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)

1. An ADP-ribosyltransferase activity which appears to be capable of activating adenylyl cyclase was identified in a plasma membrane fraction from rabbit corpora lutea and partially characterized by comparing the properties of the luteal transferase with those of cholera toxin. 2. Incubation of luteal membranes in the presence of GTP and varying concentrations of NAD resulted in concentration-dependent increases in adenylyl cyclase activity. 3. Stimulation of adenylyl cyclase by NAD and cholera toxin plus NAD was observed in the presence of GTP but not in the presence of guanosine-5'-O-(2-thiodiphosphate) or guanyl-5'-yl imidodiphosphate. 4. NAD or cholera toxin plus NAD reduced the Kact values for luteinizing hormone to activate adenylyl cyclase 3- to 3.5-fold. 5. NAD or cholera toxin plus NAD increased the extent to which cholate extracts from luteal membranes were able to reconstitute adenylyl cyclase activity in S49 cyc- mouse lymphoma membranes. 6. It was necessary to add ADP-ribose and arginine to the incubation mixture in order to demonstrate cholera toxin-specific ADP-ribosylation of a protein corresponding to the alpha subunit of the stimulatory guanine nucleotide-binding regulatory component (alpha Gs). 7. Treatment of luteal membranes with NAD prior to incubation in the presence of [32P]NAD plus cholera toxin resulted in reduced labeling of alpha Gs. 8. Endogenous ADP-ribosylation of alpha Gs was enhanced by Mg but was not altered by guanine nucleotide, NaF or luteinizing hormone and was inhibited by cAMP. 9. Incubation of luteal membranes in the presence of [32P]ADP-ribose in the absence and presence of cholera toxin did not result in the labeling of any membrane proteins.
...
PMID:Evidence for a rabbit luteal ADP-ribosyltransferase activity which appears to be capable of activating adenylyl cyclase. 164 18

The culture medium of certain strains of Clostridium botulinum type C contains two separable ADP-ribosyltransferases. Besides the ADP-ribosylation of actin due to botulinum C2 I toxin, a second microbial enzyme causes the mono-ADP-ribosylation of a eukaryotic protein with a molecular mass of about 20 kDa found in platelets, neuroblastoma X glioma hybrid cells, S49 lymphoma cells, chick embryo fibroblasts and sperm. The eukaryotic substrate is inactivated by heating and trypsin treatment. In contrast, the novel ADP-ribosyltransferase, which can be separated by DEAE-Sephadex chromatography, is largely resistant in the short term to trypsin digestion.
...
PMID:Clostridium botulinum type C produces a novel ADP-ribosyltransferase distinct from botulinum C2 toxin. 310 Mar 33

Post-irradiation changes in DNA synthesis and ADP-ribosyltransferase (ADPRT) activity in L5178YS and L5178YR, radiation sensitive and resistant murine lymphoma cells are described. DNA synthesis was inhibited to a greater extent in L5178YS than in L5178YR cells. The stimulation of ADPRT activity by irradiation was not significantly different between these two cell lines. These observations contribute to other evidence which has failed to confirm a general association of ADP-ribosylation with the DNA synthesis inhibition response. The contrast between the response of L5178Y cells and the corresponding behaviour of ataxia telangiectasia cells and normal human cells indicate that entirely different mechanisms are involved in determining the differences in radiosensitivity in these two systems.
...
PMID:Post-irradiation inhibition of scheduled DNA synthesis and stimulation of ADP-ribosylation in sensitive and resistant L5178Y murine lymphoma cells. 631 90

Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator of the growth of normal and malignant hematopoietic cells and synergizes with other factors such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The action of G-CSF is mediated through a specific membrane receptor, however it is not clear if all of the effects of G-CSF are direct or indirect. As a step towards addressing this problem, a recombinant diphtheria toxin (DT)-related human G-CSF fusion protein has been constructed and purified from E. coli. The 70,000 dalton chimeric protein has immunologic determinants characteristic of both DT and G-CSF. At high concentrations, DAB486-G-CSF is cytotoxic towards G-CSF-dependent OCI/AML1 cells, but not factor independent OCI/AML3 cells; colony formation by G-CSF-responsive leukemic blasts from a patient with acute myeloblastic leukemia (AML) was also inhibited. The G-CSF fusion toxin displayed ADP-ribosyltransferase activity in a cell-free system. Genetic conjugation of G-CSF to an enzymatically inactive DT mutant, CRM197, resulted in a 200-fold reduction in the ability of G-CSF to stimulate normal bone marrow colony formation. These results suggest that fusion of G-CSF to DT sequences interferes with some of the activity but not the specificity of the ligand binding domain of the molecule. Nevertheless, DAB486-G-CSF may be included with the increasing number of other toxin-hormone fusion proteins whose toxicity is directed towards specific receptor-bearing cells, and may represent a novel approach towards the study and treatment of leukemia.
Leuk Lymphoma 1993 Oct
PMID:Cytotoxicity of a recombinant diphtheria toxin-granulocyte colony-stimulating factor fusion protein on human leukemic blast cells. 750 48

