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)

The present study has elucidated two distinct mechanisms that may explain how a mutant of cholera toxin (mCT), E112K, retains adjuvant effects though it lacks ADP-ribosyltransferase activity and associated toxicity. In the first mechanism, we show that mCT E112K, like native cholera toxin (nCT), enhances B7-2 expression, but, to some extent, also enhances B7-1 on Peyer's patch B cells and macrophages. Cocultivation of CD4+ T cells with E112K- or nCT-treated B cells and macrophages in the presence of anti-CD3 stimulation resulted in the induction of T cell-proliferative responses. Further, the responses were blocked by mAbs to B7-1 and/or B7-2; however, the effect of anti-B7-1 was minimal. In the second mechanism, addition of mCT E112K or nCT to anti-CD3 mAb-stimulated Peyer's patch CD4+ T cells inhibited proliferative responses, while recombinant CT-B subunit (rCT-B) did not. Analysis of cytokine responses showed that both mCT E112K and nCT preferentially inhibited IFN-gamma production. Interestingly, however, nCT, but not mCT E112K, induced apoptosis in CD4+ T cells activated via the TCR-CD3 complex. These results indicate that CT uses at least two pathways for inhibition of Th1 responses and that, while nCT induces cAMP accumulation that in turn leads to apoptosis in Th1-type cells, mCT E112K, which lacks ADP-ribosyltransferase activity, inhibits IFN-gamma synthesis by a separate mechanism. Thus, mCT E112K, like nCT, induces adjuvant responses via up-regulation of mainly B7-2 on APCs and through preferential inhibition of Th1-type CD4+ T cell responses in the absence of ADP-ribosyltransferase activity.
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PMID:Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant. 1035 43

Mucosal delivery of vaccines is dependent on the identification of safe and effective adjuvants that can enhance the immunogenicity of protein antigens administered by nasal or oral routes. In this study we demonstrate that two mutants of Escherichia coli heat-labile toxin (LT), LTK63, which lacks ADP-ribosylating activity, and LTR72, which has partial enzyme activity, act as potent mucosal adjuvants for the nasal delivery of an acellular pertussis (Pa) vaccine. Both LTK63 and LTR72 enhanced antigen-specific serum immunoglobulin G (IgG), secretory IgA, and local and systemic T-cell responses. Furthermore, using the murine respiratory challenge model for infection with Bordetella pertussis, we demonstrated that a nasally delivered diphtheria, tetanus, and acellular pertussis (DTPa) combination vaccine formulated with LTK63 as an adjuvant conferred a high level of protection, equivalent to that generated with a parenterally delivered DTPa vaccine formulated with alum. This study also provides significant new information on the roles of the binding and enzyme components of LT in the modulation of Th1 and Th2 responses. LTK63, which lacks enzyme activity, promoted T-cell responses with a mixed Th1-Th2 profile, but LTR72, which retains partial enzyme activity, and the wild-type toxin, especially at low dose, induced a more polarized Th2-type response and very high IgA and IgG antibody titers. Our findings suggest that the nontoxic AB complex has broad adjuvant activity for T-cell responses and that the ADP-ribosyltransferase activity of the A subunit also appears to modulate cytokine production, but its effect on T-cell subtypes, as well as enhancing, may be selectively suppressive.
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PMID:Mutants of Escherichia coli heat-labile toxin act as effective mucosal adjuvants for nasal delivery of an acellular pertussis vaccine: differential effects of the nontoxic AB complex and enzyme activity on Th1 and Th2 cells. 1056 37

Recently a new member of the human tumor necrosis factor (TNF) family named as VEGI was reported. However, very little is known about the biological activities displayed by this cytokine. In this report, we show that in myeloid cells VEGI activated the transcription factor kappa B (NF-kappa B) as determined by the electrophoretic mobility shift assay, induced degradation of I kappa B alpha, and nuclear translocation of p65 subunit of NF-kappa B. VEGI also activated NF-kappa B-dependent reporter gene expression. In addition, VEGI activated c-Jun N-terminal kinase. When examined for growth modulatory effects, VEGI inhibited the proliferation of breast carcinoma (MCF-7), epithelial (HeLa), and myeloid (U-937 and ML-1a) tumor cells; and activated caspase-3 leading to PARP cleavage. VEGI-induced cytotoxicity was potentiated by inhibitors of protein synthesis. VEGI also induced proliferation of normal human foreskin fibroblast cells. The activity of VEGI could neither be neutralized by antibodies against TNF, nor could it compete with TNF binding, indicating that the activity of VEGI is not due to TNF and it binds to a distinct receptor. These results suggest that VEGI, a new member of the TNF family, has a signaling pathway similar to TNF and is most likely a multifunctional cytokine.
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PMID:VEGI, a new member of the TNF family activates nuclear factor-kappa B and c-Jun N-terminal kinase and modulates cell growth. 1059 52

