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)

Nasopharyngeal carcinoma (NPC) is a malignant disease of the head/neck region with a 5-year survival level of approximately 65%. To explore the novel therapeutic strategies in the management of this disease, the potential effects of photodynamic therapy (PDT) in NPC cells were investigated. PDT, a new mode of treatment, is based on the combined use of light-absorbing compounds and light irradiation. Two human NPC cells such as, poorly differentiated (NPC/CNE2) and moderately differentiated (NPC/TW0-1) and other types of tumor cells like colon (CCL-220.1) and bladder (SD) undergo rapid apoptosis when treated with PDT sensitized with hypericin (HY). It has been shown that this compound has a strong photodynamic effect on tumors and viruses. However, the initiating events of PDT sensitized HY-induced apoptosis are not identified completely. In this study, we sought to determine whether Fas/FasL upregulation and involvement of mitochondrial events are an early event in HY-treated PDT induced apoptosis. Loss of mitochondrial transmembrane potential, release of cytochrome c, involvement of caspases 8 and 3 and the status caspase-3 specific substrate PARP, were evaluated in PDT treated tumor cells. Photosensitization of HY enhanced both CD95/CD95L expression and induced CD95-signaling dependent cell death in all tumor cell lines studied. CD95/CD95L expression appeared within 2 h following light irradiation and appeared to be a principal event in PDT induced apoptosis. Furthermore, these results indicate that release of mitochondrial cytochrome c into the cytoplasm within 2-3 h post PDT is a secondary event following the activation of initiator caspase-8 preceding Apaf-1, caspase-9 and caspase-3 activation, cleavage of PARP and DNA fragmentation.
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PMID:Hypericin induced death receptor-mediated apoptosis in photoactivated tumor cells. 1201 77

Deprivation of tyrosine (Tyr) and phenylalanine (Phe) inhibits growth and induces programmed cell death (apoptosis) of human A375 melanoma cells. Herein, we found that activation of caspases and release of mitochondrial cytochrome c are required for this process. Culturing A375 cells in Tyr/Phe-free medium, containing 10% dialyzed fetal bovine serum, results in activation of caspase-3-like activity. This is accompanied by decreased cell viability and increased apoptosis. Tyr/Phe deprivation also stimulates proteolytic cleavage of the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP). Western blot analysis showed that caspases 3, 7, 8, and 9 are activated by deprivation of Tyr/Phe. Tyr/Phe deprivation decreases mitochondrial membrane potential, induces cleavage of Bid, increases translocation of Bax from the cytosol to mitochondria, and results in release of cytochrome c from the mitochondria to the cytosol. Apoptosis due to Tyr/Phe deprivation is almost completely inhibited by the broad-spectrum cell-permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z.VAD.fmk). This inhibitor suppresses the cleavage of Bid, the release of cytochrome c from the mitochondria to the cytosol, and the cleavage of PARP. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, does not suppress the activation of caspase 8 but suppresses release of cytochrome c, activation of caspase 9, and induction of apoptosis. These results indicate that activation of caspases, cleavage of Bid, and mitochondrial release of cytochrome c are required for apoptosis induced by Tyr/Phe deprivation.
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PMID:Activation of caspases and cleavage of Bid are required for tyrosine and phenylalanine deficiency-induced apoptosis of human A375 melanoma cells. 1206 1