By catalyzing posttranslational modifications of nuclear proteins, poly(ADP-ribose) polymerase (PARP) controls their functions and therefore constitutes an enzyme of crucial importance in tumor development. In this study, we have investigated the action of 6(5H)-phenanthridinone, an isoquinoline derivative and one of the most potent PARP inhibitors described so far, on RDM4 murine lymphoma cells in culture. We also examined whether this compound could act synergistically with an antineoplastic drug in tumor-cell destruction. Our results demonstrate that a marked inhibition of PARP activity can be obtained in whole cells after a short incubation, and that this compound, when associated with an alkylating agent, dichloro-2,2' N-methyldiethylamine (chloromethine), leads to a marked drop in the RDM4 proliferation, indicative of a synergy between the two compounds.
...
PMID:Effect of 6(5H)-phenanthridinone, an inhibitor of poly(ADP-ribose) polymerase, on cultured tumor cells. 770 25

Mono-ADP-ribosylation is a post-translational modification of proteins in which the ADP-ribose moiety of NAD is transferred to proteins and is responsible for the toxicity of some bacterial toxins (e.g. cholera toxin and pertussis toxin). NAD:arginine ADP-ribosyltransferases cloned from human and rabbit skeletal muscle and from mouse lymphoma (Yac-1) cells are glycosylphosphatidylinositol-anchored and have similar enzymatic and physical properties; transferases cloned from chicken heterophils and red cells have signal peptides and may be secreted. We report here the cloning and characterization of an ADP-ribosyltransferase (Yac-2), also from Yac-1 lymphoma cells, that differs in properties from the previously identified eukaryotic transferases. The nucleotide and deduced amino acid sequences of the Yac-1 and Yac-2 transferases are 58 and 33% identical, respectively. The Yac-2 protein is membrane-bound but, unlike the Yac-1 enzyme, appears not to be glycosylphosphatidylinositol-anchored. The Yac-1 and Yac-2 enzymes, expressed as glutathione S-transferase fusion proteins in Escherichia coli, were used to compare their ADP-ribosyltransferase and NAD glycohydrolase activities. Using agmatine as the ADP-ribose acceptor, the Yac-1 enzyme was predominantly an ADP-ribosyltransferase, whereas the transferase and NAD glycohydrolase activities of the recombinant Yac-2 protein were equivalent. The deduced amino acid sequence of the Yac-2 transferase contained consensus regions common to several bacterial toxin and mammalian transferases and NAD glycohydrolases, consistent with the hypothesis that there is a common mechanism of NAD binding and catalysis among ADP-ribosyltransferases.
...
PMID:Cloning and characterization of a novel membrane-associated lymphocyte NAD:arginine ADP-ribosyltransferase. 870 12

Transfection of NMU (rat mammary adenocarcinoma) cells with NAD:arginine ADP-ribosyltransferase cDNAs from Yac-1 murine lymphoma cells or rabbit muscle increased NAD glycohydrolase and ADP-ribosyltransferase activities. The ADP-ribosyltransferase activity was released from transformed NMU cells by phosphatidylinositol-specific phospholipase C (PI-PLC) and hence glycosylphosphatidylinositol (GPI)-anchored, whereas the NAD glycohydrolase (NADase) activity remained cell-associated. By gel permeation chromatography, the size of the PI-PLC-released transferase was approximately 40 kDa and that of the detergent-solubilized NADase was approximately 100 kDa. Using polyclonal antibodies against rabbit muscle transferase on Western blots, approximately 18- and approximately 30-kDa band were visualized among proteins from the NADase fractions and 38-40-kDa bands with protein from the transferase fractions. Incubation of blots with [32P]NAD led to the incorporation of radioactivity into the immunoreactive transferase bands of 38 kDa and the immunoreactive NADase band of approximately 18 kDa. These data suggest that proteolysis of ADP-ribosyltransferase synthesized in transformed NMU cells might result in the formation of aggregates of an 18-kDa NAD glycohydrolase. A fusion protein with glutathione S-transferase linked to the amino terminus of Yac-1 transferase, from which the amino-terminal 121 amino acids had been deleted (GST-Yac-1-delta121), exhibited NADase, but not transferase, activity. The size of the recombinant fusion protein was similar to that of the proteolytic fragment seen in NMU cells transformed with transferase cDNA. These results are compatible with the conclusion that the NAD glycohydrolase activity was generated in NMU cells by proteolysis of ADP-ribosyltransferase, with release of a carboxyl-terminal fragment that possesses glycohydrolase but not transferase activity, i.e. the carboxyl-terminal portion of the transferase can exist as a catalytically active NADase.
...
PMID:An 18-kDa domain of a glycosylphosphatidylinositol-linked NAD:arginine ADP-ribosyltransferase possesses NAD glycohydrolase activity. 908 12

