenance of the genomic integrity will be presented.
 ...
PMID:Poly(ADP-ribose) polymerase: structure-function relationship. 757 29

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.
 ...
PMID:Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation. 757 30

1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.
 ...
PMID:Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide. 759 Jan 13

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.
 ...
PMID:Inhibition of poly(ADP-ribose) polymerase preserves surfactant synthesis after hydrogen peroxide exposure. 763 15

We have used two different approaches to study the consequences of NAD/poly(ADP-ribose) deficiency on p53 expression and its activity in V79-derived cell lines. In the first approach, we have used two cell lines that are deficient in poly(ADP-ribose) (pADPR) synthesis because of deficiency in the enzyme poly(ADP-ribose) polymerase (PARP). In a second approach, we have used a cell line that is deficient in NAD/pADPR metabolism due to unavailability of NAD, the substrate for PARP. These NAD/PARP-deficient cell lines exhibit a significant reduction in both baseline p53 expression and its activity compared to their parental V79 cells. Furthermore, etoposide, a topoisomerase II inhibitor that was shown to cause an increase in p53 expression and subsequent apoptosis in V79 cells, failed to produce any significant increase in p53 expression or apoptotic DNA fragmentation in NAD/PARP-deficient cell lines. Thus, our studies suggest that NAD/pADPR synthesis may be involved in the regulation of p53 and its dependent pathways.
 ...
PMID:Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences. 764 Nov 78

The proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) is an early biochemical event, which occurs during apoptosis. A recent study suggested that PARP cleavage can be mediated by a novel cytosolic protease (prICE) that resembles interleukin-1 beta converting enzyme (ICE), but cannot be mediated by ICE itself (Lazebnik, Y.A., Kaufmann, S.H., Desnoyers, S., Poirier, G.G., and Earnshaw, W.C. (1994) Nature 371, 346-347). We have used a COS cell co-transfection assay to investigate if ICE or any known ICE-like protease is active in PARP cleavage within the cell. Here we report that co-expression of human PARP with human ICE, or the ICE homologs TX and Nedd-2, resulted in a cleavage of PARP identical to that observed in apoptotic cells. Experiments with purified recombinant human ICE indicated that PARP polypeptide can be specifically cleaved in vitro by ICE in a time- and enzyme concentration-dependent manner. PARP cleavage, however, requires a 50-100-fold higher ICE concentration than does processing of the interleukin-1 beta precursor at an equivalent substrate concentration. The abilities of ICE, TX, and Nedd-2, when expressed at high intracellular concentrations, to cleave PARP are consistent with their induction of apoptosis in transfected cells.
 ...
PMID:Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2. 764 16

By catalyzing posttranslational modifications of nuclear proteins, poly(ADP-ribose) polymerase (PARP) controls their functions and therefore constitutes an enzyme of crucial importance in tumor development. In this study, we have investigated the action of 6(5H)-phenanthridinone, an isoquinoline derivative and one of the most potent PARP inhibitors described so far, on RDM4 murine lymphoma cells in culture. We also examined whether this compound could act synergistically with an antineoplastic drug in tumor-cell destruction. Our results demonstrate that a marked inhibition of PARP activity can be obtained in whole cells after a short incubation, and that this compound, when associated with an alkylating agent, dichloro-2,2' N-methyldiethylamine (chloromethine), leads to a marked drop in the RDM4 proliferation, indicative of a synergy between the two compounds.
 ...
PMID:Effect of 6(5H)-phenanthridinone, an inhibitor of poly(ADP-ribose) polymerase, on cultured tumor cells. 770 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>