In vivo and in vitro studies have shown an increase in apoptosis in gastric epithelial cells in persons infected with Helicobacter pylori. H. pylori-induced activation of caspase-8 and -3 was evaluated using a human gastric adenocarcinoma cell line (AGS) and gastric tissue from humans and monkeys colonized with H. pylori. The enzymatic activity of caspase-8 was detected only in AGS cells exposed to H. pylori up to 24 h. The active form of caspase-8 was present by Western blot after exposure to H. pylori for 3 h and persisted through 24 h. Caspase-3 activity was present in AGS cells exposed to H. pylori for 3 h, reaching a maximum after 24 h (a sevenfold increase in activity). Caspase-8-mediated cleavage of procaspase-3 generated a 20-kDa band (indicative of the presence of active caspase-3) present only in AGS cells exposed to H. pylori. Active caspase-3 staining was markedly increased in gastric mucosa from infected persons and animals, compared to uninfected controls by immunohistochemistry. Stimulation of downstream events leading to apoptosis, such as the cleavage of PARP (poly adenosine-diphosphate-ribose polymerase) and DFF45 (DNA fragmentation factor 45) as a result of activation of caspase-3, was evaluated. PARP was cleaved, resulting in the presence of both an 89- and a 24-kDa band along with DFF45, resulting in the presence of 10- and 12-kDa bands only in gastric cells exposed to H. pylori. Our data show that H. pylori stimulates the activation of caspases and downstream mediators of caspase-induced apoptosis. This suggests that H. pylori-induced apoptosis is mediated through caspase pathways, which include the activation of caspase-8 and subsequent cleavage and activation of caspase-3. This is consistent with caspase-3 activation that was found in the gastric mucosa of humans and monkeys infected with H. pylori.
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PMID:In vivo and in vitro activation of caspase-8 and -3 associated with Helicobacter pylori infection. 1206 31

Shiga-like toxin-producing Escherichia coli causes hemorrhagic colitis and hemolytic-uremic syndrome in association with the production of Shiga-like toxins, which induce cell death via either necrosis or apoptosis. However, the abilities of different Shiga-like toxins to trigger apoptosis and the sequence of intracellular signaling events mediating the death of epithelial cells have not been completely defined. Fluorescent dye staining with acridine orange and ethidium bromide showed that Shiga-like toxin 1 (Stx1) induced apoptosis of HEp-2 cells in a dose- and time-dependent manner. Stx2 also induced apoptosis in a dose-dependent manner. Apoptosis induced by Stx1 (200 ng/ml) and apoptosis induced by Stx2 (200 ng/ml) were maximal following incubation with cells for 24 h (94.3% +/- 1.8% and 81.7% +/- 5.2% of the cells, respectively). Toxin-treated cells showed characteristic features of apoptosis, including membrane blebbing, DNA fragmentation, chromatin condensation, cell shrinkage, and the formation of apoptotic bodies, as assessed by transmission electron microscopy. Stx2c induced apoptosis weakly even at a high dose (1,000 ng/ml for 24 h; 26.7% +/- 1.3% of the cells), whereas Stx2e did not induce apoptosis of HEp-2 cells. Thin-layer chromatography confirmed that HEp-2 cells express the Stx1-Stx2-Stx2c receptor, globotriaosylceramide (Gb3), but not the Stx2e receptor, globotetraosylceramide (Gb4). Western blot analysis of poly(ADP-ribose) polymerase (PARP), a DNA repair enzyme, demonstrated that incubation with Stx1 and Stx2 induced cleavage, whereas incubation with Stx2e did not result in cleavage of PARP. A pan-caspase inhibitor (Z-VAD-FMK) and a caspase-8-specific inhibitor (Z-IETD-FMK) eliminated, in a dose-dependent fashion, the cleavage of PARP induced by Shiga-like toxins. Caspase-8 activation was confirmed by detection of cleavage of this enzyme by immunoblotting. Cleavage of caspase-9 and the proapoptotic member of the Bcl-2 family BID was also induced by Stx1, as determined by immunoblot analyses. We conclude that different Shiga-like toxins induce different degrees of apoptosis that correlates with toxin binding to the glycolipid receptor Gb3 and that caspases play an integral role in the signal transduction cascade leading to toxin-mediated programmed cell death.
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PMID:Escherichia coli shiga-like toxins induce apoptosis and cleavage of poly(ADP-ribose) polymerase via in vitro activation of caspases. 1211 81

