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)

Poly(ADP-ribose) polymerase 3 (PARP-3) is a novel member of the PARP family of enzymes that synthesize poly(ADP-ribose) on themselves and other acceptor proteins. Very little is known about this PARP, which is closely related to PARP-1 and PARP-2. By sequence analysis, we find that PARP-3 may be expressed in two isoforms which we studied in more detail to gain insight into their possible functions. We find that both PARP-3 isoforms, transiently expressed as GFP or FLAG fusions, are nuclear. Detection of endogenous PARP-3 with a specific antibody also shows a widespread nuclear distribution, appearing in numerous small foci and a small number of larger foci. Through co-localization experiments and immunoprecipitations, the larger nuclear foci were identified as Polycomb group bodies (PcG bodies) and we found that PARP-3 is part of Polycomb group protein complexes. Furthermore, using a proteomics approach, we determined that both PARP-3 isoforms are part of complexes comprising DNA-PKcs, PARP-1, DNA ligase III, DNA ligase IV, Ku70, and Ku80. Our findings suggest that PARP-3 is a nuclear protein involved in transcriptional silencing and in the cellular response to DNA damage.
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PMID:PARP-3 associates with polycomb group bodies and with components of the DNA damage repair machinery. 1692 74

The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of PKC412 in the treatment of MM is justified.
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PMID:PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. 1703 22

In a previous study, it was shown that the hornet venom or, more specifically, its venom sac extract (VSE) possesses deoxyribonuclease activity that exerts an effect both on insects as well as on mammals. We have now examined the effect of hornet VSE on primary culture of rat cortical neurons. Judging on the basis of our results, VSE induces a rapid cell death by a) permeabilizing the cell membrane, b) inducing DNA breaks, and c) cleaving the nuclear protein poly-ADP-ribose polymerase (PARP-1), thereby preventing DNA repair.
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PMID:A fatal effect of hornet venom on rat-brain cortical neurons. 1719 89

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress induced robust DNA damage and wide spread inflammatory responses are common pathologies of various CNS diseases, the interest toward PARP-1 as a therapeutic target has peaked. This review introduces mechanism of PARP-1 activation, the role of PARP-1 in cell physiology and pathology, and discusses the potential of PARP-1 inhibition as a therapy in acute and chronic CNS diseases.
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PMID:Multiple roles for poly(ADP-ribose)polymerase-1 in neurological disease. 1722 47

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.
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PMID:DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. 1724 36

Labd-14-ene-8, 13-diol (sclareol) is a labdane-type diterpene, which has demonstrated significant cytotoxic activity against human leukemic cell lines, but its effect on solid tumor-derived cells is uknown. Here, we demonstrate that addition of sclareol to cultures of human colon cancer HCT116 cells results in inhibition of DNA synthesis, arrest of cells at the G(1) phase of the cell cycle, activation of caspases-8, -9, PARP degradation, and DNA fragmentation, events characteristic of induction of apoptosis. Intraperitoneal (ip) administration of sclareol alone, at the maximum tolerated dose, was unable to induce suppression of growth of HCT116 tumors established as xenografts in immunodeficient SCID mice. In contrast, ip administration of liposome-encapsulated sclareol, following a specific schedule, induced suppression of tumor growth by arresting tumor cell proliferation as assessed by detecting the presence of the cell proliferation-associated nuclear protein, Ki67, in thin tumor sections. These findings suggest that sclareol incorporated into liposomes may possess chemotherapeutic potential for the treatment of colorectal and other types of human cancer.
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PMID:Sclareol induces apoptosis in human HCT116 colon cancer cells in vitro and suppression of HCT116 tumor growth in immunodeficient mice. 1726 Jan 86

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer's disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 -410 and -1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A -889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 -410 and PARP-1 -1672 haplotypes were associated with an increased risk for AD (global haplotype association p value=0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A -889 allele 2.
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PMID:Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk. 1729 Jan 4

