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 lymphocytes stimulated with the mitogen phytohaemagglutinin, an inhibitor of the enzyme ADP-ribosyltransferase (ADPRT) completely blocks the proliferative response and the increase in expression of the proto-oncogene c-myc without affecting c-fos significantly. Conversely, in fibroblasts the serum-induced growth is not affected by the ADPRT inhibitor, and both oncogenes are dramatically super-induced. Hence there are differences between lymphocyte and fibroblast early responses to mitogenic stimulation and also between regulation of c-fos and c-myc gene expression.
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PMID:Differential control of proto-oncogene c-myc and c-fos expression in lymphocytes and fibroblasts. 311 47

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

Leukemia-inhibitory factor (LIF) is a neuropoietin able to regulate the differentiation and the survival of many cell types, which include some neuronal populations. The present study describes the genetic construction, expression, purification and properties of a diphtheria-toxin-related LIF gene fusion in which the native receptor-binding domain of diphtheria toxin was replaced with a gene encoding human LIF. The fusion protein expressed from the chimeric tox gene was designated DT-(1-389)-LIF-(2-184)-peptide. This fusion protein has a deduced molecular mass of 65980 Da and is formed by fusion of the first 389 amino acids of diphtheria toxin to amino acids 2-184 of mature human LIF, using a linker of 34 amino acids that includes six consecutive histidine residues. The latter span allows for single-step purification of the fusion protein by Ni(2+)-resin affinity chromatography. This linker provides a high degree of flexibility between the diphtheria toxin and LIF domains, thereby permitting aggregation-free refolding of the chimeric protein while bound to the affinity column. Both LIF and DT-(1-389)-LIF-(2-184)-peptide induced the phosphorylation of CLIP1 and CLIP2 in LIF-responsive neuroblastoma SH-N-BE cells. DT-(1-389)-LIF-(2-184)-peptide was selectively cytotoxic for cultured neuroblastoma cells bearing the LIF receptor, and for sympathetic neurons. The cytotoxic action of DT-(1-389)-LIF-(2-184)-peptide, 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 latter point was confirmed by the fact that, while both LIF and DT-(1-389)-LIF-(2-184)-peptide increased c-fos mRNA expression in SH-N-BE cells, only LIF induced proenkephalin and c-fos promoter activities in cells transiently transfected with c-fos-chloramphenicol acetyltransferase and proenkephalin-chloramphenicol acetyltransferase fusion genes. Mutational analysis suggested that the C-terminal helix (helix D) of human LIF may, in part, constitute or contribute to the active site for LIF receptor binding and cell activation. The cytotoxic properties of DT-(1-389)-LIF-(2-184)-peptide may be useful in selectively depleting neuronal and immune cell populations that express the LIF beta receptor.
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PMID:Synthesis, cytotoxic properties and effects on early and late gene induction of a chimeric diphtheria toxin-leukemia-inhibitory factor protein. 891 49

Apoptosis has been hypothesized to be mediated through the induction of free radicals via oxidative pathway. In this study, we demonstrated the induction of cellular apoptosis by anoxia-hyperoxia shift, but not by anoxia or hyperoxia alone in NIH3T3 cells. The decrement of ROS by anoxia thus appears to be an essential early event leading to apoptosis. G1 arrest was detected in anoxia-treated cells, and postanoxic oxygen recovery could reverse this effect, and induce apoptosis. On analysis of the binding activity of AP-1, we found biphasic induction of binding ability in cells undergoing anoxia-hyperoxia shift. In the early stage of anoxia, a transitional increase of AP-1 binding activity was detected, which was reduced to the minimal levels after 24 h of anoxia. During the period of postanoxic hyperoxia treatment, the binding activity of AP-1 was reinduced and increased remarkably with time up to 24 h. These results were in accordance with the expressions of c-jun and c-fos proteins. Enhancement of poly(ADP-ribosyl)ation activities, especially ADP-ribosylation of histone H1 was detected in post-anoxic hyperoxia-treated cells, and cleavage of PARP and activation of caspase 3 were also observed in post-anoxic hyperoxia (recovery) treated cells, but not in anoxia-treated cells. We propose that the differential induction of c-jun/c-fos (AP-1) gene expressions and sequential activation of PARP activity are essential in anoxia/hyperoxia-induced apoptosis.
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PMID:Elevation of apoptotic potential by anoxia hyperoxia shift in NIH3T3 cells. 1048 34

