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)

Previous studies on skeletal muscle differentiation showed that myogenesis is regulated by extracellular signal-regulated kinases (ERK-1/-2) and p38 mitogen activated kinase (MAPK) pathways. Present study shows that c-Jun NH2-terminal protein kinase (JNK) activities were up regulated during skeletal muscle differentiation in rat skeletal muscle L6E9 cells, as determined by Western immunoblot of differentiating cells probed with anti-phospho-JNK antibody. Inhibition of JNK activities by JNK inhibitor II drastically inhibited differentiation as determined by decreased myosin, myogenin expression and creatine kinase activity. The inhibition of the differentiation was regulated by apoptosis as determined by the detection of poly(ADP-ribose) polymerase (PARP) cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells when JNK activities were inhibited. Apoptosis was accompanied by marked expression and activation of c-Jun and p53 transcription factors. Taken together, our results indicate that basal JNK activities are essential for regulating skeletal muscle differentiation, and inhibition of JNK activation affects myogenesis by apoptosis dependent on c-Jun and p53 transcription factors.
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PMID:Involvement of c-Jun N-terminal kinase activities in skeletal muscle differentiation. 1575 Aug 49

Myristicin, 1-allyl-3,4-methylenedioxy-5-methoxybenzene, is a naturally occurring alkenylbenzene compound found in the nutmeg. The present study was conducted to assess the cytotoxic and apoptotic effects of myristicin on the human neuroblastoma SK-N-SH cells. We found that a dose-dependent reduction in cell viability occurs at myristicin concentration > or =0.5 mM in SK-N-SH cells. Apoptotic cell death was confirmed using DNA fragmentation, terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labeling and by 4,6-diamidino-2-phenylindole staining. Microscopy was used to observe apoptotic cell morphology. Western blotting was used to investigate the protein expression of known apoptotic mediators including cytochrome c, caspase-3, and PARP. The apoptosis triggered by myristicin was accompanied by an accumulation of cytochrome c and by the activation of caspase-3. The results obtained suggest that myristicin induces cytotoxicity in human neuroblastoma SK-N-SH cells by an apoptotic mechanism. This myristicin-induced apoptosis provides further insight of the molecular mechanisms of myristicin toxicity.
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PMID:Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells. 1579 93

Whether DNA damage caused by cigarette smoke leads to repair or apoptosis has not been fully elucidated. The current study demonstrates that cigarette smoke induces single-strand DNA damage in human bronchial epithelial cells. Cigarette smoke also stimulated caspase 3 precursors as well as intact poly (ADP-ribose) polymerase (PARP) production, but did not activate caspase 3 or cleave PARP, while the alkaloid camptothecin did so. Neither apoptosis nor necrosis was induced by cigarette smoke when the insult was removed within a designated time period. In contrast, DNA damage following cigarette smoke exposure was repaired as evidenced by decreasing terminal dUTP-biotin nick-end labeling positivity. The PARP inhibitor, 3-aminobenzamide blocked this repair. Furthermore, cells subjected to DNA damage were able to survive and proliferate clonogenically when changed to smoke-free conditions. These results suggest that cigarette smoke-induced DNA damage in bronchial epithelial cells is not necessarily lethal, and that PARP functions in the repair process. Our data also suggest that the potency of cigarettes as a carcinogen may result from their ability to induce DNA damage while failing to trigger the apoptotic progression permitting survival of cells harboring potentially oncogenic mutations.
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PMID:Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells. 1584 67

The purpose of the present study was to investigate the anti-proliferative and apoptotic effects of MCS-C2, a novel synthetic analogue of the pyrrolo[2,3-d]pyrimidine nucleoside toyocamycin and sangivamycin, in human promyelocytic leukemia (HL-60) cells. When treated with 5 microM MCS-C2, inhibited proliferation associated with apoptotic induction was found in the HL-60 cells in a concentration-dependent and time-dependent manner, plus nuclear DAPI staining revealed the typical nuclear features of apoptosis. However, MCS-C2 showed almost no antiproliferative effect and no apoptotic induction in normal lymphocyte cells used as a control when compared with those in HL-60 cancer cells. Moreover, a flow cytometric analysis of the HL-60 cells using FITC-dUTP and propidium iodide (PI) showed that the apoptotic cell population increased gradually from <1% at 0 h to 34% at 12 h after exposure to 5 microM MCS-C2. This apoptotic induction was associated with the cleavage of Bid and a release of cytochrome c from mitochondria into the cytosol, followed by the activation of caspase-3 and inactivation of poly(ADP-ribose) polymerase (PARP). However, there was no significant change in any other mitochondrial membrane proteins, such as Bcl-2 and Bax. Consequently, the current findings suggest that the mitochondrial pathway was primarily involved in the MCS-C2-induced apoptosis in the human promyelocytic leukemia HL-60 cells.
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PMID:Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release. 1589 58

