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)

Ciliary neurotrophic factor (CNTF) is a multifunctional cytokine that can regulate the survival and differentiation of many types of developing and adult neurons. This study describes the genetic construction, expression, purification and properties of a diphtheria toxin-related CNTF fusion gene in which the native receptor binding domain of diphtheria toxin was genetically replaced with a synthetic gene encoding human CNTF. The fusion protein expressed from the chimeric tox gene was designated DAB389-CNTF. This fusion toxin has a deduced molecular weight of 67 440 and is formed by the fusion of the first 389 amino acids of diphtheria toxin to amino acids 15-200 of mature human CNTF (Cys17-->Ser), using a bridge of 34 additional amino acids including six consecutive histidine residues. This latter span allows for a single-step purification of the fusion protein by Ni(2+)-immobilized metal ion affinity chromatography, and provides a degree of flexibility which facilitates polypeptide refolding. DAB389-CNTF was selectively cytotoxic for clonal cells bearing CNTF receptors and for CNTF-responsive spinal sensory ganglion neurons in primary culture. The cytotoxic action of DAB389-CNTF, like that of native diphtheria toxin, required receptor-mediated endocytosis, passage through an acidic compartment and delivery of an ADP-ribosyltransferase to the cytosol of target cells. The delivery of the catalytic domain to the target cell cytosol results in inhibition of protein synthesis and cell death. This latter point was confirmed by the observation that both CNTF and DAB389-CNTF increased c-fos mRNA expression, but only CNTF induced Fos protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production, characterization and cytotoxic properties of a diphtheria toxin-ciliary neurotrophic factor fusion protein. 763 Aug 88

Previous studies suggest that heavy chain isotype switch (S) recombination is directed by cytokine-induced transcription of the unrearranged CH gene before recombination. In studies aimed at identifying other signaling pathways that promote switching, we discovered that inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) increase LPS-induced switching to IgA in the B cell lymphoma 1.29 mu and to IgG1 in LPS + IL-4-treated splenic B cells. PARP, which binds to and is activated by DNA strand breaks, catalyzes the removal of ADP-ribose from NAD+ and poly(ADP-ribosylation) of chromatin-associated acceptor proteins. This enzyme is believed to function in cellular processes involving DNA strand breaks as well as in modulating chromatin structure. In 1.29 mu cells, PARP inhibitors increase IgA switching by day 2 and cause a fivefold increase in switching on day 3 as assayed by immunofluorescence microscopy. In spleen B cells, the PARP inhibitor nicotinamide increases IgG1 switching by about twofold. Nicotinamide also causes a reduced intensity of hybridization of C mu- and C alpha-specific probes to genomic DNA fragments containing the expressed VDJ-C mu and the unrearranged S alpha-C alpha segments, respectively, in 1.29 mu cells, indicating that PARP inhibition increases rearrangement of these fragments. Induction of switching by PARP inhibitors is not mimicked by treatment with cAMP analogues or reduced by inhibitors of protein kinase A. Induction of switching by PARP inhibitors does not appear to involve increased levels of transcription of the unrearranged C alpha gene.
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PMID:Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching. 825 3

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.
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PMID:Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2. 897 13

Interleukin-1beta-converting enzyme (ICE) is a novel cysteine protease responsible for the cleavage of pre-interleukin-1beta (pre-IL-1beta) to the mature cytokine and a member of a family of related proteases (the caspases) that includes the Caenorhabditis elegans cell death gene product, CED-3. In addition to their sequence homology, these cysteine proteases display an unusual substrate specificity for peptidyl sequences with a P1 aspartate residue. We have examined the kinetics of processing pre-IL-1beta to the mature form by ICE and three of its homologs, TX, CPP-32, and CMH-1. Of the ICE homologs, only TX processes pre-IL-1beta, albeit with a catalytic efficiency 250-fold less than ICE itself. We also investigated the ability of these four proteases to process poly(ADP-ribose) polymerase, a DNA repair enzyme that is cleaved within minutes of the onset of apoptosis. Every caspase examined cleaves PARP, with catalytic efficiencies ranging from 2.3 x 10(6) M-1 s-1 for CPP32 to 1.0 x 10(3) M-1 s-1 for TX. In addition, we report kinetic constants for several reversible inhibitors and irreversible inactivators, which have been used to implicate one or more caspases in the apoptotic proteolysis cascade. Ac-Asp-Glu-Val-Asp aldehyde (DEVD-CHO) is a potent inhibitor of CPP-32 with a Ki value of 0.5 nM, but is also potent as inhibitor of CMH-1 (Ki = 35 nM) and ICE (Ki = 15 nM). The x-ray crystal structure of DEVD-CHO complexed to ICE presented here reveals electrostatic interactions not present in the Ac-YVAD-CHO co-complex structure (Wilson, K. P., Black, J.-A. F., Thomson, J. A., Kim, E. E., Griffith, J. P., Navia, M. A., Murcko, M. A., Chambers, S. P., Aldape, R. A., Raybuck, S. A., and Livingston, D. J. (1994) Nature 370, 270-275), accounting for the surprising potency of this inhibitor against ICE.
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PMID:Substrate and inhibitor specificity of interleukin-1 beta-converting enzyme and related caspases. 905 18

