Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rabies virus has been shown to induce apoptosis in infected cells, but the intracellular pathway of cell killing is unknown. In this report, we show that rabies virus infected mouse neuroblastoma cells underwent chromatin condensation and DNA fragmentation within 48 h post-infection. An increased level of the apoptotic enhancer, Bax, was detected within 24 h after infection. In contrast to Bax, the production of the apoptotic antagonist, Bcl-2, remained unchanged. Shortly after detection of Bax, caspase 1 (ICE) was upregulated. Reduction of DNA fragmentation in rabies virus infected cultures pretreated with YVAD and DEVD suggested that more than one subfamily of caspase functioned in the death process. Significant degradation of the DNA repair enzyme, poly ADP-ribose polymerase (PARP), was revealed after caspase upregulation. This study showed that replication of rabies viruses in mouse neuroblastoma cells induced the Bax-related death program leading to destruction of the DNA repair system probably by caspase activity.
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PMID:Rabies virus replication induces Bax-related, caspase dependent apoptosis in mouse neuroblastoma cells. 978 70

Angiotensin II (Ang II) type 2 (AT2) receptors are highly expressed in neonate brain and may have a role in developmental processes such as apoptosis. Concurrent activation of c-Jun N-terminal kinase (JNK) and inhibition of Erk mitogen-activated protein kinase activities is important for apoptosis in many cells, and we previously demonstrated that stimulation of AT2 receptors causes decreased mitogen-activated protein kinase activity in neurons cultured from newborn rat hypothalamus and brain stem. Using such cultures we have employed terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling and internucleosomal DNA fragmentation to assess the role of AT2 receptors in neuronal apoptosis. Ang II (100 nM; 4-72 h) alone produced no significant neuronal apoptosis, and AT2 receptor activation did not stimulate JNK activity. However, exposure of cultures to UV radiation (6 J/m2/sec for 4 sec) to stimulate JNK elicited neuronal apoptosis that was significantly enhanced by Ang II, an effect that was abolished by the AT2 receptor antagonist PD 123,319 (1 microM) or the serine/threonine phosphatase inhibitor okadaic acid (3 nM). Additionally, Ang II enhanced the UV radiation-induced decrease in the levels of the DNA repair enzyme poly-(ADP-ribose) polymerase. These data indicate that Ang II, via AT2 receptors and activation of a serine/threonine phosphatase, contributes to neuronal apoptosis.
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PMID:Angiotensin II type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. 988 63

In hepatocytes the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) is not proteolytically cleaved during apoptosis. The reason for this was investigated using a cell-free system that consisted of isolated nuclei from hepatocytes or thymocytes and cytosolic extracts from hepatocytes or thymocytes undergoing apoptosis. It was found that liver PARP is resistant to proteolytic cleavage by the caspases present in the cytosolic extracts. Furthermore, liver PARP was not cleaved by recombinant human caspase-3. It is concluded that PARP proteolysis cannot be used as a marker for hepatocyte apoptosis.
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PMID:Liver poly(ADP-ribose)polymerase is resistant to cleavage by caspases. 1007 3

The aim of this study was to establish a link between the highly expressed angiotensin II (Ang II) type 2 receptor (AT2) in human fetal adrenal cells and the proposed apoptotic activity in the center of the gland. There was an important increase in apoptotic DNA fragmentation with age in adrenal glands of fetuses from 15-20 weeks gestation. Adrenal cells showing the characteristic apoptotic internucleosomal DNA fragmentation were localized in the central portion of the fetal zone. In cells cultured for 24 h, Ang II, via the AT2 receptor, induced DNA fragmentation and cleavage of the DNA repair enzyme, poly-(ADP-ribose) polymerase. Furthermore, characteristic membrane blebbing was observed specifically on cells of the fetal zone. Immunofluorescence studies demonstrated that stimulation with Ang II or CGP 42112 (an agonist of the AT2 receptor) strongly modified the actin network, now localized exclusively along the plasma membrane, with a predominance of labeling at the base of the bleb formation. This rearrangement of actin distribution was different in cells from the definitive zone, corroborating the observation that these cells express many more Ang II type 1 receptors (AT1) than AT2 receptors. Taken together, our data indicate that the AT2 receptor is involved in the apoptotic process observed in the human fetal adrenal gland and could participate in the morphological changes occurring after birth, leading to involution of the fetal zone.
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PMID:Involvement of the angiotensin II type 2 receptor in apoptosis during human fetal adrenal gland development. 1059 41

