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)

Treatment of the Daudi Burkitt lymphoma-derived cell line with human interferon alpha, which inhibits cell proliferation in this system, induces differentiation of these B-lymphoid cells into cells with a plasmacytoid phenotype. This differentiation, quantified by the appearance of surface antigens characteristic of mature plasma cells, is impaired by addition to the culture medium of the ADP-ribosyltransferase (ADPRT; EC 2.4.2.30) inhibitors 3-methoxybenzamide or 3-aminobenzamide. These agents also protect the cells against the inhibition of proliferation induced by low doses of interferon alpha. In contrast, the large inhibition of thymidine incorporation into DNA caused by interferon treatment is not affected by the ADPRT inhibitors. The phorbol ester phorbol 12-tetradecanoate 13-acetate induces the same plasma cell surface antigens that are induced by interferon treatment, and this effect is also impaired by the ADPRT inhibitors. These results suggest that interferons and phorbol esters share a mechanism of action that requires ADPRT activity. Protection of the cells against the antiproliferative effect of interferons by the ADPRT inhibitors suggests that growth inhibition may be a consequence of cell differentiation. In contrast, the inhibition of thymidine incorporation alone is not sufficient for the cessation of cell proliferation and is not a true reflection of the rate of DNA synthesis.
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PMID:Induction of B-cell differentiation antigens in interferon- or phorbol ester-treated Daudi cells is impaired by inhibitors of ADP-ribosyltransferase. 311 50

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

Cells of the Epstein-Barr virus genome-negative Ramos-Burkitt lymphoma (Ramos-BL) B cell line can be rescued from antigen receptor (AgR)-triggered growth inhibition and apoptosis by signals transduced through their surface CD40. This study investigates whether phosphatidylinositol 3-kinase (PI3-kinase), which has been reported to be intimately involved in the regulation of normal and neoplastic cell growth, plays a role in CD40-promoted Ramos-BL B cell survival and uses the selective and reversible PI3-kinase inhibitor, LY294002 (LY). LY-mediated inhibition of PI3-kinase activity triggers growth inhibition and leads to the processing of caspase-3, caspase-3-like activity, cleavage of the death substrate poly(ADP-ribose) polymerase (PARP), and apoptosis from the G1 phase of cell cycle. These data indicate that constitutive PI3-kinase activity is critical for Ramos-BL B cell progression through the cell cycle such that if this PI3-kinase-dependent pathway(s) is inhibited, the cells default to apoptosis. Signals transduced through CD40 abrogate LY-triggered caspase-3-like activity and PARP cleavage but fail to inhibit LY-triggered growth inhibition, processing of caspase-3, and apoptosis. Likewise, in the presence of LY, signals transduced through CD40 abrogate AgR-triggered caspase-3-like activity and PARP cleavage but fail to inhibit AgR-triggered growth inhibition, caspase-3 processing, and apoptosis. The LY-mediated induction of growth inhibition and apoptosis occurs in the presence of the CD40-induced anti-apoptotic protein Bcl-XL. Taken together these data indicate that the CD40 of Ramos BL B cells is linked to PI3-kinase-independent and -dependent routes of survival: CD40-mediated inhibition of AgR-triggered caspase-3-like activity, PARP cleavage, and CD40-triggered Bcl-XL expression are PI3-kinase-independent, whereas PI3-kinase is critical for CD40-mediated rescue of this cellular population from AgR-triggered growth inhibition, caspase-3 processing, and apoptosis.
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PMID:LY294002-mediated inhibition of phosphatidylinositol 3-kinase activity triggers growth inhibition and apoptosis in CD40-triggered Ramos-Burkitt lymphoma B cells. 973 95

