Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protease-activated receptors (PARs) belong to the family of membrane receptors coupled to G-proteins; their presence is reported in a wide variety of cells. The object of this study was to demonstrate the presence of PAR-1 and PAR-2 in myenteric glia of the guinea pig, and to elucidate the cellular mechanisms that are triggered upon receptor activation. Thrombin and PAR-1 agonist peptide (PARP-1) activate PAR-1 with a maximum mean +/- SEM change in intracellular calcium concentration with respect to basal level (Delta[Ca2+]i) of 183 +/- 18 nm and 169 +/- 6 nm, respectively. Trypsin and PAR-2 agonist peptide (PARP-2) activate PAR-2 with a maximum Delta[Ca2+]i of 364 +/- 28 nm and 239 +/- 19 nm, respectively. Inhibition of phospholipase C by U73312 (1 microm) decreased the Delta[Ca2+]i due to PAR-1 activation from 167 +/- 10 nm to 87 +/- 6 nm. The PAR-2-mediated Delta[Ca2+]i decreased from 193 +/- 10 nm to 124 +/- 8 nm when phospholipase C activity was inhibited. Blockade of sphingosine kinase with dimethylsphingosine (1 microm) decreased the Delta[Ca2+]i due to PAR-2 activation from 149 +/- 19 nm to 67 +/- 1 nm, but did not influence the PAR-1-mediated Delta[Ca2+]i. PAR-1 and PAR-2 were localized in myenteric glia by immunolabeling. Our results indicate that PAR-1 and PAR-2 are present in myenteric glia of the guinea pig, and their activation leads to increases in intracellular calcium via different signal transduction mechanisms that involve activation of phospholipase C and sphingosine kinase.
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PMID:Presence of functionally active protease-activated receptors 1 and 2 in myenteric glia. 1239 May 17

Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs--fluoxetine, paroxetine, and citalopram--act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and-because of its association with AIDS-increasingly more common Burkitt lymphoma.
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PMID:Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. 1251 26

Dykellic acid is a novel microbial metabolite isolated from the broth of Westerdykella multispora F50733. Investigations on the molecular function of dykellic acid revealed that this compound partially inhibits calcium influx, resulting in a decrease in Ca(2+)-dependent endonuclease activation and DNA fragmentation induced by camptothecin. In our experiments, active caspase-3-like protease cleavage of procaspase-3, PARP, and cytosolic cytochrome c was inhibited by dykellic acid in a concentration-dependent manner when the apoptosis was induced by camptothecin as well as doxorubicin. We confirmed that dykellic acid did not bind to camptothecin using surface plasmon resonance analysis. These results suggest that dykellic acid inhibits drug-induced apoptosis via a caspase-3-like protease-suppressing mechanism. Our data provide important information on the mechanism of action of dykellic acid and indicate that this compound may be employed in the treatment of specific caspase-3-like protease-mediated diseases.
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PMID:Dykellic acid inhibits drug-induced caspase-3-like protease activation. 1261 68

We studied the mechanism of the cytotoxic effects of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT; induction with 1 mM ALA for 4 h followed by a blue light dose of 18 J/cm(2)) on the human promyelocytic leukemia cell line HL60 using biochemical and electron microscopy methods. The disruption of mitochondrial membrane potential, deltapsi(m), was paralleled by a decrease in ATP level, unmasking of the mitochondrial antigen 7A6, release of cytochrome c into the cytoplasm, activation of caspases 9 and 3 and cleavage of poly(ADP-ribose) polymerase (PARP). This was followed by DNA fragmentation. These data suggest that ALA-PDT activates the mitochondrial apoptotic pathway. The level of endoplasmic reticulum Ca(2+)-binding chaperones ERp57 and ERp72 and of anti-apoptotic proteins Bcl-2 and Bcl-x(L) was decreased whereas that of Ca(2+)-binding protein calmodulin and the stress protein HSP60 was elevated following ALA-PDT. Inhibition of the initiator caspase 9, execution caspase 3 and Ca(2+)-dependent protease m-calpain, did not prevent DNA fragmentation. We conclude that, in our in vitro model, ALA-based photodynamic treatment initiates several signaling processes in HL60 cells that lead to rapidly progressing apoptosis, which is followed by slow necrosis. Two apoptotic processes proceed in parallel, one representing the mitochondrial pathway, the other involving disruption of calcium homeostasis and activation of the endoplasmic reticulum stress-mediated pathway.
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PMID:Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells. 1263 80

