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)

Sindbis virus (SV) induces apoptosis in many vertebrate cells, but the mechanism is unknown. To gain insight into this mechanism, the nature and time course of intracellular changes related to programmed cell death were studied in SV-infected mouse neuroblastoma cells. New virus production began at 5 h after infection and reach a peak at 12 h. Hoechst 33342 staining of DNA analyzed by flow cytometry demonstrated changes in chromatin beginning 6 h after infection. These chromatin changes were cell cycle dependent, affecting cells in G0/G1 but not S phase. Apoptosis was not dependent on increases in intracellular Ca2+ and occurred more rapidly in the absence of extracellular Ca2+. Nuclear changes were accompanied by activation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), resulting in increased consumption of NAD which was apparent by 10 h after infection. SV-induced apoptosis also involved the proteolytic cleavage of PARP. This cleavage was detectable at 16 h after infection approximately the same time that DNA fragmentation was apparent by agarose gel electrophoresis. We conclude that SV-induced apoptosis of neuroblastoma cells is dependent on viral replication, is not dependent on a rise in intracellular Ca2+, and is accompanied by activation of PARP and of a protease that cleaves PARP.
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PMID:Temporal changes in chromatin, intracellular calcium, and poly(ADP-ribose) polymerase during Sindbis virus-induced apoptosis of neuroblastoma cells. 864 45

The new and growing family of interleukin-1beta-converting enzyme (ICE) cysteine proteases are now recognised to be major effectors of cellular death by apoptosis. Like other members of this family, the CPP32/Yama proform is activated by processing to its active heterodimeric enzyme or apopain when it likely contributes to the process of apoptosis by cleaving poly(ADP-ribose) polymerase (PARP) and thereby inhibiting much of its DNA repair activity. Apoptosis plays a fundamental role in the regulation of the immune system where it is involved in the selection of both T and B lymphocytes bearing antigen receptor (AgR) for non-self. Cells of the Ramos Epstein-Barr virus (EBV)-genome-negative Burkitt lymphoma (BL) B cell line (Ramos-BL) can be triggered into growth arrest and apoptosis by treating with the calcium ionophore ionomycin or by crosslinking their surface AgR with antibodies directed against immunoglobulin (Ig)M (anti-IgM). Ionomycin- and AgR-triggered growth arrest and apoptosis are arrested by signals transduced through the surface CD40 of Ramos-BL B cells. Both ionomycin and anti-IgM trigger activation of CPP32 and cleavage of PARP prior to the onset of apoptosis; this process is abrogated by treatment with anti-CD40 and is independent of Bcl-2 expression. A tripeptide inhibitor of ICE family cysteine proteases, Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) inhibits ionomycin- and AgR-triggered CPP32 activation, PARP cleavage and apoptosis, but not growth arrest, in Ramos-BL B cells. Thus, in this report we demonstrate that in a physiological system, activation of endogenous members of the ICE family, including CPP32, and cleavage of the death substrate PARP act as major effectors of apoptotic death.
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PMID:Ligation of CD40 rescues Ramos-Burkitt lymphoma B cells from calcium ionophore- and antigen receptor-triggered apoptosis by inhibiting activation of the cysteine protease CPP32/Yama and cleavage of its substrate PARP. 864 64

1. We investigated the effect of Clostridium botulinum C3 ADP-ribosyltransferase upon beta-hexosaminidase release induced by various stimuli from streptolysin-O (0.5-1 U/ml)-permeabilized rat basophilic leukemia (RBL-2H3) cells. 2. The C3 transferase inhibited beta-hexosaminidase release induced by Ca2+ or by guanosine-5'-(3-thiotriphosphate) (GTP gamma S) plus Ca2+. 3. The C3 transferase also inhibited beta-hexosaminidase release induced by stimulating high affinity IgE and m3 muscarinic acetylcholine receptors. 4. The substrate for the C3 transferase was present in cytosol of RBL-2H3 cells, indicating the presence of rho p21. About 60% of the total cellular substrate protein remained within the cells permeabilized by 1 U/ml of streptolysin-O. 5. The protein rho p21 appears to be regulated by several pathways and it may function as an integration point for exocytosis.
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PMID:Regulation of exocytosis by the small GTP-binding protein Rho in rat basophilic leukemia (RBL-2H3) cells. 869 Feb 50