Flaviviruses such as dengue virus (DEN) and Japanese encephalitis virus (JEV) are medically important in humans. The lipid kinase, phosphatidylinositol 3-kinase (PI3K) and its downstream target Akt have been implicated in the regulation of diverse cellular functions such as proliferation, and apoptosis. Since JEV and DEN appear to trigger apoptosis in cultured cells at a rather late stage of infection, we evaluated the possible roles of the PI3K/Akt signaling pathway in flavivirus-infected cells. We found that Akt phosphorylation was noticeable in the JEV- and DEN serotype 2 (DEN-2)-infected neuronal N18 cells in an early, transient, PI3K- and lipid raft-dependent manner. Blocking of PI3K activation by its specific inhibitor LY294002 or wortmannin greatly enhanced virus-induced cytopathic effects (CPEs), even at an early stage of infection, but had no effect on virus production. This severe CPE was characterized as apoptotic cell death as evidenced by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining and cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Mechanically, the initiator and effector caspases involved are mainly caspase-9 and caspase-6, since only a pan-caspase inhibitor and the inhibitors preferentially target caspase-9 and -6, but not the ones antagonizing caspase-8, -3, or -7 alleviated the levels of PARP cleavage after virus infection and PI3K blockage. Furthermore, Bcl-2 appears to be a crucial mediator downstream of PI3K/Akt signaling, since overexpression of Bcl-2 reduced virus-induced apoptosis even when PI3K activation was repressed. Collectively, our results suggest an anti-apoptotic role for the PI3K/Akt pathway triggered by JEV and DEN-2 to protect infected cells from early apoptotic cell death.
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PMID:Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection. 1595 83

Thymidylate synthase (TS) is an important target of several chemotherapeutic agents. During TS inhibition, dTTP levels decrease with a subsequent increase in dUTP. Uracil incorporated into the genome is removed by base excision repair (BER). BER has been hypothesized to play a role in the response to thymidylate deprivation, despite a lack of direct evidence. We previously found that beta-pol null murine fibroblasts were approximately six-fold more resistant than wild-type cells to raltitrexed, a folate-based inhibitor specific for TS. In this study, a number of endpoints were determined to understand the influence of BER and beta-pol during raltitrexed treatment. Raltitrexed induced apoptosis in wild-type cells to a greater extent than in beta-pol null cells. A PARP inhibitor decreased the sensitivity to raltitrexed, although the extent was not different between wild-type and beta-pol null cells. No evidence was seen for extensive strand break formation that preceded apoptosis, although raltitrexed induced more sister chromatid exchanges in wild-type cells. Increased levels of uracil in DNA were detected following treatment in wild-type and beta-pol null cells. However, uracil levels were only approximately two-fold higher in DNA from treated cells compared to untreated. Uracil DNA glycosylase activity was slightly higher in beta-pol null cells, although not sufficiently different to explain the difference in sensitivity to raltitrexed. Taken together, the data suggest that the sensitivity of the wild-type cells to raltitrexed is not associated with activation of PARP-1 dependent BER, extensive uracil incorporation into DNA and persistent strand breaks, but rather with changes suggestive of DNA recombination.
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PMID:Determination of apoptosis, uracil incorporation, DNA strand breaks, and sister chromatid exchanges under conditions of thymidylate deprivation in a model of BER deficiency. 1619 27

Cadmium causes cellular damage but the exact mechanism of apoptosis in cadmium induced acute lung injury is not clear. We investigated the sequential expression of apoptotic nuclei and detected related molecules in tissue of cadmium-induced acute lung injury. Forty Sprague-Dawley rats were sacrificed at days 1, 3, 7 and 10 after intra-tracheal cadmium injection (2.5mg/kg). Light microscopic, ultrastructural terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling (TUNEL), and Western blot analysis for detection of FasL, Bid, cytochrome c, caspase 3 and PARP were carried out. Apoptosis occurred at day 1, and markedly decreased at days 3, 7 and 10 (11.8, 2.8, 0.9, 0.5%, respectively) determined by light microscopy and TUNEL assay. Ultrastructural TUNEL revealed two patterns of nuclear morphology according to the apoptotic stage. One pattern showed chromatin fragmentation and apoptotic nuclear body formation. The other pattern had bleb formation in the chromatin, budding with projection out to the nuclear membranes, fragmentation, segregation of chromatin clumps and apoptotic body formation. Western blot analysis showed prominent expression of FasL at days 1 and 3. Expression of Bid, cytochrome c and caspase 3 were prominent at day 1 compared to days 3, 7 and 10. PARP cleavage was prominent at day 1. In conclusion, intra-tracheal cadmium injection showed active alveolar cell apoptosis at day 1. Ultrastructural TUNEL showed various expressions according to the apoptotic nuclear stage. These studies suggest that cadmium-induced alveolar cell apoptosis is mediated by FasL and caspase-dependent mitochondrial apoptosis pathways.
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PMID:Expression of apoptotic nuclei by ultrastructural terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling and detection of FasL, caspases and PARP protein molecules in cadmium induced acute alveolar cell injury. 1632 65