In the central nervous system (CNS), astrocytes play an integral role in the maintenance of neuronal viability and function. Inflammation within the CNS increases the concentration of oxidative metabolites and, therefore, the potential for NAD depletion through increased poly-(ADP-ribose) polymerase (PARP) activity. However, the activity of indoleamine 2,3-dioxygenase (IDO), the rate limiting enzyme for de novo NAD synthesis, is also markedly increased in astrocytes during inflammation. This study investigated the role of IDO induction in the maintenance of intracellular NAD and its relationship to improved cell viability under conditions of increased oxidative stress in the human astroglioma cell line, HTB-138. Treatment with the pro-inflammatory cytokine IFN-gamma increased IDO activity in these cells. Intracellular NAD levels also increased significantly after treatment with IFN-gamma in the presence of a PARP inhibitor. Pretreatment of astroglial cells with IFN-gamma significantly moderated both the drop in intracellular NAD concentration and cell death following exposure to hydrogen peroxide. These results suggest that induction of IDO and subsequent de novo NAD synthesis may contribute to the maintenance of intracellular NAD levels and cell viability under conditions of increased oxidative stress.
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PMID:IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress. 1093 83

Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.
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PMID:Inhibition of poly(ADP-ribose) polymerase attenuates inflammation in a model of chronic colitis. 1096 Mar 65

The melanoma growth stimulatory activity/growth-regulated protein, CXCL1, is constitutively expressed at high levels during inflammation and progression of melanocytes into malignant melanoma. It has been shown previously that CXCL1 overexpression in melanoma cells is due to increased transcription as well as stability of the CXCL1 message. The transcription of CXCL1 is regulated through several cis-acting elements including Sp1, NF-kappaB, HMGI(Y), and the immediate upstream region (IUR) element (nucleotides -94 to -78), which lies immediately upstream to the nuclear factor kappaB (NF-kappaB) element. Previously, it has been shown that the IUR is necessary for basal and cytokine-induced transcription of the CXCL1 gene. UV cross-linking and Southwestern blot analyses indicate that the IUR oligonucleotide probe selectively binds a 115-kDa protein. In this study, the IUR element has been further characterized. We show here that proximity of the IUR element to the adjacent NF-kappaB element is critical to its function as a positive regulatory element. Using binding site oligonucleotide affinity chromatography, we have selectively purified the 115-kDa IUR-F. Mass spectrometry/mass spectrometry/matrix-assisted laser desorption ionization/time of flight spectroscopy and amino acid analysis as well as microcapillary reverse phase chromatography electrospray ionization tandem mass spectrometry identified this protein as the 114-kDa poly(ADP-ribose) polymerase (PARP1). Furthermore, 3-aminobenzamide, an inhibitor of PARP-specific ADP-ribosylation, inhibits CXCL1 promoter activity and reduces levels of CXCL1 mRNA. The data point to the possibility that PARP may be a coactivator of CXCL1 transcription.
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PMID:A role for poly(ADP-ribose) polymerase in the transcriptional regulation of the melanoma growth stimulatory activity (CXCL1) gene expression. 1111 86

Expression of the lytic cycle genes of Epstain-Barr virus (EBV) is induced in type I Burkitt's lymphoma-derived cells by treatment with phorbol esters (e.g., phorbol myristate acetate [PMA]), anti-immunoglobulin, or the cytokine transforming growth factor beta (TGF-beta). Concomitantly, all these agents induce apoptosis as judged by a sub-G1 fluorescence-activated cell sorter (FACS) profile, proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. However, caspase activation is not required for induction of the lytic cycle since the latter is not blocked by the caspase inhibitor ZVAD. Furthermore, not all agents that induce apoptosis in these cultures (for example, cisplatin and ceramide) induce the EBV lytic programme. Although it is closely associated with the lytic cycle, apoptosis is neither necessary nor sufficient for its activation. Multiparameter FACS analysis of cultures treated with PMA, anti-Ig, or TGF-beta revealed BZLF1-expressing cells distributed in different phases of the cell cycle according to which inducer was used. However, BZLF1-positive cells did not appear to undergo apoptosis and accumulate with a sub-G1 DNA content, irrespective of the inducer used. This result, which suggests that lytic gene expression is protective, was confirmed and extended by immunofluorescence staining doubled with TUNEL analysis. BZLF1- and also gp350-expressing cells were almost always shown to be negative for TUNEL staining. Similar experiments using EBV-positive and -negative subclones of Akata BL cells carrying an episomal BZLF1 reporter plasmid confirmed that protection from apoptosis was associated with the presence of the EBV genome. Finally, treatment with phosphonoacetic acid or acyclovir prior to induction with PMA, anti-Ig, or TGF-beta blocked the protective effect in Mutu-I cells. These data suggest that a late gene product(s) may be particularly important for protection against caspase activity and cell death.
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PMID:Activators of the Epstein-Barr virus lytic program concomitantly induce apoptosis, but lytic gene expression protects from cell death. 1116 Jul 43

