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

---

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 (PARP) may play important roles in nuclear events such as cell cycle, cell proliferation, and maintenance of chromosomal stability. However, the exact biological role played by PARP or how PARP is involved in these cellular functions is still unclear. To elucidate the biological functions of PARP in vivo, we have constructed transgenic flies that overexpress Drosophila PARP in the developing eye primordia. These flies showed mild roughening of the normally smooth ommatidial lattice and tissue polarity disruption caused by improper rotation and chirality of the ommatidia. To clarify how this phenotypical change was induced, here we analyzed transgenic flies overexpressing PARP in the developing eye, embryo, and adult in detail. PARP mRNA level and the phenotype were enhanced in flies carrying more copies of the transgene. Developing eyes from third instar larvae were analyzed by using the neural cell marker to examine the involvement of PARP in cell fate. Morphological disorder of non-neuronal accessory cells was observed in PARP transgenic flies. Interestingly, overexpression of PARP did not interfere with the cell cycle or apoptosis, but it did disrupt the organization of cytoskeletal F-actin, resulting in aberrant cell and tissue morphology. Furthermore, heat-induced PARP expression disrupted organization of cytoskeletal F-actin in embryos and tissue polarity in adult flies. Because these phenotypes closely resembled mutants or transgenic flies of the tissue polarity genes, genetic interaction of PARP with known tissue polarity genes was examined. Transgenic flies expressing either PARP or RhoA GTPase in the eye were crossed, and co-expression of PARP suppressed the effect of RhoA GTPase. Our results indicate that PARP may play a role in cytoskeletal or cytoplasmic events in developmental processes of Drosophila.
...
PMID:Overexpression of poly(ADP-ribose) polymerase disrupts organization of cytoskeletal F-actin and tissue polarity in Drosophila. 1174 2

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA damage. Activated PARP cleaves NAD(+) into nicotinamide and (ADP-ribose) and polymerizes the latter on nuclear acceptor proteins. Over-activation of PARP by reactive oxygen and nitrogen intermediates represents a pathogenetic factor in various forms of inflammation, shock, and reperfusion injury. Using a novel commercially available substrate, 6-biotin-17-nicotinamide-adenine-dinucleotide (bio-NAD(+)), we have developed three applications, enzyme cytochemistry, enzyme histochemistry, and cell ELISA, to detect the activation of PARP in oxidatively stressed cells and tissues. With the novel assay we were able to detect basal and hydrogen peroxide-induced PARP activity in J774 macrophages. We also observed that mitotic cells display remarkably elevated PARP activity. Hydrogen peroxide-induced PARP activation could also be detected in wild-type peritoneal macrophages but not in macrophages from PARP-deficient mice. Application of hydrogen peroxide to the skin of mice also induced bio-NAD(+) incorporation in the keratinocyte nuclei. Hydrogen peroxide-induced PARP activation and its inhibition by pharmacological PARP inhibitors could be detected in J774 cells with the ELISA assay that showed good correlation with the traditional [(3)H]-NAD incorporation method. The bio-NAD(+) assays represent sensitive, specific, and non-radioactive alternatives for detection of PARP activation.
...
PMID:Detection of poly(ADP-ribose) polymerase activation in oxidatively stressed cells and tissues using biotinylated NAD substrate. 1174 98

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme that is activated by DNA strand breaks and catalyzes the transfer of ADP-ribose groups from NAD to itself and other nuclear proteins. Although caspase-mediated PARP-1 cleavage occurs during almost all forms of apoptosis, the contribution of PARP-1 activation and cleavage to this cell death process remains unclear. Using immortalized fibroblasts from wild-type (PARP-1(+/+)) and PARP-1 knockout (PARP-1(-/-)) mice, and a mouse neuroblastoma cell line (N18), the role that poly(ADP-ribosyl)ation plays in Sindbis virus (SV)-induced apoptosis was examined. Robust PARP-1 activation occurred in SV-infected cells prior to morphologic changes associated with apoptotic cell death and PARP-1 activity ceased simultaneously with caspase-3 activation and PARP-1 proteolysis. PARP-1 activity was maximal before detectable DNA fragmentation, but was absent when DNA damage was most intense. SV and staurosporine-induced cell death was delayed in fibroblasts lacking PARP-1 activity, suggesting that PARP-1 activation contributes to apoptotic cell death induced by these stimuli. SV replication was not affected by lack of PARP-1 activity, but DNA fragmentation and caspase-3 activation were delayed and occurred at lower levels in PARP-1-deficient fibroblasts. Early virus-induced PARP-1 activation may represent a novel way by which cells signal to the nucleus to regulate protein function by poly(ADP-ribosyl)ation in response to virus infection.
...
PMID:Rapid activation of poly(ADP-ribose) polymerase contributes to Sindbis virus and staurosporine-induced apoptotic cell death. 1185 9

