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)

In recent years, pyridine nucleotides NAD(H) and NADP(H) have been established as an important molecules in physiological and pathophysiological signaling and cell injury pathways. Protein modification is catalyzed by ADP-ribosyl transferases that attach the ADP-ribose moiety of NAD+ to specific aminoacid residues of the acceptor proteins, with significant changes in the function of these acceptors. Mono(ADP-ribosyl)ation reactions have been implicated to play a role both in physiological responses and in cellular responses to bacterial toxins. Cyclic ADP-ribose formation also utilizes NAD+ and primarily serves as physiological, signal transduction mechanisms regulating intracellular calcium homeostasis. In pathophysiological conditions associated with oxidative stress (such as various forms of inflammation and reperfusion injury), activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) occurs, with subsequent, substantial fall in cellular NAD+ and ATP levels, which can determine the viability and function of the affected cells. In addition, NADPH oxidases can significantly affect the balance and fate of NAD+ and NADP in oxidatively stressed cells and can facilitate the generation of various positive feedback cycles of injury. Under severe oxidant conditions, direct oxidative damage to NAD+ has also been reported. The current review focuses on PARP and on NADPH oxidases, as pathophysiologically relevant factors in creating disturbances in the cellular pyridine nucleotide balance. A separate section describes how these mechanisms apply to the pathogenesis of endothelial cell injury in selected cardiovascular pathophysiological conditions.
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PMID:Pathophysiological aspects of cellular pyridine nucleotide metabolism: focus on the vascular endothelium. Review. 1459 89

The dietary status of niacin (vitamin B3) has the potential to influence DNA repair, genomic stability, and the immune system, eventually having an impact on cancer risk, as well as the side effects of chemotherapy in the cancer patient. In addition to its well-known redox functions in energy metabolism, niacin, in the form of NAD, participates in a wide variety of ADP-ribosylation reactions. Poly(ADP-ribose) is a negatively charged polymer synthesized, predominantly on nuclear proteins, by at least seven different enzymes. Poly(ADP-ribose) polymerase-1 (PARP-1) is responsible for the majority of polymer synthesis and plays important roles in DNA damage responses, including repair, maintenance of genomic stability, and signaling events for stress responses such as apoptosis. NAD is also used in the synthesis of mono(ADP-ribose), often on G proteins, with poorly understood roles in signal transduction. Last, NAD and NADP are required for the synthesis of cyclic ADP-ribose and nicotinic acid adenine dinucleotide (NAADP), two mediators of intracellular calcium signaling pathways. Disruption of any of these processes has the potential to impair genomic stability and deregulate cell division, leading to enhanced cancer risk. There are various sources of evidence that niacin status does have an impact on cancer risk, including animal models of leukemogenesis and skin cancer, as well as epidemiological data from human populations.
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PMID:Niacin and carcinogenesis. 1469 Jul 85

The enzymatic mechanism of poly(ADP-ribose) polymerase (PARP-1) has been analyzed in two in vitro systems: (a) in solution and (b) when the acceptor histones were attached to a solid surface. In system (a), it was established that the coenzymatic function of dsDNAs was sequence-independent. However, it is apparent from the calculated specificity constants that the AT homopolymer is by far the most effective coenzyme and randomly damaged DNA is the poorest. Rates of auto(poly-ADP-ribosylation) with dsDNAs as coenzymes were nearly linear for 20 min, in contrast to rates with dcDNA, which showed product [(ADPR)n] inhibition. An allosteric activation of auto(poly-ADP-ribosylation) by physiologic cellular components, Mg2+, Ca2+, and polyamines, was demonstrated, with spermine as the most powerful activator. On a molar basis, histones H(1) and H(3) were the most effective PARP-1 activators, and their action was abolished by acetylation of lysine end groups. It was shown in system (b) that oligo(ADP-ribosyl) transfer to histone H(1) is 1% of that of auto(poly-ADP-ribosylation) of PARP-1, and this trans(ADP-ribosylation) is selectively regulated by putrescine (activator). Physiologic cellular concentrations of ATP inhibit PARP-1 auto(poly-ADP-ribosylation) but less so the transfer of oligo(ADP-ribose) to histones, indicating that PARP-1 auto(ADP-ribosylation) activity is dormant in bioenergetically intact cells, allowing only trans(ADP-ribosylation) to take place. The inhibitory mechanism of ATP on PARP-1 consists of a noncompetitive interaction with the NAD site and competition with the coenzymic DNA binding site. A novel regulation of PARP-1 activity and its chromatin-related functions by cellular bioenergetics is proposed that occurs in functional cells not exposed to catastrophic DNA damage.
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PMID:Regulation of the enzymatic catalysis of poly(ADP-ribose) polymerase by dsDNA, polyamines, Mg2+, Ca2+, histones H1 and H3, and ATP. 1470 47