ADP-ribosyltransferase (ADPRT) is a glycosylphosphatidylinositol-anchored cell surface enzyme on CTL. Expression of this enzyme correlates with suppression of CTL functions in the presence of its substrate beta-nicotinamide adenine dinucleotide (NAD). To investigate the immunoregulatory importance of ADPRT on normal lymphocytes in vivo, NAD was injected into mice and the effects on cell-mediated and humoral immunity were assessed. Induction of both delayed-type hypersensitivity and CTL, but not Ab responses, are shown to be suppressed by NAD. Consistent with this, mature T cells, but not B cells or macrophages, express ADPRT and are able to ADP-ribosylate cell surface proteins. ADP-ribosylated molecules were identified as LFA-1, CD8, CD27, CD43, CD44, and CD45. Concomitant to ADP-ribosylation of these molecules, T cell trafficking to secondary lymphoid organs is suppressed by NAD. To examine whether this is due to effects of NAD on cell activation, Ag-stimulated responses were assayed in vitro. NAD is shown to inhibit induction of cell proliferation, cytotoxicity, and cytokine secretion. It is suggested that ADPRT regulates T cells on the level of transmembrane signaling via ADP-ribosylation of cell surface molecules. This effect is reported to be indirect, as it involves transmission of signals through TCRs, which are not ADP-ribosylated.
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PMID:Expression of ADP-ribosyltransferase on normal T lymphocytes and effects of nicotinamide adenine dinucleotide on their function. 957 19

Murine myeloid progenitor cells that are dependent on interleukin-3 (IL-3) undergo apoptosis when this essential cytokine is withdrawn. To determine whether IL-3 withdrawal leads to the activation of caspase proteases, known mediators of apoptosis, we studied proteolytic cleavage of the caspase substrate protein poly(ADP-ribose) polymerase (PARP) in two IL3-dependent myeloid progenitor cell lines, 32D and FDCP-1. We observed that IL-3 withdrawal leads to PARP cleavage in both cell lines, with complete cleavage occurring by 24 h after cytokine removal. The induced PARP cleavage activities were blocked by the caspase inhibitors z-DEVD-fluoromethyl ketone (z-DEVD-FMK) and z-VAD-fluoromethyl ketone (z-VAD-FMK), or by overexpression in 32D cells of Bcl-2 or BCR/ABL. By contrast, overexpression in 32D cells of cowpox virus CrmA protein, an inhibitor of Fas-mediated PARP cleavage, failed to inhibit PARP cleavage following IL-3 withdrawal. CrmA also failed to block DNA fragmentation and loss of cell viability. We propose that a CrmA-insensitive caspase protease is activated in the IL-3-deprived myeloid precursors, and that activation of this protease may direct the cells on a path towards commitment to death.
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PMID:IL-3 withdrawal activates a CrmA-insensitive poly(ADP-ribose) polymerase cleavage enzyme in factor-dependent myeloid progenitor cells. 959 65