A detailed understanding of aging and senescence is limited by the complex interplay of the effects of extracellular and environmental stimuli on cellular metabolic, mutational, and epigenetic phenomena. For example, STASIS (stress or aberrant signaling-induced senescence) is affected by the exposure to free radicals and conditions that cause an increased cellular production of reactive oxygen species (ROS) during normal life span. In addition, progressive telomere erosion and telomeric dysfunction contribute to a cellular feature termed replicative or cellular senescence. To focus on distinct cellular pathways that contribute to these different forms of senescence, we investigated the reversible differentiation and aging process of the human U937 leukemia cell line. This was compared to cellular senescence that occurred in normal primary human mammary epithelial cells (HMECs). These two cell systems revealed an important role of the proteolytic activity of the 20S proteasome and its activation by the nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) during "retrodifferentiation" and rejuvenation of the leukemic cells. Moreover, reduced extracellular proteolytic activity of certain matrix metalloproteinases-for example, MMP-7-is associated with accelerated aging and senescence in normal HMECs.
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PMID:Matrix metalloproteinase-7 and the 20S proteasome contribute to cellular senescence. 1836 12

Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) is an abundant nuclear protein that is involved in DNA repair, cell cycle control, programmed cell death and transcriptional regulation. It also plays critical roles in the pathogenesis of inflammatory disorders. Here we have performed a detailed analysis of the interplay between the apicomplexan parasite Toxoplasma gondii and host cell PARP and its consequences for the host-parasite relationship. Our results have shown that T. gondii significantly decreased PARP expression in its host cells within 10min of infection but that the amount of PARP normalized during prolonged infection. Importantly, down-regulation of PARP expression after infection abrogated the ADP-ribosylation of acceptor proteins in response to oxidative stress. Overexpression of PARP in RAW264.7 cells revealed that elevated amounts of PARP neither affected host cell invasion nor intracellular development of T. gondii in non-stimulated or IFN-gamma/LPS-stimulated monocytes/macrophages. Furthermore, measurements of the activities of effector caspases 3 and 7 indicated that the blockade of host cell apoptosis by T. gondii occurs independently of the inhibition of PARP after infection. These findings suggest that the prominent decrease of host cell PARP and poly(ADP-ribos)ylation after parasitic infection do not affect the intracellular development of T. gondii in vitro.
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PMID:Transient inhibition of poly(ADP-ribose) polymerase expression and activity by Toxoplasma gondii is dispensable for parasite-mediated blockade of host cell apoptosis and intracellular parasite replication. 1839 34

Poly(ADP-ribose) polymerase-1 (PARP-1) is a multimodular nuclear protein that participates in many fundamental cellular activities. Stimulated by binding to nicked DNA, PARP-1 catalyzes poly(ADP-ribosyl)ation of the acceptor proteins using NAD (+) as a substrate. In this work, NMR methods were used to determine the solution structure of human PARP-1 protein. Domain C was found to contain a zinc-binding motif of three antiparallel beta-strands with four conserved cysteines positioned to coordinate the metal ligand, in addition to a helical region. The zinc-binding motif is structurally reminiscent of the "zinc-ribbon" fold, but with a novel spacing between the conserved cysteines (CX2CX12CX 9C). Domain C alone does not appear to bind to DNA. Interestingly, domain C is essential for PARP-1 activity, since a mixture containing nicked DNA and the PARP-1 ABDEF domains has only basal enzymatic activity, while the addition of domain C to the mixture initiated NAD (+) hydrolysis and the formation of poly(ADP-ribose), as detected by an NMR-based assay and autoradiography. The structural model for domain C in solution provides an important framework for further studies aimed at improving our understanding of how the various domains within the complex PARP-1 enzyme play their respective roles in regulating the enzyme activity when cells are under conditions of genotoxic stress.
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PMID:Domain C of human poly(ADP-ribose) polymerase-1 is important for enzyme activity and contains a novel zinc-ribbon motif. 1845 7


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