In the present study, we examined whether melatonin can protect rodent pancreatic islets against streptozotocin (STZ) and interleukin-1beta (IL-1beta)-induced suppression of beta-cell function. Formation of free radicals, DNA damage and extensive DNA repair leading to depletion of intracellular nicotinamide adenine dinucleotide (NAD) may mediate STZ toxicity. Activation of inducible nitric oxide synthase and nitric oxide (NO) formation may cause IL-1beta -induced beta-cell impairment. We also studied the effect of melatonin against STZ-induced hyperglycemia in C57BL/Ks mice. For in vitro studies, cultured rat islets were exposed to melatonin (100 microM-1 mM) 30 min prior to STZ (0.5 mM) or IL-1beta (25 U/mL) addition. After an additional 30 min incubation with STZ, islet function and NAD content were analyzed either acutely or after 18 hr of recovery in fresh culture medium. For IL-1beta experiments, islets were incubated for 48 hr with the cytokine before evaluation of islet function. We found that melatonin counteracted STZ-induced inhibition of glucose metabolism and insulin release in cultured rat islets after 18 hr of recovery. Moreover, NAD levels were higher in the melatonin-treated group at this time point. Melatonin had no effect on IL-1beta-induced islet inhibition of glucose oxidation or NO formation. Diabetes induced by STZ (140 mg/kg body weight; i.v.) was effectively prevented by administration of melatonin (100 mg/kg body weight; i.p.) 30 min before STZ injection. We conclude that the protective effects of melatonin against beta-cell damage may be related to interference with DNA damage and poly(ADP-ribose) polymerase (PARP) activation rather than through effects on NO generation pathways.
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PMID:Melatonin protects against streptozotocin, but not interleukin-1beta-induced damage of rodent pancreatic beta-cells. 1131 26

Activation of poly(ADP-ribose) synthetase (PARS, also termed polyADP-ribose polymerase or PARP) has been proposed as a major mechanism contributing to beta-cell destruction in type I diabetes. In the present study, we have investigated the role of PARS in mediating the induction of diabetes and beta-cell death in the multiple-low-dose-streptozotocin (MLDS) model of type I diabetes. Mice genetically deficient in PARS were found to be less sensitive to MLDS than wild type mice, with a lower incidence of diabetes and reduced hyperglycemia. A potent inhibitor of PARS, 5-iodo-6-amino-1,2-benzopyrone (INH(2)BP), was also found to protect mice from MLDS and prevent beta-cell loss, in a dose-dependent manner. Paradoxically, in the PARS deficient mice, the compound increased the onset of diabetes. In vitro the cytokine combination; interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma inhibited glucose-stimulated insulin secretion from isolated rat islets of Langerhans and decreased RIN-5F cell viability. The PARS inhibitor, INH(2)BP, protected both the rat islets and the beta-cell line, RIN-5F, from these cytokine-mediated effects. These protective effects were not mediated by inhibition of cytokine-induced nitric oxide formation. Inhibition of PARS by INH(2)BP was unable to protect rat islet cells from cytokine-mediated apoptosis. Cytokines, peroxynitrite and streptozotocin were all shown to induce PARS activation in RIN-5F cells, an effect suppressed by INH(2)BP. The present study provides evidence for in vivo PARS activation contributing to beta-cell damage and death in the MLDS model of diabetes, and indicates a role for PARS activation in cytokine-mediated depression of insulin secretion and cell viability in vitro.
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PMID:Inhibition of poly (ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-1,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes. 1145 65

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) has been found to protect a variety of epithelial and cancer cell types against cytotoxicity and apoptosis induced by DNA damage, but the specific apoptotic signaling events and the levels at which they are blocked by HGF/SF have not been identified. We found that treatment of MDA-MB-453 human breast cancer cells with adriamycin (also known as doxorubicin, a DNA topoisomerase IIalpha inhibitor) induced a series of time-dependent events, including the mitochondrial release of cytochrome c and apoptosis-inducing factor, mitochondrial membrane depolarization, activation of a set of caspases (caspase-9, -3, -7, -2, and -8), cleavage of poly(ADP-ribose) polymerase (PARP), and up-regulation of expression of the Fas ligand. All of these events were blocked by preincubation of the cells with HGF/SF. In contrast, the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone blocked some of these events (e.g. caspase-3 activation and PARP cleavage) but did not block cytochrome c release or mitochondrial depolarization. These findings suggest that HGF/SF functions, in part, upstream of the mitochondria to block mitochondrial apoptosis signaling, prevent activation of multiple caspases, and protect breast cancer cells against apoptosis.
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PMID:Hepatocyte growth factor/scatter factor blocks the mitochondrial pathway of apoptosis signaling in breast cancer cells. 1157 Dec 97


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