Divalent cations, including Zinc and Manganese ions, are important modulators of cell activation. We investigated the ability of these two divalent cations to modulate apoptosis in human Burkitt lymphoma B cells line (Ramos). We found that Zinc (from 10 to 50 microM) inhibited Manganese-induced caspase-3 activation and apoptosis of Ramos cells. Higher concentration of Zinc (50 to 100 microM) did not prevent Manganese-mediated apoptosis but rather increased cell death among Ramos cells. This Zinc-mediated cell death was associated with apoptotic features such as cell shrinkage, the presence of phosphatidylserine residues on the outer leaflet of the cells, chromatin condensation, DNA fragmentation and decrease of mitochondrial transmembrane potential. Zinc-mediated apoptosis was associated with caspase-9 and caspase-3 activation as revealed by the appearance of active p35 fragment of caspase-9 and p19 and p17 of caspase-3 as well as in vivo cleavage of PARP and of a cell-permeable fluorogenic caspase-3 substrate (Phiphilux-G(1)D(2)). Both Zinc-mediated apoptosis and caspase-3 activation were prevented by the cell-permeable, broad-spectrum inhibitor of caspases (zVAD-fmk) or overexpression of bcl-2. In addition, we show that Zinc-induced loss of transmembrane mitochondrial potential is a caspase-independent event, since it is not modified by the presence of zVAD-fmk, which is inhibited by overexpression of bcl-2. These results indicate that depending on its concentration, Zinc can exert opposite effects on caspase-3 activation and apoptosis in human B lymphoma cells: concentrations below 50 microM inhibit caspase-3 activation and apoptosis whereas higher concentrations of Zinc activate a death pathway associated with apoptotic-like features and caspase-3 activation.
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PMID:Zinc-mediated regulation of caspases activity: dose-dependent inhibition or activation of caspase-3 in the human Burkitt lymphoma B cells (Ramos). 1131 17

Death receptor-mediated apoptosis is involved in the regulation of immune responses and in the maintenance of immunological tolerance. FLICE-inhibitory proteins (FLIPs) are important modulators of death receptor-mediated apoptosis. To date, the FLIP family encompasses multiple members, of which some are reported to be antiapoptotic and others pro-apoptotic. This led us to investigate the activity of several FLIP proteins in vitro. Concomitant with the cloning of various FLIP isoforms, a new and unexpected member of the FLIP family, denoted FLIPR, was isolated from the human Burkitt lymphoma B-cell line Raji. During the characterization of FLIPR, the genomic sequence of human FLIP was found in the NCBI GenBank. This enabled us to present the complete exon-intron constellation of the human FLIP gene and the generation of all known human FLIP isoforms by alternative splicing. We show that the human FLIP gene with a size of approximately 48 kb, consists of at least 14 exons and can give rise to 11 distinct isoforms by alternative splicing. When studying the activity of some of these isoforms, including FLIPR, they all efficiently inhibited Fas-mediated apoptosis in A20 B lymphoma cells by impeding caspase-8, -3 and -7 activity as well as poly(ADP-ribose) polymerase (PARP) cleavage.
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PMID:Characterization of the human FLICE-inhibitory protein locus and comparison of the anti-apoptotic activity of four different flip isoforms. 1143 65

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

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
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PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 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

We demonstrate here that selective activation of endogenous members of the caspase family and cleavage of substrates responsible for the maintenance of nuclear functional and structural integrity are major effectors of antigen receptor (AgR)- and ionomycin-triggered apoptosis in Ramos-Burkitt lymphoma (Ramos-BL) B cells. Ramos-BL B cells express significant proenzyme levels of caspase-2, -3, -7 and -8, low levels of caspase-6 and are caspase-1-negative. However, while anti-IgM and ionomycin trigger for significant activation of caspase-3, -7 and -8 at 12-16 h and at 4 h post-stimulation respectively, both anti-IgM and ionomycin fail to activate caspase-2 indicating that AgR- and ionomycin-triggered Ramos-BL B cell apoptosis is mediated by the selective activation of, at least, caspase-3, -7 and -8. Anti-IgM triggers for cleavage of the resident nuclear proteins poly(ADP-ribose) polymerase (PARP) at 8 h, lamins B1 and B2 from 12 to 16 h; likewise, ionomycin triggers for degradation of PARP at 2 h, lamins B1 and B2 at 4 h. Signal transduction through CD40 rescues Ramos-BL B cells from AgR- and ionomycin-triggered apoptosis at a very early stage of the apoptotic process by inhibiting both the early cleavage of PARP as well as the activation of caspase-3, -7 and -8 and cleavage of lamin B1; CD40-mediated rescue occurs upstream of CD40-induced expression of Bcl-2 and increased expression of Bcl-xL. In such cellular populations subject to regulation through apoptosis, dysregulation of the apoptotic mechanisms can have devastating consequences by contributing to the pathogenesis of malignancy as well as to lymphoproliferative and autoantibody disorders. An understanding of the role played by caspases in the execution of apoptosis may provide insight into the pathogenesis of these disease states and thereby provide targets for novel therapeutic strategy.
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PMID:Temporal ordering of caspase activation and substrate cleavage during antigen receptor-triggered apoptosis in Ramos-Burkitt lymphoma B cells. 1285 74

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


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