Certain pore-forming bacterial toxins, including the leukotoxin (Ltx) produced by Actinobacillus actinomycetemcomitans, induce apoptosis in susceptible target cells. Although binding to the target cell surface represents the first step in the initiation of this process, the downstream events leading to toxin-induced apoptotic cell death have not been identified. Perturbation of mitochondrial function has been shown to have a major role in regulating progression of apoptosis initiated by exposure to numerous stimuli. Using Ltx as a model, the aim of this study was to evaluate whether induction of apoptosis by pore-forming toxins follows a similar paradigm. After exposure to Ltx, Epstein-Barr virus transformed B cells (JY cell line) exhibited the classical morphological features of apoptosis including decreased cell size, plasma membrane blebbing, selective alterations in plasma membrane permeability and condensation of nuclear DNA. The morphologic changes were accompanied by swelling of the mitochondria, a decrease in mitochondrial transmembrane potential (Psi(m)), hyperproduction of reactive oxygen intermediates (ROIs) and release of cytochrome c from the intermembrane space. Subsequently, we detected activation of the c ysteine asp artate-specific prote ases (caspases)-3 and -9, cleavage of the nuclear DNA repair enzyme, poly(ADP-ribose)polymerase (PARP) and internucleosomal DNA fragmentation. These results indicate that perturbation of mitochondrial structure and function, in concert with activation of specific caspases, initiate the effector phase of Ltx-induced apoptosis.
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PMID:Perturbation of mitochondrial structure and function plays a central role in Actinobacillus actinomycetemcomitans leukotoxin-induced apoptosis. 1103 Nov 21

Neuronal damage and dementia are common sequelae of HIV encephalitis. The mechanism by which HIV infection of CNS macrophages results in neuronal damage is not known. We examined the brains from 15 AIDS autopsies (8 with HIV encephalitis and 7 without) and 4 non-infected control autopsies for the presence of DNA strand breaks, for associated changes in the expression of the DNA repair enzymes KU80 and Poly (ADP-ribose) polymerase (PARP), and for accumulation of amyloid precursor protein (APP). Abundant DNA damage was observed with terminal transferase-mediated dUTP nick end-labeling (TUNEL), however, there was no morphologic evidence of significant neuroglial apoptosis. The DNA repair enzyme KU80 was immunocytochemically detectable in neuronal and glial cells in autopsy brains from patients with and without HIV encephalitis; however, in cases with HIV encephalitis the staining was more prominent than in the infected or non-infected controls without encephalitis. There was no difference in KU80 immunostaining in oligodendroglia from autopsies with and without encephalitis. Immunostaining for PARP was more intense in gray and white matter of cases with HIV encephalitis. No clear spatial relationship existed between expression of DNA repair enzymes and the spatial proximity of microglial nodules or HIV-infected macrophages. The cytoplasm of cortical and subcortical neurons immunostained for APP Stronger cortical neuronal APP staining was observed in cases without HIV encephalitis. Staining of deep gray matter neurons was similar, irrespective of the presence or absence of encephalitis. While foci of intense APP staining were noted in white matter not related to HIV infection, they were associated with foci of opportunistic infections (e.g. due to CMV or PML). We conclude that damaged DNA and altered patterns of expression of DNA repair proteins and APP are common findings in the brains of AIDS patients at autopsy, but do not have a spatial relationship to HIV-infected macrophages.
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PMID:Damage and repair of DNA in HIV encephalitis. 1108 73

Apoptosis is an active form of cell death that is initiated by a variety of stimuli, including reactive oxygen species (ROS) and ultraviolet (UV) radiation. Poly (ADP-ribose) (PAR) is formed upon activation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), and therefore was suggested as a new marker of apoptosis. Since DNA of epidermal cells represents a well-known chromophore for UVB irradiation, and UVB is known to generate H2O2 in keratinocytes, we hypothesized that PAR is a very sensitive marker of UVB- and H2O2-induced apoptosis in keratinocytes. In order to test this hypothesis, human immortalized keratinocytes (HaCaT) were UVB-irradiated or treated with H2O2, and subsequently apoptosis was identified by comparing conventional parameters such as morphological analysis, DNA laddering, and TUNEL assay, with PAR formation. Both, UVB and H2O2 treatment induced PAR formation in HaCaT cells in a dose-dependent manner, and its formation was detected as early as 4 h after irradiation, and at lower UVB doses (10 mJ/cm2) than observed by DNA laddering and the TUNEL assay. In conclusion, the detection of PAR formation is a very sensitive and early method for the identification of apoptotic cells in UVB-induced apoptosis of human keratinocytes.
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PMID:Detection of poly(ADP-ribose) by immunocytochemistry: a sensitive new method for the early identification of UVB- and H2O2-induced apoptosis in keratinocytes. 1203 59