Stimulation of monoblastic U937 cells with transforming growth factor beta 1 and 1,25-(OH)2 vitamin D3 (TGF-beta 1/D3) upregulates urokinase receptor (uPAR) and confers urokinase-dependent adhesiveness to the cells for serum- or vitronectin-coated surfaces. Recent studies show that uPAR itself is a high-affinity adhesion receptor for vitronectin and that urokinase (uPA) is an activator of this adhesive function. In the course of exploring possible G-protein involvement in this adhesion it was observed that TGF-beta 1/D3-primed U937 cells became adhesive to vitronectin in an uPAR-dependent manner when exposed to pertussis toxin (PTX). The adherent response is concentration- and time-dependent, and was not due to the ADP-ribosyltransferase activity of the toxin because the purified B-subunit of PTX was equally effective. Although promoting adhesion to serum- or vitronectin-coated surfaces, PTX blocked spontaneous cell adhesion to fibrinogen, an endogenous ligand for the Mac-1 receptor (CD11b/CD18). Flow cytometry study showed that expression of the alpha-subunit of Mac-1 (CD11b) on primed cells was increased by nearly threefold. Monoclonal antibody to CD11b abolished the PTX-induced cell adhesion and the binding of the primed cells to PTX-coated plates. Activation of Mac-1 receptor by its endogenous ligand fibrinogen induced cell adherent response similar to PTX. PTX, but not uPA, triggered a rapid rise in [Ca2+]i in primed U937 cells, and PTX-induced adhesion was significantly attenuated by 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy-methyl ester (BAPTA/AM), a selective membrane-permeant [Ca2+]i chelator. PTX-induced cell adhesion was also prevented by antibodies to uPAR and by conditioned medium containing soluble uPAR. Together these data indicate that PTX B-subunit may bind to Mac-1 integrin, which leads to a rapid rise in [Ca2+]i and subsequent activation of uPAR for adherence to vitronectin, suggesting a functional link between Mac-1 and activation of uPAR important to cellular trafficking and host defence in response to Bordetella pertussis infection.
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PMID:Mechanisms of pertussis toxin-induced myelomonocytic cell adhesion: role of Mac-1(CD11b/CD18) and urokinase receptor (CD87). 870 56

Exocytosis is a common phenomenon in neutrophil functions. We earlier reported the co-localization of arginine-specific ADP-ribosyltransferase [EC 2.4.2.31] and its target protein p33 (mim-1 protein) in cytoplasmic granules in chicken polymorphonuclear leukocytes (so-called heterophils) [Mishima, K., Terashima, M., Obara, S., Yamada, K., Imai, K., and Shimoyama, M. (1991) J. Biochem. 110, 388-394]. In the present study, we obtained evidence that the transferase and p33 were released into the extracellular space by the stimulus of calcium ionophore A23187 or serum-opsonized zymosan, but scarcely by phorbol myristate acetate (PMA) or N-formyl-Met-Leu-Phe (fMLP), thereby indicating the co-localization of the transferase and p33 in the azurophilic granules, and not in specific granules. [32P]ADP-ribosylation of p33 occurred in the extracellular space, induced by the stimulus of A23187 or opsonized zymosan in the presence of [32P]NAD. Our findings are interpreted to mean that heterophil transferase and p33 may be involved in neutrophil functions during processes of inflammation.
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PMID:Exocytosis of arginine-specific ADP-ribosyltransferase and p33 induced by A23187 and calcium or serum-opsonized zymosan in chicken polymorphonuclear leukocytes. 901 Jul 72

Weanling male F344 rats were fed either a semi-purified diet low in methionine and lacking in choline and folic acid (folate/methyl deficient) or a supplemented control diet for periods of 2, 5, 7 days, 3 weeks, and 9 weeks. Two days after initiating the folate/methyl deficient diet in weanling F344 rats, the incidence of apoptotic bodies, identified by in situ end-labeling of 3'-OH DNA strand breaks, was significantly increased in liver sections from the deficient rats. Apoptotic cell death was confirmed biochemically by an increase in nuclear Ca2+/Mg2+-dependent endonuclease activity that paralleled the increase in apoptotic bodies over the 9-week feeding period. There was no morphologic evidence of necrotic foci or necrosis-associated inflammatory response over the 9-week period. Confirming that cell turnover is chronically elevated in this model, the increase in apoptotic rate was accompanied by a sustained increase in the mitotic index (MI). The DNA repair-associated enzyme, poly(ADPribose) polymerase (PARP), was similarly elevated and was associated with significant decreases in the substrate for ADPribose polymer synthesis, nicotinamide adenine dinucleotide (NAD). Because folate metabolites are essential for de novo purine and thymidine biosynthesis, prolonged deficiency in folic acid can induce an imbalance in the deoxynucleotide precursors for DNA replication/repair and negatively affect the fidelity of DNA synthesis. Using an HPLC method, hepatic deoxyuridine triphosphate (dUTP) levels were increased at 3 and 9 weeks after initiation of the deficient diet and levels of thymidine triphosphate (dTTP) were reduced. An increase in dUTP/ dTTP ratio is consistent with a block in folate-dependent de novo thymidylate biosynthesis and may predispose to uracil misincorporation and DNA repair-related DNA strand breaks.
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PMID:Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. 905 20

