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)

We studied the mechanism by which the human granulocytic ehrlichiosis (HGE) agent induces programmed cell death (apoptosis) in human promyelocytic HL-60 leukemia cells. Using several New York HGE isolates, we show that the HGE agent-elicited apoptosis is accompanied by increased processing of nuclear enzyme poly(ADP-ribose) polymerase (PARP), concurrent with a noticeable increase in caspase 3 activities. A marked increase in the amounts of the signaling molecule ceramide but not of diacylglycerol was also observed in HGE agent-infected HL-60 cells, compared with the amounts in uninfected controls. Simultaneous or prior treatment of infected HL-60 cells with the ceramide synthase inhibitor fumonisin B1 did not affect the magnitude of infection by the intracellular pathogen, as determined by both the presence of morulae and the expression of its outer surface membrane protein, p44. These results suggest that the observed changes in ceramide are generated through the sphingomyelinase pathway and not by way of de novo synthesis of ceramide. We also assayed for changes in intracellular hydrogen peroxide and show that the HGE agent causes a decrease in its concentrations in infected cells.
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PMID:Specific processing of poly(ADP-ribose) polymerase, accompanied by activation of caspase-3 and elevation/reduction of ceramide/hydrogen peroxide levels, during induction of apoptosis in host HL-60 cells infected by the human granulocytic ehrlichiosis (HGE) agent. 1077 41

EB1089, a novel 1,25-dihydroxyvitamin D3 analogue, has been known to have potent antiproliferative properties in a variety of malignant cells both in vitro and in vivo. In the present study, we analysed the effect of EB1089 on NCI-H929 human myeloma cells. EB1089 inhibited cell growth of NCI-H929 and efficiently induced the G1 phase arrest of the cell cycle in a dose-dependent manner. We could also detect apoptosis in NCI-H929 cells exposed to EB1089 (1 x 10-7 M for 72 h) using the sub-G1 group of the cell cycle by FACS and annexin V binding assays. Induction of apoptosis by EB1089 was associated with down-regulation of the Bcl-2 protein without change of the Bax protein. Regarding caspase activity, which plays a crucial role in apoptosis, EB1089-treated NCI-H929 cells revealed an increased activity of caspase 3 protease accompanied by degradation of the PARP protein in a dose- and time-dependent manner. In addition, EB1089 caused the down-regulation of p44 extracellular signal-related kinase (ERK) activity and up-regulation of the p38 kinase activity during apoptosis of NCI-H929 cells. These results suggest that EB1089 inhibits growth of NCI-H929 cells via G1 cell cycle arrest as well as apoptosis by activating p38 kinase and suppressing ERK activity.
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PMID:Induction of apoptosis by vitamin D3 analogue EB1089 in NCI-H929 myeloma cells via activation of caspase 3 and p38 MAP kinase. 1088 7

We have investigated the effects of hydrogen peroxide (H(2)O(2)), a potent naturally occurring oxidant on cell signaling and viability in the pluripotent HT29 intestinal cell line. There was a dose-dependent reduction in cell viability upon exposure to H(2)O(2) as measured by the XTT assay. Features of apoptosis were indicated by the findings of PARP and caspase 3 cleavage, as well as changes in cell morphology using phase contrast and nuclear fragmentation using fluorescence microscopy. There was a dose-dependent increase in the activation of p45-JNK, p42/p44-ERK, and p38-HOG. Surprisingly, oxidant-induced cell injury could be attenuated by preincubation with PD98059 to 50% of untreated control cells (P = 0.002). This and UO126, another MEK inhibitor were ably to reproducibly inhibit p45-JNK activation induced by hydrogen peroxide. Transfection with kinase-inactive constructs of JNK and ERK revealed that the improvement in cell viability was due to inhibition of JNK and not ERK. Transient transfections with AP-1 and NF-kappaB luciferase reporter constructs did not reveal any transcriptional activation due to hydrogen peroxide exposure however, in both cases the basal levels of transcriptional activity were suppressed in the presence of PD98059. It is concluded that JNK mediates H(2)O(2)-induced cellular injury in the HT29 cell line, and additionally, we report for the first time that JNK activation can be inhibited by both PD98059 and UO126 at conventional doses used to inhibit MEK.
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PMID:PD98059 attenuates hydrogen peroxide-induced cell death through inhibition of Jun N-Terminal Kinase in HT29 cells. 1128 30

