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)

In vitro studies indicate that in lymphomas, execution of apoptosis involves activation of effector caspases. To investigate activation of effector caspases in vivo in biopsy specimens of lymphomas, a new assay was developed using antibodies against active caspase 3 and p89, a protein fragment generated by caspase-specific cleavage of poly-ADP ribose polymerase (PARP). Using this assay, it was found that in B-cell lymphomas, levels of active caspase 3/p89-positive cells correlate strongly with morphologically recognizable apoptotic cells. The number of active caspase 3/p89-positive cells was low in follicular lymphomas and usually high in diffuse large cell lymphomas. Highest numbers were found in Burkitt lymphomas and in two biopsies of diffuse large B-cell lymphomas (DLCLs) obtained several days after initiation of therapy. It is concluded that apoptosis in reactive lymphoid tissues and in B-cell lymphomas always involves activation of effector caspase 3 and cleavage of one of the major effector caspase substrates, PARP-1. Moreover, levels of effector caspase activation are constantly low in low-grade follicular lymphomas and vary considerably in DLCL and Burkitt lymphoma.
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PMID:Apoptosis in B-cell lymphomas and reactive lymphoid tissues always involves activation of caspase 3 as determined by a new in situ detection method. 1185 94

We have previously reported that combretastatin-A4 prodrug (CA4P), anantitubulin/antiangiogenic agent isolated from the South African willow tree Combretum caffrum, induced cell death primarily through mitotic catastrophe in a panel of human B-lymphoid tumors. In this study, we investigated the molecular aspects of the mitotic catastrophe and whether or not it shares the same pathways of apoptosis. For this we studied the effect of CA4P on selected markers of apoptosis [caspases 9 and 3, poly(ADP-ribose) polymerase (PARP), bcl-2, and bax] and G2-M protein regulators (p53, MDM2, 14-3-3sigma, GADD45, cdc2, cdc25, chk1, wee1, p21, and cyclin B1). The chronic lymphocytic leukemia cell line WSU-CLL was used for this purpose. Western blot analysis showed that 24 h of CA4P (5 nM) exposure induces caspase 9 activation and PARP cleavage. However, the addition of Z-Val-Ala-Asp-fluoromethylketone (a general caspase inhibitor) or Z-Leu-Glu(OMe)-His-Asp(OMe)-CH2F (a caspase 9 inhibitor) before CA4P treatment did not block cell death. No change in bcl-2 or bax protein expression was observed. Exposure of WSU-CLL cells to 4 and 5 nM CA4P was associated with overproduction of total p53 and no dramatic change in MDM2, 14-3-3sigma, GADD45, the cyclin-dependent kinase cdc2, its inhibitory phosphorylation, the cdc2-inhibitory kinase (wee1), chk1, or cdc25 hyperphosphorylation. The overaccumulation of p21 and cyclin B1 protein was obvious at 24 h. Furthermore, CA4P treatment showed an increase in the expression of a marker of mitosis (mitotic protein monoclonal-2 antibody) and an overaccumulation of the cyclin B in the nucleus. Our findings suggest that CA4P induces mitotic catastrophe and arrest of WSU-CLL cells mostly in the M phase independent of p53 and independent of chk1 and cdc2 phosphorylation pathways. Apoptosis is a secondary mechanism of death in a small proportion of cells through activation of caspase 9 and PARP cleavage. The two mechanisms of cell death, i.e., mitotic catastrophe and apoptosis, are independent of each other in our model.
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PMID:Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly(ADP-ribose) polymerase cleavage. 1217 7