The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.
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PMID:Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. 1503 10

In the early 1980s we found that streptozotocin and alloxan, typical diabetogenic agents, induce pancreatic beta-cell DNA strand breaks through the formation of free radicals. The breaks induce DNA repair involving the activation of poly(ADP-ribose) polymerase (PARP), which uses NAD+ as a substrate. As a result, the intracellular levels of NAD+ fall dramatically. The fall in NAD+ inhibits cellular functions including insulin synthesis and secretion, and thus the beta-cell ultimately dies. We subsequently proposed that maintenance of the NAD+ level is essential for the synthesis and secretion of insulin, and presented a unifying model for beta-cell damage and its prevention (The Okamoto model), in which PARP activation plays an essential role. Recently, the model was reconfirmed by experiments using PARP knockout mice and has been recognized as providing the basis for necrotic death of various cells and tissues. In 1993, we found that cyclic ADP-ribose (cADPR), a metabolite of NAD+, is a second messenger for intracellular Ca2+ mobilization for insulin secretion by glucose, and proposed a novel mechanism of insulin secretion, the CD38-cADPR signal system. Recently, various physiological phenomena from animal to plant cells become understandable in terms of this signal system. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library we found a novel beta-cell growth factor gene, Reg (Regenerating Gene), and elucidated the mechanism of Reg gene expression in beta-cells, in which PARP acts as a transcription factor for Reg gene expression. PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex. The complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance and stabilize the complex formation for Reg gene transcription. Reg protein acts as an autocrine/paracrine growth factor to induce beta-cell replication via the Reg receptor and ameliorates experimental diabetes.
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PMID:Recent advances in physiological and pathological significance of tryptophan-NAD+ metabolites: lessons from insulin-producing pancreatic beta-cells. 1520 38

Immunohistochemical techniques revealed a significant increase of poly(ADP-ribose) polymerase (PARP)-containing nuclei in the dopaminergic neurons of the substantia nigra (SN) in Parkinson disease and in diffuse Lewy body disease as compared with a group of patients with other neurodegenerative diseases and normal controls. The nuclear translocation of nuclear factor kappa B (NF-kappa B) was also noted in the same cells. The over-activation of PARP and the transcriptional activation of NF-kappa B can contribute to the pathomechanism of the disease specific lesion of the neurons in the SN. However, in another subgroup of dopaminergic cells of the SN an increased parvalbumin content was detected reflecting a natural protective mechanism against the putative increase of intracellular calcium caused by excitotoxic injury and oxidative stress.
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PMID:The expression of PARP, NF-kappa B and parvalbumin is increased in Parkinson disease. 1525 33

Neurons exposed to zinc exhibit activation of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme that normally participates in DNA repair but promotes cell death when extensively activated. Endogenous, vesicular zinc in brain is released to the extracellular space under conditions causing neuronal depolarization. Here, we used a rat model of insulin-induced hypoglycemia to assess the role of zinc release in PARP-1 activation and neuronal death after severe hypoglycemia. Zinc staining with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) showed depletion of presynaptic vesicular zinc from hippocampal mossy fiber terminals and accumulation of weakly bound zinc in hippocampal CA1 cell bodies after severe hypoglycemia. Intracerebroventricular injection of the zinc chelator calcium ethylene-diamine tetraacetic acid (CaEDTA) blocked the zinc accumulation and significantly reduced hypoglycemia-induced neuronal death. CaEDTA also attenuated the accumulation of poly(ADP-ribose), the enzymatic product of PARP-1, in hippocampal neurons. These results suggest that zinc translocation is an intermediary step linking hypoglycemia to PARP-1 activation and neuronal death.
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PMID:Zinc release contributes to hypoglycemia-induced neuronal death. 1526 65