The ability of 6(5H)-phenanthridinone (Phen), a new potent poly(ADP-ribose)polymerase (PARP) inhibitor, to potentiate the effect of ionizing radiation on tumour cells was evaluated. RDM4 murine lymphoma cells were irradiated using a 60Co panoramic source and then examined for their growth, cell cycle distribution and apoptosis. Phen (100 microM) was found to inhibit more than 90% of the PARP activity in control and irradiated cells. Cell proliferation was assessed using Alamar Blue, a new fluorometric assay. Phen was found to sharply increase the radiation-induced inhibition of cell proliferation. Indeed, at 2.5 Gy the relative cell number of Phen-treated cells was 60% below control levels. At the same radiation dose, the G2M arrest was also significantly reinforced by the addition of Phen. Furthermore, this PARP inhibitor was shown to significantly increase the amount of DNA fragmentation as revealed by the DNA migration pattern in agarose gel electrophoresis. Comparable results were obtained with 3-aminobenzamide, another PARP inhibitor, but at concentrations 200-fold higher. Taken together, these results indicate the potential interest of Phen as a valuable pharmacological probe for investigating the role of PARP in cellular responses to radiation. They also suggest a possible use of Phen as an adjuvant in radiotherapy.
...
PMID:Effect of 6(5H)-phenanthridinone, a poly (ADP-ribose)polymerase inhibitor, and ionizing radiation on the growth of cultured lymphoma cells. 941 91

Cytochrome c release from mitochondria to and subsequent accumulation in the cytosol has been considered a prerequisite for apoptosis. In this study, we present evidence for apoptosis induction without accumulation of cytochrome c in the cytosol. U937 lymphoma cells treated with staurosprine released cytochrome c from mitochondria to cytosol prior to PARP cleavage and DNA fragmentation. However, U937 cells treated with BMD188 (a hydroxamic acid and a potent apoptosis inducer) did not demonstrate any cytochrome c accumulation in the cytosol during apoptosis induction. This different pattern of cytochrome c alterations was also observed with these two inducers on leukemic HL60 cells and epithelial PC3 cells. Furthermore, when PC3 cells were treated with a panel of apoptosis-inducing agents, it was found that camptothecin, bleomycin, VP16 and TNF-alpha induced varying amounts of cytosolic accumulation of cytochrome c either prior to or concurrent with PARP cleavage while vinblastine and BHPP did not. Taken together, the present results suggest that cytochrome c accumulation in the cytosol during apoptosis is a cell type- and inducer-dependent phenomenon.
...
PMID:Apoptosis in the absence of cytochrome c accumulation in the cytosol. 944 3

Apoptosis induced by numerous cancer chemotherapeutic and other toxic agents has been shown to proceed through a cascade of proteases, now termed caspases, culminating in cleavage of a set of proteins. The ability of photodynamic treatment (PDT) with the phthalocyanine Pc 4 to activate cellular caspases has been assessed during the rapid apoptosis in murine lymphoma L5178Y-R cells. Cells were exposed to combinations of Pc 4 and activating red light that result in > or =90% cell death, as judged by a clonogenic assay. The rate of entry of cells into apoptosis was dose dependent. For 0.5 microM Pc 4 and either 2.1 or 3 kJ/m2, which kill 90 or 99.9% of the cells, oligonucleosomal fragmentation was visible on agarose gels as early as 60 or 30 min after PDT, respectively. To assess caspase activation, cells were harvested at various times after PDT, and cell proteins were subjected to electrophoresis and Western blot analysis, using an antibody to poly(ADP-ribose) polymerase (PARP). The cleavage of the normally Mr 116,000 PARP into fragments of Mr approximately 90,000 was observed at approximately the same time as the earliest DNA fragmentation. An antibody to the polymer, poly(ADP-ribose), did not recognize the Mr approximately 90,000 PARP cleavage products, in contrast to the parent enzyme. This analysis also revealed that levels of a poly(ADP-ribosylated) Mr 100,000 protein, tentatively identified as topoisomerase I, were maintained in cells after PARP was fully cleaved. Caspase-3 (and/or caspase-7) activity, as measured in cell lysates with the fluorogenic substrate DEVD-AMC, was elevated almost immediately after PDT. The cell-permeable, irreversible caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoro-methylketone, inhibited PDT-induced apoptosis and PARP cleavage, whereas the inactive peptide analogue, benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone, was without effect. The results indicate that PDT-induced apoptosis is mediated by activation of caspase-3 and/or other similar caspases.
...
PMID:Protease activation and cleavage of poly(ADP-ribose) polymerase: an integral part of apoptosis in response to photodynamic treatment. 950 Apr 54


1 2 3 4 5 6 7 8 9 10 Next >>

---