The effects of interleukin 7 (IL-7) on apoptosis in interleukin 2 (IL-2)-dependent, activated, primary, human T lymphocytes (hT cells) was examined. IL-7 (like IL-2) rescued cells from apoptosis, as measured by their cellular DNA profile and fragmentation. IL-2 also acted as a mitogen in these T cells. Both cytokines abrogated the dexamethasone-induced stimulation of Caspase 3 and prevented the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate for the Caspase 3. IL-7 upregulated the expression of Bc1xL and counteracted the downregulation of this anti-apoptotic protein by the synthetic glucocorticoid, dexamethasone. Bcl-2 protein expression was uupregulated by IL-7 with or without dexamethasone, but Bc1-2 was expressed at a much lower level than BclxL in these cells. Levels of Bax did not markedly change on either cytokine stimulation or dexamethasone treatment. An unidentified 23-kDa band, which was recognized by the anti-Bc1-2 antibody, was induced by dexamthasone and suppressed by IL-7 and IL-2. This protein was subject to independent regulation as compared to the p26 Bc1-2 protein, suggesting that it may be a novel factor, possibly involved in the regulation of apoptosis. A clear role for IL-7 as a survival factor for cytokine withdrawal and glucocorticoid induced apoptosis in activated primary hT cells is implicated. In addition, regulation of BclxL and downstream inhibition of Caspase 3 activity may mediate this rescue signal.
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PMID:The role of caspase 3 and BclxL in the action of interleukin 7 (IL-7): a survival factor in activated human T cells. 977 Mar 27

Here we report that photoactivated hypericin can induce either apoptosis or necrosis in HeLa cells. Under apoptotic conditions the cleavage of poly(ADP-ribose) polymerase (PARP) into the 85-kDa product is blocked by the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk). Both inhibitors protect cells from apoptosis but cannot prevent hypericin-induced necrosis. Conversely, HeLa cells overexpressing the viral cytokine response modifier A (CrmA), which inhibits caspase-1 and -8, still undergo hypericin-induced apoptosis and necrosis. Evidence is provided for the release of mitochondrial cytochrome c in the cytosol and for procaspase-3 activation in the hypericin-induced cell killing.
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PMID:Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis. Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis. 986 16

The mechanism of cell death caused by cytokine deprivation remains largely unknown. FL5.12 cells (a murine prolymphocytic cell line), following interleukin-3 (IL-3) withdrawal, undergo a decrease in intracellular glutathione (GSH) that precedes the onset of apoptosis. In the present study, the induction of apoptosis following IL-3 withdrawal or GSH depletion with DL-buthionine-[S,R,]-sulfoximine (BSO) was examined. Both conditions caused time-dependent increases in phosphatidylserine externalization, acridine orange and ethidium bromide staining, decreases in mitochondrial membrane potential, processing and activation of caspase-3 and proteolysis of the endogenous caspase substrate poly(adenosine diphosphate ribose)polymerase (PARP). Apoptosis induced by IL-3 deprivation but not BSO also caused lamin B1 cleavage, suggesting activation of caspase-6. Despite a more profound depletion of GSH after BSO than withdrawal of IL-3, the extent of apoptosis was somewhat lower. Benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone (z-VAD.fmk) blocked this caspase activity and prevented cell death after BSO exposure but not after IL-3 deprivation. Following IL-3 withdrawal, the caspase inhibitors z-VAD.fmk and boc-asp(OMe)fluoromethylketone (boc-asp.fmk) prevented the cleavage and activation of caspase-3, the breakdown of lamin B1 and partially mitigated PARP degradation. However, the externalization of phosphatidylserine, the fall in mitochondrial membrane potential and subsequent apoptotic cell death still occurred. These results suggest that IL-3 withdrawal may mediate cell death by a mechanism independent of both caspase activation and the accompanying loss of GSH.
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PMID:Apoptosis in hematopoietic cells (FL5.12) caused by interleukin-3 withdrawal: relationship to caspase activity and the loss of glutathione. 1020 May 49

Myeloic cells express a peculiar surface receptor for extracellular ATP, called the P2Z/P2X7 purinoreceptor, which is involved in cell death signalling. Here, we investigated the role of caspases, a family of proteases implicated in apoptosis and the cytokine secretion. We observed that extracellular ATP induced the activation of multiple caspases including caspase-1, -3 and -8, and subsequent cleavage of the caspase substrates PARP and lamin B. Using caspase inhibitors, it was found that caspases were specifically involved in ATP-induced apoptotic damage such as chromatin condensation and DNA fragmentation. In contrast, inhibition of caspases only marginally affected necrotic alterations and cell death proceeded normally whether or not nuclear damage was blocked. Our results therefore suggest that the activation of caspases by the P2Z receptor is required for apoptotic but not necrotic alterations of ATP-induced cell death.
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PMID:P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death. 1021 85


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