The present study investigates the modulating effects of nicotinamide on the cytokine response to endotoxin. In an in vitro model of endotoxaemia, human whole blood was stimulated for two hours with endotoxin at 1 ng/ml, achieving high levels of the proinflammatory cytokines IL-1 beta, IL-6, IL-8 and TNF alpha. When coincubating whole blood, endotoxin and the vitamin B3 derivative nicotinamide, all four cytokines measured were inhibited in a dose dependent manner. Inhibition was observed already at a nicotinamide concentration of 2 mmol/l. At a concentration of 40 mmol/l, the IL-1 beta, IL-6 and TNF alpha responses were reduced by more than 95% and the IL-8 levels reduced by 85%. Endotoxin stimulation activates poly(ADP-ribose)polymerase (PARP), a nuclear DNA repair enzyme. It has been hypothesized that the anti-inflammatory properties of nicotinamide are due to PARP inhibition. In the present study, the endotoxin induced PARP activation was dose dependently decreased with 4-40 mmol/l nicotinamide or 4-100 micro mol/l 6(5H) phenanthridinone, a specific PARP inhibitor. 6(5H)phenanthridinone however, failed to inhibit the proinflammatory cytokines. Thus, the mechanism behind the cytokine inhibition in our model seems not to be due to PARP inhibition. In conclusion, the present study could not only confirm previous reports of a down-regulatory effect on TNFalpha, but demonstrates that nicotinamide is a potent modulator of several proinflammatory cytokines. These findings demonstrate that nicotinamide has a potent immunomodulatory effect in vitro, and may have great potential for treatment of human inflammatory disease.
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PMID:Nicotinamide is a potent inhibitor of proinflammatory cytokines. 1251 85

The repair of DNA single-strand breaks in mammalian cells is mediated by poly(ADP-ribose) polymerase 1 (PARP-1), DNA ligase IIIalpha, and XRCC1. Since these proteins are not found in lower eukaryotes, this DNA repair pathway plays a unique role in maintaining genome stability in more complex organisms. XRCC1 not only forms a stable complex with DNA ligase IIIalpha but also interacts with several other DNA repair factors. Here we have used affinity chromatography to identify proteins that associate with DNA ligase III. PARP-1 binds directly to an N-terminal region of DNA ligase III immediately adjacent to its zinc finger. In further studies, we have shown that DNA ligase III also binds directly to poly(ADP-ribose) and preferentially associates with poly(ADP-ribosyl)ated PARP-1 in vitro and in vivo. Our biochemical studies have revealed that the zinc finger of DNA ligase III increases DNA joining in the presence of either poly(ADP-ribosyl)ated PARP-1 or poly(ADP-ribose). This provides a mechanism for the recruitment of the DNA ligase IIIalpha-XRCC1 complex to in vivo DNA single-strand breaks and suggests that the zinc finger of DNA ligase III enables this complex and associated repair factors to locate the strand break in the presence of the negatively charged poly(ADP-ribose) polymer.
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PMID:Physical and functional interaction between DNA ligase IIIalpha and poly(ADP-Ribose) polymerase 1 in DNA single-strand break repair. 1289 60

Excessive oxidative stress has been implicated in the induction of cell death in a variety of neurodegenerative diseases. In the present study, hydrogen peroxide (H2O2)-induced cell death in rat C6 glioma cells was used as a model system for studying the molecular events associated with oxidative stress-induced cell death in glial cells. We demonstrate that exposure of C6 glioma cells to H2O2 results in apoptotic cell death in a concentration-dependent manner, and caused activation of a member of the caspase-3-like family of proteases resulting in cleavage of the DNA repair enzyme poly(ADP-ribose)polymerase, PARP. Furthermore, H2O2 induced a transient activation of the transcription factor, nuclear factor kappa B (NF(Kappa)B). Pre-treatment of cells with the antioxidant N-acetylcysteine, (NAC), prevented both the activation of NF(Kappa)B and the induction of apoptosis by H2O2, suggesting a possible role for this transcription factor in oxidant-induced apoptosis in glial cells. Exposure of the cells to H2O2 led to transient activation of both c-Jun N-terminal kinase (JNK) and p38 kinase but has no effect on extracellular regulated kinase (ERK) activity. Inhibition of p38 by SB203580 did not protect the cells against H2O2-induced apoptosis suggesting that activation of p38 is not essential for H2O2-mediated cell death in C6 glioma cells.
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PMID:Oxidative stress induces apoptosis in C6 glioma cells: involvement of mitogen-activated protein kinases and nuclear factor kappa B. 1471 69


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