This is the first study reporting the inactivation of a member of the mouse gene family of toxin-related ecto-ADP-ribosyltransferases (ARTs). Transfer of the ADP-ribose moiety from NAD onto extracellular arginine residues on T-cell membrane proteins is mediated by glycosylphosphatidylinositol-linked cell surface ARTs. Exposure of T cells to ecto-NAD blocks T-cell activation and induces T-cell apoptosis. To determine a possible role of ecto-ART2.1 and ART2.2 in these processes, we generated ART2.1/ART2.2 double-knockout mice. ART2-deficient mice were healthy and fertile and showed normal development of lymphoid organs. ART2-deficient T cells showed a dramatically reduced capacity to ADP-ribosylate cell surface proteins, indicating that most if not all ART activity on the T-cell surface can be attributed to the ART2s. Moreover, ART2-deficient T cells were completely resistant to NAD-induced apoptosis and partially resistant to NAD-mediated suppression of proliferation. These results demonstrate that the ART2 ectoenzymes are an essential component in the regulation of T-cell functions by extracellular NAD, e.g., following release of NAD upon lysis of cells in tissue injury and inflammation.
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PMID:Generation and characterization of ecto-ADP-ribosyltransferase ART2.1/ART2.2-deficient mice. 1237 Mar

The fate of cellular mRNAs was analyzed in several cell lines of lymphoid origin, after induction of apoptosis by different mechanisms. Cytoplasmic mRNAs are specifically degraded as part of the early apoptotic response. This degradation is not species restricted and is independent of the cell line, the apoptotic stimulus, the intrinsic half-life of the mRNAs, and the transcriptional status of the gene (constitutive or inducible). mRNA degradation precedes DNA fragmentation and correlates with the appearance of phosphatidylserine in the outer cell membrane. In addition, apoptosis-induced mRNA degradation is an active process that can be dissected from other apoptotic hallmarks (degradation of annexin V, DNA, and poly(ADP-ribose) polymerase [PARP]), which suggests that apoptosis-induced mRNA degradation is controlled by a distinct signaling pathway. Furthermore, mRNA degradation also occurs in vivo, specifically during thymocyte apoptosis. Taken together, these data support the notion that degradation of mRNA is a general early apoptotic event that may become a new apoptotic hallmark.
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PMID:Degradation of cellular mRNA is a general early apoptosis-induced event. 1239 88

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

1. Arvanil (N-arachidonoylvanillamine), a nonpungent capsaicin-anandamide hybrid molecule, has been shown to exert biological activities through VR1/CB1-dependent and -independent pathways. We have found that arvanil induces dose-dependent apoptosis in the lymphoid Jurkat T-cell line, but not in peripheral blood T lymphocytes. Apoptosis was assessed by DNA fragmentation through cell cycle and TUNEL analyses. 2. Arvanil-induced apoptosis was initiated independently of any specific phase of the cell cycle, and it was inhibited by specific caspase-8 and -3 inhibitors and by the activation of protein kinase C. In addition, kinetic analysis by Western blots and fluorimetry showed that arvanil rapidly activates caspase-8, -7 and -3, and induces PARP cleavage. 3. The arvanil-mediated apoptotic response was greatly inhibited in the Jurkat-FADDDN cell line, which constitutively expresses a negative dominant form of the adapter molecule Fas-associated death domain (FADD). This cell line does not undergo apoptosis in response to Fas (CD95) stimulation. 4. Using a cytofluorimetric approach, we have found that arvanil induced the production of reactive oxygen species (ROS) in both Jurkat-FADD+ and Jurkat-FADDDN cell lines. However, ROS accumulation only plays a residual role in arvanil-induced apoptosis. 5. These results demonstrate that arvanil-induced apoptosis is essentially mediated through a mechanism that is typical of type II cells, and implicates the death-inducing signalling complex and the activation of caspase-8. This arvanil-apoptotic activity is TRPV1 and CB-independent, and can be of importance for the development of potential anti-inflammatory and antitumoral drugs.
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PMID:The CB1/VR1 agonist arvanil induces apoptosis through an FADD/caspase-8-dependent pathway. 1453 Feb 15