Clostridium difficile toxin B that inactivates Rho subfamily proteins by glucosylation, inhibited dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and phorbol 12-myristate 13-acetate (PMA)-induced mast cell activation by 80 to 90% in a concentration- and time dependent manner with a delay of about 30 min. Activation of mast cells by compound 48/80 and calcium ionophore A23187 was maximally inhibited by about 50%. Inhibition by toxin B was observed with suspended, attached and permeabilised mast cells. C3 ADP-ribosyltransferase, which selectively inactivates RhoA,B,C subtype proteins inhibited antigen, compound 48/80, PMA, A23187 and GTP[S]-induced degranulation of permeabilised mast cells C3-induced inhibition of stimulated histamine release was smaller than that observed with toxin B and both inhibitory effects were not additive. These findings suggest the involvement of Rho subtype GTPases and additionally, of other members of the Rho subfamily GTPases in activation of rat peritoneal mast cells.
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PMID:Effects of Clostridium difficile toxin B on activation of rat peritoneal mast cells. 908 62

To investigate the involvement of different proteases in the execution step of apoptosis and to determine their intracellular location, isolated rat thymocyte nuclei were incubated either in the presence of Ca2+ and Mg2+ or with cytosolic extract from Jurkat T lymphocytes treated with anti-Fas (APO-1, CD-95) antibody. Inhibitors of caspases, VADcmk and DEVDcho, were not effective in hindering Ca2+-induced apoptotic changes in isolated nuclei, but did prevent similar changes in nuclei treated with the cytosolic extract from apoptotic Jurkat cells. In contrast, the inhibitor of the Ca2+-regulated, nuclear scaffold-associated serine protease, AAPFcmk, was able to inhibit lamin B1 breakdown, as well as chromatin cleavage in nuclei incubated in the presence of Ca2+ and Mg2+, but only partially prevented the same changes induced with cytosolic extract. Our findings provide evidence for the involvement of at least two proteases in lamin cleavage. One belongs to the caspase family and to cleave lamins this enzyme must be translocated from the cytoplasm into the nucleus. The second protease has a nuclear location and is activated by Ca2+. Finally, neither of these two lamin-cleaving proteases is responsible for the cleavage of another nuclear target protein, poly(ADP-ribose)polymerase (PARP), during apoptosis.
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PMID:Two different proteases are involved in the proteolysis of lamin during apoptosis. 914 3

Arginine-specific ADP-ribosyltransferase present in granules of chicken polymorphonuclear leukocytes (so-called heterophils) is released into the extracellular space by stimulus of calcium ionophore A23187 or opsonized zymosan [Terashima et al. (1996) J. Biochem. 120, 1209-1215]. In the present work, we examined extracellular targets of the released transferase and identified tuftsin, a phagocytosis-stimulating tetrapeptide derived from leukokinin, as a preferential substrate of the enzyme in chicken plasma. Specific binding of FITC-tuftsin to murine peritoneal macrophages, observed under a fluorescent microscope, was impaired by ADP-ribosylation of the labelled peptide. Phagocytic assay analyzed by flow cytometry revealed that ADP-ribosylation of tuftsin decreased its phagocytosis-stimulating activity towards the macrophages. Thus, the ADP-ribosylation of tuftsin apparently decreases its biological activity and ADP-ribosylation may possibly be involved in inflammatory processes through alterations in tuftsin activity.
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PMID:ADP-ribosylation of tuftsin suppresses its receptor-binding capacity and phagocytosis-stimulating activity to murine peritoneal macrophages. 925 25

Recent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1beta converting enzyme (ICE)/caspase family and a Ca2+-activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolytic cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) and increased caspase protease activity, and cell-permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1 . Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.
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PMID:Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes. 934 52


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