Poly(ADP-ribose) polymerase-1 (PARP-1, EC ), a nuclear enzyme activated by DNA strand breaks, physiologically participates in DNA repair. Excessive activation of PARP-1 by cellular insults depletes its substrate beta-nicotinamide adenine dinucleotide and ATP, leading to cell death. PARP-1-deficient (PARP-1-/-) mice are protected from several forms of inflammation. In the present study, we demonstrate in PARP-1-/- glial cells a loss of several stress-activated transcription factors as well as decreased expression of genes for cytokines and cellular adhesion molecules. We also show that augmented expression of some of these genes is independent of PARP-1 catalytic activity. These findings indicate that PARP-1 plays a pivotal role in the initial inflammatory response by modulating transcription of inflammation-linked genes.
...
PMID:Poly(ADP-ribose) polymerase-1 dependence of stress-induced transcription factors and associated gene expression in glia. 1185 72

Poly(ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear enzyme involved in DNA repair. The therapeutic efficacy of drugs that inhibit PARP-1 in various disorders underscores the active role of PARP-1 in cell death. Although it is well established that excessive DNA damage causes PARP-1 hyperactivation, which leads to cell death by energy failure, a new mechanistic perspective is emerging following the identification of various PARPs that exhibit different features and subcellular distributions. Studies demonstrating the significant role of PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs will be discussed with particular focus on the regulation of transcription factors such as nuclear factor kappaB and p53. (An animation depicting the involvement of PARP-1 in the 'suicide hypothesis' is available at http://archive.bmn.com/supp/tips/tips2303a.html)
...
PMID:Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. 1187 79

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme that is catalytically activated by DNA strand breaks, plays a complex role in DNA repair. Using NAD(+) as a precursor, it catalyzes the formation of ADP-ribose polymers, which are attached to various proteins. Defects in DNA repair pathways have been associated with increased risks for cancer in humans. We investigated whether differences in the activity of PARP are associated with the risk for laryngeal cancer. In a case-control study on genetic, lifestyle and occupational risk factors for laryngeal cancer, PARP activity was assessed as DNA damage-induced poly(ADP-ribose) formation in human peripheral blood lymphocytes by quantitative immunofluorescence analysis. Polymer formation was determined as the cellular response to bleomycin, a well-known inducer of DNA strand breaks, in lymphocytes from 69 laryngeal cancer patients and 125 healthy controls. The frequency of bleomycin-induced polymer formation, measured as mean pixel intensity, was significantly lower in cases (74.6, SE = 3.7) than in controls (94.5, SE = 3.5) and not influenced by smoking, age or sex. There was no significant difference between cases (59.1, SE = 5.2) and controls (50.5, SE = 3.7) in basal polymer formation (in cells not treated with bleomycin). When the highest tertile of polymer formation was used as the reference, the odds ratio for the lowest tertile of bleomycin-induced polymer formation was 3.79 (95% confidence interval 1.37-10.47, p = 0.01). Peripheral blood lymphocytes from laryngeal cancer patients thus showed significantly less bleomycin-induced poly(ADP-ribose) formation. Our results suggest that a reduced capacity of somatic cells to synthesize poly(ADP-ribose) might be associated with an increased risk for laryngeal cancer. The underlying mechanism remains to be investigated.
...
PMID:Reduced poly(ADP-ribosyl)ation in lymphocytes of laryngeal cancer patients: results of a case-control study. 1192 Jun 51

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.
...
PMID:Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-Ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes. 1197 44