The present study was designed to investigate the hypothesis that trans fatty acids can induce apoptosis of human umbilical vein endothelial cells (HUVEC). To test this hypothesis apoptosis was measured in HUVEC treated with 0.1, 1.0 or 5.0 mM trans elaidic acid (t-18:1) or linoelaidic acid (t,t-18:2) for 24 hours. For the detection of apoptosis, TdT-mediated dUTP nick end labelling assay (TUNEL), cell binding of annexin V and propidium iodide uptake were measured. Active Caspase-3 and cleaved PARP (poly-ADP-ribose polymerase) were also measured in the cell lysate. Moreover, cellular ability to produce ROS (reactive oxygen species) was measured by DCF fluorescence Both acids studied induce both early (annexin-positive cells) and late stages of apoptosis (cells stained by propidium iodide) in a dose-dependent manner. Also the appearance of TUNEL-positive cells was induced by both trans fatty acids tested, in a dose dependent manner. Both trans acids induce apoptosis through their effect on Caspase-3 activity and on intracellular ROS production. It is worth emphasising that linoelaidic acid proved to be a more potent inducer of apoptosis and ROS production in endothelial cells than elaidic acid. The present studies suggest that trans fatty acids may play a role in damaging and death of vascular endothelial cells in atherosclerosis.
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PMID:Trans fatty acids induce apoptosis in human endothelial cells. 1639 18

An elevated level of homocysteine (Hcy) limits the growth and induces apoptosis. However, the mechanism of Hcy-induced programmed cell death in endothelial cells is largely unknown. We hypothesize that Hcy induces intracellular reactive oxygen species (ROS) production that leads to the loss of transmembrane mitochondrial potential (Deltapsi(m)) accompanied by the release of cytochrome-c from mitochondria. Cytochrome-c release contributes to caspase activation, such as caspase-9, caspase-6, and caspase-3, which results in the degradation of numerous nuclear proteins including poly (ADP-ribose) polymerase (PARP), which subsequently leads to the internucleosomal cleavage of DNA, resulting cell death. In this study, rat heart microvascular endothelial cells (MVEC) were treated with different doses of Hcy at different time intervals. Apoptosis was measured by DNA laddering and transferase-mediated dUTP nick-end labeling (TUNEL) assay. ROS production and MP were determined using fluorescent probes (2,7-dichlorofluorescein (DCFH-DA) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzamidazolocarbocyanin iodide (JC-1), respectively, by confocal microscopy. Differential gene expression for apoptosis was analyzed by cDNA array. The results showed that Hcy-mediated ROS production preceded the loss of MP, the release of cytochrome-c, and the activation of caspase-9 and -3. Moreover the Hcy treatment resulted in a decrease in Bcl(2)/Bax ratio, evaluated by mRNA levels. Caspase-9 and -3 were activated, causing cleavage of PARP, a hallmark of apoptosis and internucleosomal DNA fragmentation. The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC. Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP. Our data suggested that Hcy-mediated ROS production promotes endothelial cell death in part by disturbing MP, which results in subsequent release of cytochrome-c and activation of caspase-9 and 3, leading to cell death.
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PMID:Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia. 1651 65

Survivin (SVV), an inhibitor of apoptosis protein, is found to be upregulated in many cancers. We previously demonstrated that a dominant-negative mutant SVV-D53A was able to induce apoptosis in a p53-independent manner. Here, we report the construction and characterization of a recombinant replication-deficient adenoviral vector encoding a human SVV-D53A gene for its effectiveness against tumor growth both in vitro and in vivo. Transfection of liver tumor cells QGY-7703 with Ad-SVV-D53A results in significant apoptosis as measured by an increase in sub-G1 DNA content, procaspase-9 activation and further downstream PARP-1 cleavage. Furthermore, animal studies using QGY-7703 liver carcinoma xenografts in nude mice revealed that treatment of QGY-7703 cells with dominant-negative SVV-D53A, but not with wild-type SVV-adenovirus, prevents tumor outgrowth, inhibits growth of established tumors and results in a notably improved survival advantages in xenograft studies. Both the transferase-mediated dUTP nick-end labeling assay and immunostaining experiment demonstrated that tumor growth inhibition is associated with apoptosis induced by SVV-D53A expression. Taken together, these data suggest that recombinant adenovirus Ad-SVV-D53A carrying a Survivin dominant-negative gene SVV-D53A promotes apoptosis-mediated tumor suppression and could potentially be a promising candidate for cancer therapies.
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PMID:Suppression of tumor growth using a recombinant adenoviral vector carrying the dominant-negative mutant gene Survivin-D53A in a nude mice model. 1654 17


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