Satratoxins have been recognized as potential immunomodulatory agents in outbreaks of building-related illness. Here we report that satratoxin G-treated human leukemia HL-60 cells underwent apoptosis through the action of caspase-3 which was activated by both caspase-8 and caspase-9. Western blot analysis of caspase-3 in the satratoxin G-treated cells apparently indicated the appearance of a catalytically active fragment of 17 kDa. Increased caspase-3 activity was also detected by using a fluorogenic substrate, DEVD-AMC. Next, exposure to satratoxin G led to cleavage of PARP from its native 116 kDa form to a 85 kDa product. Moreover, DFF-45/ICAD were cleaved into a 12.5 kDa fragment via satratoxin G treatment. Enzymic assay on IETD-AMC revealed that caspase-8 is strongly activated by exposure to satratoxin G while T-2 toxin (T-2) could not activate caspase-8 at an early stage of apoptosis. Furthermore, satratoxin G caused a release of cytochrome c from mitochondria into the cytosol and increased the activity of caspase-9 against LEHD-AMC. These findings indicate that satratoxin G-induced apoptosis involves activation of caspase-3 and DFF-40/CAD through both activation of caspase-8 and cytosolic accumulation of cytochrome c along with activation of caspase-9.
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PMID:Molecular mechanism of satratoxin-induced apoptosis in HL-60 cells: activation of caspase-8 and caspase-9 is involved in activation of caspase-3. 1216 Dec 80

Responses to the CDK inhibitor flavopiridol (FP) have been examined in U937 leukemia cells ectopically expressing full-length Bcl-2 or an N-terminal phosphorylation loop-deleted protein (Bcl-2). A 3-fold increase in full-length Bcl-2 protein conferred substantial resistance to ara-C-associated lethality, but not to FP-mediated cytochrome c release, caspase-3 and-9 activation and apoptosis. In a second clonal line, a 6-fold increase in Bcl-2 expression delayed but did not ultimately prevent FP-associated apoptosis. In marked contrast, cells ectopically expressing the Bcl-2 loop-deleted protein (32-80) were highly resistant to FP-mediated cytochrome c release, caspase-3, -8, and -9 activation, Bid and PARP cleavage, and apoptosis despite relatively low levels of protein expression. The loop-deleted Bcl-2, but not full-length Bcl-2 protein also protected clonogenic cells from FP-mediated lethality. Finally, in Bcl-2-overexpressing cells, FP lethality was not attenuated by the caspase-8 inhibitor IETD-FMK, arguing against a role for the extrinsic, receptor-mediated pathway in circumventing Bcl-2-associated resistance. Collectively, these findings indicate that FP induces cytochrome c release in leukemic cells despite overexpression of Bcl-2, and suggest that this event may be modulated by negative regulatory factors residing within the N-terminal phosphorylation loop region.
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PMID:Loss of the Bcl-2 phosphorylation loop domain is required to protect human myeloid leukemia cells from flavopiridol-mediated mitochondrial damage and apoptosis. 1217 Jul 73

Apoptosis plays an important role in the pathogenesis of many viral infections. Despite this fact, the apoptotic pathways triggered during viral infections are incompletely understood. We now provide the first detailed characterization of the pattern of caspase activation following infection with a cytoplasmically replicating RNA virus. Reovirus infection of HEK293 cells results in the activation of caspase-8 followed by cleavage of the pro-apoptotic protein Bid. This initiates the activation of the mitochondrial apoptotic pathway leading to release of cytochrome c and activation of caspase-9. Combined activation of death receptor and mitochondrial pathways results in downstream activation of effector caspases including caspase-3 and caspase-7 and cleavage of cellular substrates including PARP. Apoptosis is initiated by death receptor pathways but requires mitochondrial amplification producing a biphasic pattern of caspase-8, Bid, and caspase-3 activation.
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PMID:Reovirus-induced apoptosis requires both death receptor- and mitochondrial-mediated caspase-dependent pathways of cell death. 1218 43

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.
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PMID:Prevention of bile acid-induced apoptosis by betaine in rat liver. 1229 30