Nasal application of native cholera toxin (nCT) as a mucosal adjuvant has potential toxicity for the CNS through binding to GM1 gangliosides in the olfactory nerves. Although mutants of cholera toxin (mCTs) have been developed that show mucosal adjuvant activity without toxicity, it still remains unclear whether these mCTs will induce CNS damage. To help overcome these concerns, in this study we created new double mutant CTs (dmCTs) that have two amino acid substitutions in the ADP-ribosyltransferase active center (E112K) and COOH-terminal KDEL (E112K/KDEV or E112K/KDGL). Confocal microscopic analysis showed that intracellular localization of dmCTs differed from that of mCTs and nCTs in intestinal epithelial T84 cells. Furthermore, both dmCTs exhibited very low toxicity in the Y1 cell assay and mouse ileal loop tests. When mucosal adjuvanticity was examined, both dmCTs induced enhanced OVA-specific immune responses in both mucosal and systemic lymphoid tissues. Interestingly, although both dmCT E112K/KDEV and dmCT E112K/KDGL showed high Th2-type and significant Th1-type cytokine responses by OVA-specific CD4+ T cells, dmCT E112K/KDEV exhibited significantly lower Th1-type cytokine responses than did nCT and dmCT E112K/KDGL. These results show that newly developed dmCTs retain strong biological adjuvant activity without CNS toxicity.
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PMID:A second generation of double mutant cholera toxin adjuvants: enhanced immunity without intracellular trafficking. 1692 Sep 41

Bovine viral diarrhea virus (BVDV), a pestivirus of the Flaviviridae family, is an economically important cattle pathogen with a worldwide distribution. Besides the segregation into two distinct species (BVDV1/BVDV2) two different biotypes, a cytopathic (cp) and a noncytopathic (ncp) biotype, are distinguished based on their behavior in epithelial cell cultures. One of the most serious forms of BVDV infection affecting immunocompetent animals of all ages is severe acute BVD (sa BVD) which is caused by highly virulent ncp BVDV2 strains. Previous studies revealed that these highly virulent ncp viruses cause cell death in a lymphoid cell line (BL3) which is not clearly associated with typical apoptotic changes (e.g. PARP cleavage) observed after infection with cp BVDV. To further characterize the underlying molecular mechanisms, we first analyzed the role of the mitochondria and caspases as key mediators of apoptosis. Compared to infection with cp BVDV2, infection with highly virulent ncp BVDV2 resulted in a delayed and less pronounced disruption of the mitochondrial transmembrane potential (DeltaPsi(m)) and a weaker activation of the caspase cascade. In contrast, infection with low virulence ncp BVDV2 showed no significant differences from the uninfected control cells. Since different pro- and anti-apoptotic cellular signaling pathways may become activated upon virus infection, we compared the effect of different BVDV2 strains on cellular signaling pathways in BL3 cells. Stress-mediated p38 MAPK phosphorylation was detected only in cells infected with cp BVDV2. Interestingly, infection with highly virulent ncp BVDV2 was found to influence the phosphoinositide 3-kinase (PI3K)-Akt pathway. This indicates that BL3 cells respond differently to infection with BVDV depending on virulence and biotype.
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PMID:Activation of cell signaling pathways is dependant on the biotype of bovine viral diarrhea viruses type 2. 1737 55