Many natural components of plant extracts are studied for their beneficial effects for health and particularly on carcinogenesis chemoprevention. In the present study, we investigated the effects of diosgenin on erythroleukemia HEL cells. Our results demonstrated that diosgenin induced G2/M arrest of cell cycle progression through p21 up-regulation in a p53-independent pathway and strong induction of apoptosis in HEL cells. Apoptosis induction was accompanied by an increase in Bax/Bcl-2 ratio, PARP cleavage and DNA fragmentation. Moreover, we showed for the first time that diosgenin provoked a collapse of mitochondrial membrane potential with an increase in intracellular calcium levels. It is well known that [Ca2+]i increase is one of the major activators of cytosolic PLA2. In our study, we demonstrated that diosgenin treatment induced cPLA2 activation through translocation to the cellular membrane. Moreover, arachidonic acid metabolism activation led to cyclooxygenase-2 (COX-2) but not lipoxygenase overexpression. Surprisingly, we observed a COX-2 up-regulation associated with apoptosis induction by diosgenin. These findings suggest that diosgenin has a potential chemopreventive effect; future studies should evaluate the mechanism of COX-2 activation during diosgenin-induced apoptosis in cancer cell lines.
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PMID:Diosgenin induces cell cycle arrest and apoptosis in HEL cells with increase in intracellular calcium level, activation of cPLA2 and COX-2 overexpression. 1528 56

TRPM2 is a member of the transient receptor potential (TRP) protein superfamily of calcium-permeable, voltage-independent ion channels expressed in nonexcitable cells. Activation of TRPM2 by oxidative stress results in calcium influx and susceptibility to cell death, whereas inhibition of TRPM2 function enhances cell survival. In the present edition of this journal, Fonfria et al. demonstrate a role for poly(ADP ribose) polymerase (PARP) as a mediator between oxidative stress and TRPM2 activation. They present evidence that inhibition of either PARP or TRPM2 protects cells from plasma membrane damage and cell death. The therapeutic implications of this important observation are discussed.
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PMID:Inhibition of TRPM2 function by PARP inhibitors protects cells from oxidative stress-induced death. 1530 83

We have previously reported that murine peritoneal macrophages exposed to ultraviolet B (UV-B; 100 mJ/cm2) undergo apoptosis, as indicated by alterations in cell morphology, caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, sustained activation of p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) and inactivation of p42/44 MAPKs. It is now reported that macrophages undergoing UV-B-induced apoptosis show enhanced expression of protein kinase Cdelta (PKCdelta) in a time-dependent manner. Pretreatment of macrophages with PKCdelta-specific inhibitor rottlerin prior to the UV-B irradiation inhibits activation of caspase-3, PARP cleavage, DNA fragmentation and release of intracellular Ca2+. Inhibition of PKCdelta also blocks the sustained activation of p38 and JNK MAPKs as well as inactivation of p42/44 MAPKs. PKCalpha and PKCbeta1 expression also increases during UV-B-induced apoptosis in macrophages. Inhibition of these two isoforms with Go6976 slightly suppresses caspase-3 activation, PARP cleavage, DNA fragmentation and release of intracellular Ca2+, but has no effect on the sustained activation of p38/JNK MAPKs or inactivation of p42/44 MAPKs. It is, therefore, suggested that activation of PKCdelta might play an important role in the UV-B-induced apoptosis and that specific activated isoforms of PKC may have distinct functions in cell death.
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PMID:Role of protein kinase Cdelta in UV-B-induced apoptosis of macrophages in vitro. 1556 68


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