T-2 and HT-2 toxins belong to a group of mycotoxins that are widely encountered as natural contaminants known to elicit toxic responses in hematopoietic cells. In the present study, HL-60 cells were used to characterize the apoptotic effects of T-2 and a major metabolite, HT-2, and to examine the mechanisms involved. Apoptotic cells were identified microscopically by chromatin condensation and nuclear fragmentation, by flow cytometric analysis, and by DNA gel electrophoresis. T-2 and HT-2 induced concentration-dependent apoptosis after 24 h in HL-60 cells, starting at concentrations of 3.1 and 6.25 ng/ml respectively. An increased number of apoptotic cells could be observed 4-6 h after exposure to 12.5 ng/ml of toxin. Little cytotoxicity (plasma membrane damage) was observed even after exposure to concentrations of toxins (25-50 ng/ml) inducing apoptosis in 60-100% of the cells. The apoptotic process was almost completely blocked in the presence of the general caspase inhibitor zVAD.fmk. In contrast, no or only minor effects were observed with the more specific caspase inhibitors DEVD.CHO, IETD.fmk, and DEVD.fmk. As judged by Western blotting, the levels of several procaspases (-3, -7, -8, -9, but not -12) were reduced 3-6 h after exposure to toxin. Substantial increases in the presumed active form(s) of caspase-8 and -9 were observed. Furthermore, poly(ADP-ribose) polymerase (PARP) was already markedly cleaved 3 h after toxin treatment, indicative of active caspase-3 and -7. No or only minor changes in Bcl-2, Bcl-XL and Bax levels were observed. BAPTA-AM and ZnCl2 blocked the degradation of procaspases, the fragmentation of PARP, and the induction of apoptosis. In summary, both T-2 and HT-2 induced apoptosis, with T-2 being somewhat more potent than HT-2. The divalent calcium concentration, [Ca2+], appears to be involved in the activation of several caspases, resulting in DNA fragmentation, chromosomal condensation, and nuclear fragmentation.
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PMID:Mechanisms involved in the induction of apoptosis by T-2 and HT-2 toxins in HL-60 human promyelocytic leukemia cells. 1266 87

Peroxynitrite is formed in biological systems when superoxide and nitric oxide are produced at near equimolar ratio. Although not a free radical by chemical nature (as it has no unpaired electron), peroxynitrite is a powerful oxidant exhibiting a wide array of tissue damaging effects ranging from lipid peroxidation, inactivation of enzymes and ion channels via protein oxidation and nitration to inhibition of mitochondrial respiration. Low concentrations of peroxynitrite trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as switch between the two modes of cell death. Peroxynitrite also damages DNA and thus triggers the activation of DNA repair systems. A DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) also becomes activated upon sensing DNA breakage. Activated PARP-1 cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced overactivation of PARP consumes NAD(+) and consequently ATP culminating in cell dysfunction, apoptosis or necrosis. This cellular suicide mechanism has been implicated among others in the pathomechanism of stroke, myocardial ischemia, diabetes and diabetes-associated cardiovascular dysfunction. Here, we review the cytotoxic effects (apoptosis and necrosis) of peroxynitrite focusing on the role of accelerated ADP-ribose turnover. Regulatory mechanisms of peroxynitrite-induced cytotoxicity such as antioxidant status, calcium signalling, NFkappaB activation, protein phosphorylation, cellular adaptation are also discussed.
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PMID:Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. 1267 57