Cholangiocarcinoma is a highly malignant neoplasm of the biliary tree. It has a high rate of mortality, and currently, there is no effective chemoprevention and treatment. This study was designed to investigate the potential effect of omega 3 polyunsaturated fatty acids (omega 3-PUFA) on human cholangiocarcinoma cell growth and to determine their mechanisms of actions. Treatment of three human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two omega 3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12 to 72 h resulted in a dose- and time-dependent inhibition of cell growth; in contrast, arachidonic acid, a omega 6-PUFA, had no significant effect. The omega 3-PUFA effect is due to the induction of apoptosis, given that DHA induced the cleaved form of PARP, caspase-3, and caspase-9. DHA and EPA treatment caused dephosphorylation (and hence, the activation) of glycogen synthase kinase-3beta (GSK-3beta) with a decline of beta-catenin protein. Accordingly, DHA treatment also decreased the beta-catenin-mediated T cell factor/lymphoid enhancer factor (TCF/LEF) reporter activity, and inhibited the expression of c-Met, a beta-catenin-controlled downstream gene implicated in cholangiocarcinogenesis. The GSK-3beta inhibitor, SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF/LEF reporter activity, and restored cell growth, suggesting the involvement of GSK-3beta dephosphorylation in omega 3-PUFA-induced beta-catenin degradation. In parallel, DHA treatment also induced the formation of the beta-catenin/Axin/GSK-3beta binding complex, further leading to beta-catenin degradation. Moreover, DHA inhibited the expression of cyclooxygenase-2 (COX-2) and enhanced the expression of 15-hydroxyprostaglandin dehydrogenase, a physiologic COX-2 antagonist, in human cholangiocarcinoma cells. These findings suggest that omega 3-PUFAs block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/beta-catenin and COX-2 signaling pathways. Thus, utilization of omega 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma.
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PMID:Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. 1819 52

ADP-ribosylation of cell surface proteins in mammalian cells is a post-translational modification by which ecto-ADP-ribosyltransferases (ARTs) transfer ADP-ribose from extracellular NAD to protein targets. The ART2 locus at murine chromosome 7 encompasses the tandem Art2a and Art2b genes that encode the distinct ART2.1 and ART2.2 proteins. Although both ecto-enzymes share 80% sequence identity, ART2.1 activity is uniquely regulated by an allosteric disulfide bond that is reducible in the presence of extracellular thiols, such as cysteine and glutathione, that accumulate in hypoxic and ischemic tissues. Previous studies have characterized the expression of ART2.1 and ART2.2 in murine T lymphocytes but not in other major classes of lymphoid and myeloid leukocytes. Here, we describe the expression of ART2.1 activity in a wide range of freshly isolated or tissue-cultured murine myeloid and lymphoid leukocytes. Spleen-derived macrophages, dendritic cells (DC), and B cells constitutively express ART2.1 as their predominant ART while spleen T cells express both ART2.1 and the thiol-independent ART2.2 isoform. Although bone-marrow-derived macrophages (BMDM) and dendritic cells (BMDC) constitutively express ART2.1 at low levels, it is markedly up-regulated when these cells are stimulated in vitro with IFNbeta or IFNgamma. ART2.1 expression and activity in splenic B cells is modestly up-regulated during incubation in vitro for 24 h, a condition that promotes B cell apoptosis. This increase in ART2.1 is attenuated by IL-4 (a B cell survival factor), but is not affected by IFNbeta/gamma, suggesting a possible induction of ART2.1 as an ancillary response to B cell apoptosis. In contrast, ART2.1 and ART2.2, which are highly expressed in freshly isolated splenic T cells, are markedly down-regulated when purified T cells are incubated in vitro for 12-24 h. Studies with the BW5147 mouse thymocyte line verified basal expression of ART2.1 and ART2.2, as in primary spleen T cells, and demonstrated that both isoforms can be up-regulated when T cells are maintained in the presence of IFNs. Comparison of the surface proteins which are ADP-ribosylated by ART2.1 in the different leukocyte subtypes indicated both shared and cell-specific proteins as ART2.1 substrates. The LFA-1 integrin, a major target for ART2.2 in T cells, is also ADP-ribosylated by the ART2.1 expressed in macrophages. Thus, ART2.1, in contrast to ART2.2, is expressed in a broad range of myeloid and lymphoid leukocytes. The thiol redox-sensitive nature of this ecto-enzyme suggests an involvement in purinergic signaling that occurs in the combined context of inflammation and hypoxia/ischemia.
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PMID:Basal and inducible expression of the thiol-sensitive ART2.1 ecto-ADP-ribosyltransferase in myeloid and lymphoid leukocytes. 1940 75


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