Bordetella pertussis is an important cause of infection in humans worldwide, with full expression of the syndrome associated with characteristic increases in lung permeability and airway edema. The exact cellular mechanisms by which pertussis toxin (PTX) exerts pulmonary toxicity remain unknown, but may involve its ability to ADP-ribosylate-specific G-proteins. We determined that PTX directly and reproducibly reduced lung endothelial and epithelial cell barrier function in vitro and in vivo assessed by decreases in transmonolayer electrical resistance (TER) and isolated perfused lung preparations. Alterations in lung permeability began approximately 30 min after PTX and were dependent on intrinsic ADP-ribosyltransferase activity, as neither the cell binding beta-oligomer subunit or a genetically engineered PTX mutant (devoid of ADP-ribosyltransferase activity) altered TER. PTX-induced barrier dysfunction was associated with mild increases in F-actin stress fiber formation and causally linked to p38 MAP kinase activities. PTX-mediated p38 MAP kinase activation did not involve either p42/p44 ERK, p60src, Rho family of GTPases, or phosphatidylinositol-3' kinase pathways. PTX-mediated decreases in TER were temporally linked to phosphorylation of the actin binding proteins Hsp27 and caldesmon, known substrates for the Ser/Thr kinase MAPKAP2, whose activity is regulated by p38 MAP kinase. In addition to defining novel signaling pathways involved in PTX-induced respiratory pathophysiology, these data suggest that the direct cell-activating effects of PTX be carefully considered as a potential limitation to its use as a tool in signal transduction analysis.
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PMID:Critical involvement of p38 MAP kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability. 1208 68

Staurosporine induced apoptosis of RAW 264.7 cells, a mouse macrophage-like cell line, as determined by DNA fragmentation, the increase of annexin V-stained cells, and the cleavage of poly(ADP-ribose)polymerase (PARP), a substrate of caspase. Analysis of the increase in the percentage of sub-G(1) cells revealed that the DNA fragmentation occurred in a time- and concentration-dependent manner at 0.021-2.1 microM of staurosporine. Staurosporine induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) but suppressed spontaneous phosphorylation of p44/42 MAPK. The p38 MAPK inhibitor SB203580, the MAPK/extracellular signal-regulated kinase kinase inhibitor PD98059 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 potentiated the staurosporine-induced PARP cleavage and DNA fragmentation. The protein kinase A (PKA) inhibitor H-89 potentiated the staurosporine-induced DNA fragmentation without potentiating the PARP cleavage. In contrast, the protein kinase C (PKC) inhibitor Ro-31-8425 suppressed the PARP cleavage and DNA fragmentation. These findings suggested that staurosporine induces apoptosis via the caspase cascade in RAW 264.7 cells. The staurosporine-induced apoptosis is positively regulated by PKC, negatively regulated by p38 MAPK, p44/42 MAPK and PI3K via the caspase cascade, and negatively regulated by PKA without regulation of caspase activation.
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PMID:Participation of various kinases in staurosporine induced apoptosis of RAW 264.7 cells. 1249 57

Cruciferous vegetable-derived isothiocyanates (ITCs; chemical structure: R-N=C=S) are highly effective in affording protection against chemically induced cancers in animal models. Here, we studied the antitumor effects of benzyl isothiocyanate (BITC; Ph-CH2-N=C=S), the predominant ITC compound in broccoli, on head and neck squamous cell carcinoma (HNSCC) cell lines. Proliferation, apoptosis and immunoblotting assays were used to determine the effects and mechanism of several ITCs on HNSCC cells. The IC50 for BITC (24 h treatment) in two of the HNSCC cell lines was approximately 22 and 17 micro M, respectively. Interestingly, phenyl isothiocyanate (PITC; Ph-N=C=S), which is a close structural analog of BITC but lacks a -CH2- spacer that links the aromatic ring to N=C=S moiety, did not result in significant killing of the HNSCC cells in this dose range. BITC (but not PITC) caused activation of caspase 3 and PARP cleavage. Within 20 min of treatment, BITC (but not PITC) induced a rapid activation of p38 MAPK. In addition, BITC (but not PITC) treatment resulted in the activation of p44/42 MAPK. Co-treatment with a specific p38 MAPK inhibitor, SB203580, or an inhibitor of the MEK/MAPK pathway, U0126, partially rescued cells from BITC-induced killing. Our results show that minor structural differences in ITCs can be crucial for the antiproliferative activity of ITCs and that BITC may be a promising chemopreventive as well as therapeutic agent in HNSCC.
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PMID:Requirement of a carbon spacer in benzyl isothiocyanate-mediated cytotoxicity and MAPK activation in head and neck squamous cell carcinoma. 1289 7

Apicularen A, a macrolide isolated from the myxobacterial genus Chondromyces, suppressed the proliferation of human promyelocytic leukemia cells (HL-60 cells), increased the release of lactate dehydrogenase and induced condensation and fragmentation of chromatin at 1 to 100 nM. In addition, it induced the DNA fragmentation, increased the percentage of annexin V-stained cells, and cleaved poly(ADP-ribose) polymerase (PARP), a substrate of caspase. In contrast, apicularen B, an N-acetylglucosamine glycoside of apicularen A, had no such effects at 100 nM. These findings indicated that apicularen A induces apoptosis in HL-60 cells by activating caspases. Phosphorylation of p44/42 MAPK, p38 MAPK and Akt was not induced by apicularen A at 100 nM, suggesting that the apicularen A-induced apoptosis in HL-60 cells is not regulated by the activation of p44/42 MAPK, p38 MAPK or Akt. Furthermore, by acridine orange staining of the cells, it was suggested that apicularen A but not apicularen B inhibits vacuolar-type H+-ATPase.
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PMID:Induction of apoptosis by apicularen A in human promyelocytic leukemia cell line HL-60. 1585 5