BACKGROUND: Previous studies have demonstrated the occurrence of apoptosis in cardiomyocytes in different types of cardiovascular diseases. This report provides the first evidence for the presence of vascular apoptosis in myocardial infarction induced in rats by occluding the coronary artery for 7 weeks. METHODS AND RESULTS: Apoptosis was characterized by DNA fragmentation, upregulation of caspase-3, downregulation of poly (ADP-ribose) polymerase (PARP), increased c-fos mRNA expression and caspase-3/PARP ratio in aortic vascular smooth muscle cells. The results show apoptotic changes in 10-25% of the aortic vascular cells after myocardial infarction; these alterations were prevented after treating the 3-week operated animals with an angiotensin II receptor antagonist, losartan (25 mg/kg/day; intraperitoneal) for 4 weeks. Cultured rat aortic smooth muscle cells exposed to 10 nmol/L angiotensin II for 48 hours also exhibited apoptotic changes, which were inhibited by 10 nmol/L losartan. CONCLUSIONS: These results suggest that vascular apoptosis occurs in myocardial infarction, and this may be due to an increase in the circulating levels of angiotensin II.
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PMID:Prevention of Vascular Apoptosis in Myocardial Infarction by Losartan. 1068 26

The mechanism by which apoptosis is induced by local anesthetic bupivacaine, a potent uncoupler of mitochondrial oxidative phosphorylation, was investigated. In promyelocytic leukemia cells HL-60, bupivacaine induced formation of apoptotic bodies and DNA fragmentation in a time- and dose-dependent manner similar to typical apoptosis inducers. Caspase-3, -8 and -9, which play a pivotal role in the initiation and execution of receptor- or mitochondria-mediated apoptosis, were all clearly activated by bupivacaine in good correlation with the degree of DNA fragmentation. However, bupivacaine did not induce either mitochondrial permeability transition (PT) or release of cytochrome c in experiments with isolated mitochondria. These results suggest that an indirect action of bupivacaine on mitochondria occurs and that other mechanisms may be involved in bupivacaine-induced apoptosis. To obtain additional information concerning the mechanism of action involved in bupivacaine-induced apoptosis, a microarray analysis of gene expression in bupivacaine-treated HL-60 cells was carried out. Several apoptosis-related genes were found to be transcriptionally regulated by bupivacaine using a high-density cDNA microarray. The expression levels of heat shock protein 70 (HSP70), c-jun and c-fos genes were remarkably up-regulated and those of c-myc and poly (ADP ribose) polymerase (PARP) were down-regulated in bupivacaine-treated cells. These results are of value in developing a better understanding of the molecular mechanism of bupivacaine-induced apoptosis leading to neuro- or myotoxicity.
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PMID:Biochemical and microarray analyses of bupivacaine-induced apoptosis. 1282 May 40

The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of PKC412 in the treatment of MM is justified.
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PMID:PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. 1703 22

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.
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PMID:DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. 1724 36

PARP-1 is a highly conserved DNA-binding protein, the most abundant member of the polyADP-ribose polymerases (PARP) family, which catalyzes post-translational modification of proteins by polyADP-ribosylation. This modification affects protein-protein and protein-DNA interactions. Binding of PARP-1 to breakages in damaged DNA causes its activation and auto-polyADP-ribosylation in a process that is pivotal for DNA repair. Our recent findings outlined an alternative mechanism of PARP-1 activation via a direct interaction with phosphorylated ERK2 (externally regulated kinase), which is unrelated to DNA damage and does not involve PARP-1 binding to DNA. Furthermore, ERK2-induced PARP-1 activation dramatically amplifies ERK-signals, enhancing ERK-induced phosphorylation of the transcription factor Elk1 and enhancing core histone acetylation and expression of the Elk1 target gene, c-fos. Thus, PARP-1 activation in the ERK signaling pathway mediates epigenetic mechanisms promoting growth, proliferation and differentiation regulated by the Raf-MEK-ERK phosphorylation cascade.
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PMID:PARP-1 activation in the ERK signaling pathway. 1795 Sep 9

The nuclear protein PARP-1 [poly(ADP-ribose) polymerase-1] is activated in cardiomyocytes exposed to hypoxia causing DNA breaks. Unlike this stress-induced PARP-1 activation, our results provide evidence for Ca(2+)-induced PARP-1 activation in contracting newborn cardiomyocytes treated with growth factors and hormones that increased their contraction rate, induced intracellular Ca(2+) mobilization and its rhythmical and transient translocation into the nucleus. Furthermore, activated PARP-1 up-regulated the activity of phosphorylated ERK (extracellular-signal-regulated kinase) in the nucleus, promoting expression of the Elk1 target gene c-fos. Up-regulation of the transcription factor c-Fos/GATA-4 promoted ANF (atrial natriuretic factor) expression. Given that expression of ANF is known to be implicated in morphological changes, growth and development of cardiomyocytes, these results outline a PARP-1-dependent signal transduction mechanism that links contraction rate and Ca(2+) mobilization with the expression of genes underlying morphological changes in cardiomyocytes.
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PMID:Ca2+-induced PARP-1 activation and ANF expression are coupled events in cardiomyocytes. 2163 24


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