Annexins are widely distributed and have been described in lung as well as in other cells and tissues. Annexin I (ANX AI) is a member of the calcium-dependent phospholipid binding protein family. Besides its anti-inflammatory function, ANX AI has been involved in several mechanisms such as the Erk repression pathway or apoptosis. To investigate the role of ANX AI on apoptosis in broncho-alveolar cells, we have constructed a plasmid containing the ANX AI full length cDNA. Transfected BZR cells displayed a higher level of both forms of ANX AI (37 and 33 kDa) as well as a decrease in cell viability (two-fold versus cells transfected with an empty vector). In order to analyse the endogenous ANX AI processing during stimulus-induced apoptosis, BZR cells were treated with a commonly used inducer, i.e. C2 ceramides. In these conditions, microscopic analysis revealed chromatin condensation in dying cells and the Bcl-2, Bcl-x(L)/Bax mRNA balance was altered. Caspase-3 is one of the key executioners of apoptosis, being responsible for the cleavage of many proteins such as the nuclear enzyme poly(ADP-ribose) polymerase (PARP). We demonstrate that caspase-3 was activated after 4 h treatment in the presence of ceramide leading to the cleavage of PARP. Dose-response experiments revealed that cell morphology and viability modifications following ceramide treatment were accompanied by an increase in endogenous ANX AI processing. Interestingly, in both ceramide and transfection experiments, the ANX AI cleaved form was enhanced whereas pre-treatment with the caspase inhibitor Z-VAD-fmk abolished ANX AI cleavage. In conclusion, this study demonstrates a complex regulatory role of caspase-dependent apoptosis where ANX AI is processed at the N-terminal region which could give susceptibility to apoptosis upon ceramide treatment.
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PMID:Annexin A1 processing is associated with caspase-dependent apoptosis in BZR cells. 1283 39

Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells. In bax-/-bak-/- cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.
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PMID:Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. 1284 83

Ramos-Burkitt lymphoma (Ramos-BL) B cell line is a neoplastic model of normal B cell selection by apoptosis at the germinal center site during maturation of the humoral immune response and can be triggered into apoptosis by cross-linking their surface antigen receptor with antibodies directed against immunoglobulin (Ig)M (anti-IgM) or by treating with the calcium ionophore ionomycin. We have recently demonstrated that anti-IgM and ionomycin trigger significant activation of caspase-3, -7 and -8 and for cleavage of the resident nuclear proteins poly(ADP-ribose) polymerase (PARP) and lamin B1 in Ramos-BL B cells, suggesting that these caspases may be localized to the nucleus as well as to the cytoplasm of Ramos-BL B cells. In order to examine this hypothesis further, we fractionated Ramos-BL B cells into their cytosolic and nuclear components and examined for expression of the endogenous proform and active large subunit of caspase-3; procaspase-3 and its active p17 large subunit were identified in both the cytosolic and nuclear fractions of Ramos-BL B cells. Immunofluorescence staining together with ordinary and confocal microscopy confirmed the observations that procaspase-3 immunoreactivity was clearly identified in the cytoplasm and nucleus while Fas ligand staining was localized to the cell surface and PARP immunoactivity to the nucleus, which were used as controls; procaspase-3 exhibited granular nuclear immunoreactivity whereas PARP displayed diffuse nuclear immunoreactivity; both of which was more intense in the internucleolar regions. Taken together, we now present evidence that procaspases and their active large subunits are found in both the cytoplasm and the nucleus and that procaspases localized not only in the cytoplasm but also in the nucleus are activated following application of apoptotic stimulus in Ramos-BL B cells.
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PMID:Procaspase-3 and its active large subunit localized in both cytoplasm and nucleus are activated following application of apoptotic stimulus in Ramos-Burkitt lymphoma B cells. 1288 46

Numerous pathophysiological disorders involve some element of oxidative stress and bioenergetic deficit. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been used recently as a promising new therapeutic strategy aimed at halting the bioenergetic decline associated with oxidative brain insults and other conditions. PARP-1 uses NAD+ as a substrate and is activated during stressful circumstances, mainly in the nucleus. PARP-1 inhibitors are well known for blocking the excessive consumption of NAD+, thereby preserving energy metabolism. But what is the role of mitochondria in this process? Recent investigations have begun to focus on whether mitochondrial function can also be preserved by PARP-1 inhibitors. This review will present some of the latest mechanistic evidence documenting the potential involvement of PARP-1 inhibitors in protecting mitochondrial function and preventing necrosis, apoptosis and mitochondrial calcium cycling.
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PMID:Recent developments on the role of mitochondria in poly(ADP-ribose) polymerase inhibition. 1452 57


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