We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of the p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by the GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne and S. Pyne (2001) J. Biol. Chem. 276, 13452-13460]. In the present study, we now show that this can be blocked by pretreating HEK-293 cells with the caspase 3/7 inhibitor, Ac-DEVD-CHO [N-acetyl-Asp-Glu-Val-Asp-CHO (aldehyde)]. Therefore LPP2 and LPP3 appear to regulate the apoptotic status of serum-deprived HEK-293 cells. This was supported further by: (i) caspase 3/7-catalysed cleavage of PARP [poly(ADP-ribose) polymerase] was increased in serum-deprived LPP2-overexpressing compared with vector-transfected HEK-293 cells; and (ii) serum-deprived LPP2- and LPP3-overexpressing cells exhibited limited intranucleosomal DNA laddering, which was absent in vector-transfected cells. Moreover, LPP2 reduced basal intracellular phosphatidic acid levels, whereas LPP3 decreased intracellular S1P in serum-deprived HEK-293 cells. LPP2 and LPP3 are constitutively co-localized with SK1 (sphingosine kinase 1) in cytoplasmic vesicles in HEK-293 cells. Moreover, LPP2 but not LPP3 prevents SK1 from being recruited to a perinuclear compartment upon induction of PLD1 (phospholipase D1) in CHO (Chinese-hamster ovary) cells. Taken together, these data are consistent with an important role for LPP2 and LPP3 in regulating an intracellular pool of PA and S1P respectively, that may govern the apoptotic status of the cell upon serum deprivation.
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PMID:Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. 1596 Jun 10

The study was aimed to investigate the molecular mechanisms of histone deacetylase inhibitor SAHA-induced apoptosis of acute myeloid leukemia cell line HL-60. The effect of SAHA on HL-60 cell proliferation was detected by MTT assay and the cell morphological changes were observed with Wright-Giemsa and Hoechst33342 staining. The cell cycle distribution was determined by flow cytometry and the expression of cell signaling proteins were detected by Western-blot analysis. The results showed that SAHA inhibited the proliferation of HL-60 cells in dose- and time-dependent manners, after 2 micromol/L SAHA exposure for 12 - 48 hours, the cell cycle was arrested at G(0)/G(1) phase and apoptotic cell death was confirmed by either defined apoptotic bodies stained by Hoechst33342, Western blot showed cleaved-PARP, which represents the activation of caspase 3. The Western blot analysis indicated the activation of two important survival signal pathways after SAHA treatment, the phosphorylation of Raf and its downstream ERK kinases were remarkable downregulated, whereas the phosphorylation of AKT and its downstream molecular mTOR were not changed. It is concluded that SAHA-induced apoptosis of HL-60 cells is mediated by inactivation of p44/42 MAPK signaling pathway.
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PMID:[Histone deacetylase inhibitor SAHA induces inactivation of MAPK signaling and apoptosis in HL-60 cells]. 1749 29

Resveratrol (3,4',5-trans-trihydroxystilbene) is a natural compound found in grapes and several medicinal plants and has been shown to have anticancer effects on various human cancer cells. The aim of this study was to further investigate the molecular mechanism of this anticancer effect. Resveratrol effect on cell growth, morphology and gene expression was investigated in estrogen receptor-negative MDA-MB-231 human breast cancer cell line. We show here that resveratrol-induced growth inhibition in the estrogen receptor negative MDA-MB-231 breast cancer cells is due to the induction of apoptosis as demonstrated by morphological, nuclear staining and PARP cleavage analysis. Resveratrol-induced growth inhibition was associated with transient activation of p44/42 mitogen-activated protein kinase (MAPK) (Thr202/Tyr204). Most importantly, resveratrol inhibited both the phosphorylation at Ser240/244 and the expression of the pS6 ribosomal protein. This protein is known to play an important role in the translation of mRNAs that have oligopyrimidine tracts in their 5' untranslated regions. Interestingly, only MAPK inhibitor was able to block resveratrol-induced growth inhibition suggesting that effects of resveratrol on cell growth are dependent on MAPK signaling. The data demonstrated that resveratrol-induced apoptosis is associated with MAPK signaling and with the inhibition of proteins that are involved in protein translation. This is the first data linking resveratrol with downregulation of protein translation via p44/42 MAPK and S6 ribosomal protein. We propose to use these proteins as predictive biomarkers to evaluate the treatment efficacy of resveratrol in estrogen receptor-negative human breast cancer.
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PMID:Resveratrol-induced growth inhibition in MDA-MB-231 breast cancer cells is associated with mitogen-activated protein kinase signaling and protein translation. 1755 6


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