We asked whether the constitutive level of DNA strand breaks (SBs) in four human squamous carcinoma cell lines is associated with their radiosensitivity, measured by the clonogenic assay. Because impairment in DNA replication and the action of endogenous deoxyribonucleases are two major sources of DNA strand breaks under normal cell metabolism, we also analyzed DNA polymerase and DNA ligase activities as well as the functional status of Poly(ADP-ribose) polymerase (PARP) and nucleolytic degradation of genomic DNA. We showed that the two relatively radioresistant cell lines, UM-SCC-1 and UT-SCC-5, had a statistically significant lower constitutive level of DNA SBs, as measured by DNA precipitation technique, compared with the two relatively radiosensitive cell lines, UM-SCC-14A and UT-SCC-9. We found that cell lines with a higher level of broken DNA tended to have a higher constitutive level of DNA polymerase alpha activity, measured by incorporation of [(3)H]dTTP in DNase I-activated DNA. UM-SCC-1, UT-SCC-5, and UM-SCC-14A did not show any difference in DNA ligase activity when a nicked oligonucleotide was used as substrate. The most radiosensitive cell line, UT-SCC-9, had a significantly lower ligation efficiency compared to the other three cell lines. The functional status of the PARP was the same in the four cell lines. Although none of the four cell lines showed a characteristic apoptotic or necrotic degradation of genomic DNA, when tested with the "plasmid rejoining assay," a significant degradation of the plasmid DNA in UT-SCC-9 was detected. We conclude that the high fraction of DNA SBs for UT-SCC-9, the most radiosensitive cell line, is most likely a consequence of low ligation efficiency combined with a relatively high DNA polymerase alpha activity and the nuclease degradation of DNA.
...
PMID:Radiosensitivity of human squamous carcinoma cell lines is associated with amount of spontaneous DNA strand breaks. 1199 85

Poly(ADP-ribose) polymerase-1 (PARP-1) is activated by DNA strand breaks during cellular genotoxic stress response and catalyzes poly(ADP-ribosyl)ation of acceptor proteins. These acceptor proteins include those involved in modulation of chromatin structure, DNA synthesis, DNA repair, transcription, and cell cycle control. Thus, PARP-1 is believed to play a pivotal role in maintaining genome integrity through modulation of protein-protein and protein-DNA interactions. We previously described the association of PARP-1 with normal mammalian centromeres and human neocentromeres by affinity purification and immunofluorescence. Here we investigated the interaction of this protein with, and poly(ADP-ribosyl)ation of, three constitutive centromere proteins, Cenpa, Cenpb, and Cenpc, and a spindle checkpoint protein, Bub3. Immunoprecipitation and Western blot analyses demonstrate that Cenpa, Cenpb, and Bub3, but not Cenpc, interacted with PARP-1, and are poly(ADP-ribosyl)ated following induction of DNA damage. The results suggest a role of PARP-1 in centromere assembly/disassembly and checkpoint control. Demonstration of PARP-1-binding and poly(ADP-ribosyl)ation in three of the four proteins tested further suggests that many more centromere proteins may behave similarly and implicates PARP-1 as an important regulator of diverse centromere function.
...
PMID:Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose) polymerase-1 protein and are poly(ADP-ribosyl)ated. 1201 Oct 73

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is activated in response to genotoxic insults by binding damaged DNA and attaching polymers of ADP-ribose to nuclear proteins at the expense of its substrate NAD+. In persons affected with ataxia telangiectasia (A-T), associated mutations in the ataxia telangiectasia mutated gene render cells unable to cope with the genotoxic stresses from ionizing radiation and oxidative damage, thus resulting in a higher concentration of unrepaired DNA damage and the activation of PARP in an uncontrolled manner. In primary A-T fibroblasts, we observed a 58-96% increase in PARP activity and a concomitant loss of cellular NAD+ and ATP content. PARP protein by Western blot analysis increased only slightly in these cells, supporting the observation that the steady state levels of DNA damage is higher in A-T cells than in normals. When treated with PARP inhibitors 3-aminobenzamide or 1,5-dihydroisoquinoline, cellular growth rates reached those observed in normal fibroblast cultures. The improvement of cellular growth and NAD+ levels in A-T cells with PARP inhibition suggests that the cellular metabolic status of A-T cells is compromised and the inhibition of PARP may relieve some of the drain on cellular pyridine nucleotides and ATP. Thus, therapy utilizing PARP inhibitors may provide a benefit for individuals affected with A-T.
...
PMID:The inhibition of poly(ADP-ribose) polymerase enhances growth rates of ataxia telangiectasia cells. 1205 67


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

---