Inhibitor of differentiation-2 (Id2) is a basic helix-loop-helix protein that acts as a negative regulator of the myogenic regulatory transcription factor family, but Id2 has also been implicated in apoptosis in several cell lines. In this study, we tested the hypothesis that Id2 has a role in both apoptosis-associated muscle atrophy and muscle hypertrophy. A weight corresponding to 12% of the body weight was attached to one wing of Japanese quail to induce hypertrophy in the patagialis (PAT) muscle. Birds in group 1 were killed after 5 (n = 8), 7 (n = 10), or 14 days (n = 10) of loading. The left wing was loaded for 14 days in group 2 birds, and then the weight was removed and the PAT was examined after 7 (n = 10), 14 (n = 10), or 21 (n = 5) days of unloading. A time-released bromodeoxyuridine (BrdU) pellet was implanted subcutaneously with wing weighting to identify activated satellite cells during loading. The left wing was loaded for 14 days, unloaded for 14 days, and then the weight was reattached for a subsequent 7 (n = 10) or 14 days (n = 10) in group 3 birds. BrdU was implanted on the second loading phase in this group. Id2 mRNA as measured by kinetic PCR increased by 3.9-, 2.7-, and 1.6-fold, relative to control levels after 7, 14, and 21 days of unloading (group 2). Id2 protein as estimated by Western blots increased by 1.5-, 1.4-, and 0.75-fold after 7, 14, and 21 days of unloading (group 2). Muscle unloading induced apoptosis, because poly(ADP-ribose) polymerase-(PARP)-positive nuclei increased and caspase 8 levels increased by 2.6- and 1.7-fold after 7 or 14 days of unloading, respectively (group 2). Although BrdU-positive nuclei increased during loading (groups 1 and 3), 50% failed to survive during unloading (group 2). Id2 mRNA increased by 2.2- and 1.8-fold after 5 and 7 days of loading, respectively, but decreased to control levels by 14 days of loading in group 1. Id2 protein levels increased 2.1-fold after 5 days of loading (group 1). In contrast, Id2 did not increase in reloaded muscles of group 3 birds. These data suggest that Id2 may have a role in apoptosis-associated atrophy of skeletal muscles, but its role in muscle hypertrophy is less clear.
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PMID:Id2 expression during apoptosis and satellite cell activation in unloaded and loaded quail skeletal muscles. 1252 89

The effect of the human papillomavirus type 16 (HPV-16) E5 protein on apoptosis was investigated by using the polyclonal HaCaT-cell lines stably transfected either with E5 (HaCaT/E5) or the empty vector (HaCaT/pMSG) as reference. Apoptosis was triggered either by Fas ligand (FasL) or by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and was monitored by detection of cleavage of procaspase-8 and procaspase-3, as well as their substrate poly(ADP-ribose) polymerase (PARP). In contrast to the HaCaT/pMSG control cells we found that apoptosis induced by either of the two ligands is strongly suppressed in the E5-expressing keratinocytes. Fas expression is reduced by about a factor of two in HaCaT/E5 cells, which could be part of the mechanisms that protect the cells from FasL-induced apoptosis. For the TRAIL receptors, no such downregulation was observed. Here, E5 impairs the formation of the death-inducing signaling complex triggered by TRAIL. Apparently, E5 employs different mechanisms to inhibit death receptor signaling. This effect is not restricted to HaCaT/E5 cells since we found that the mouse fibroblast cell line A31-E5 is protected from TRAIL-induced apoptosis, as well but not the E5-lacking control cells A31-Neo. However, no such protection was observed upon FasL-induced apoptosis. Presumably, some of the antiapoptotic mechanisms employed by E5 of the human pathogenic HPV-16 are cell type specific. We propose that inhibition of ligand-mediated apoptosis in human keratinocytes is a primary function of the HPV-16 E5 protein needed to prevent apoptosis at early stages of viral infection.
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PMID:The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms. 1241 56


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