Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigates synergistic effects of the TNF-alpha inhibitor thalidomide and the poly(ADP-ribose) polymerase (PARP)-inhibitor nicotinic acid amide (NAA) in male DBA/1 hybird mice suffering from type II collagen-induced arthritis. Parameters including the arthritis index, chemiluminescence and anti-collagen antibody titers were used for the assessment of disease activity: The disease courses demonstrated clearly an inhibitory effect of thalidomide. NAA inhibited established collagen arthritis in a dose-dependent manner. The combined application of thalidomide and NAA caused a powerful synergistic inhibition of arthritis. Furthermore, thalidomide and NAA were tested ex vivo for their inhibition of the NADPH oxidase-dependent generation of reactive oxygen species by activated neutrophils and monocytes in unseparated human blood. Our data show that type II collagen-induced arthritis can be suppressed by the simultaneous inhibition of TNF-alpha, PARP, and NADPH oxidase.
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PMID:Synergistic effects of thalidomide and poly (ADP-ribose) polymerase inhibition on type II collagen-induced arthritis in mice. 872 22

Cytochrome c release from mitochondria to and subsequent accumulation in the cytosol has been considered a prerequisite for apoptosis. In this study, we present evidence for apoptosis induction without accumulation of cytochrome c in the cytosol. U937 lymphoma cells treated with staurosprine released cytochrome c from mitochondria to cytosol prior to PARP cleavage and DNA fragmentation. However, U937 cells treated with BMD188 (a hydroxamic acid and a potent apoptosis inducer) did not demonstrate any cytochrome c accumulation in the cytosol during apoptosis induction. This different pattern of cytochrome c alterations was also observed with these two inducers on leukemic HL60 cells and epithelial PC3 cells. Furthermore, when PC3 cells were treated with a panel of apoptosis-inducing agents, it was found that camptothecin, bleomycin, VP16 and TNF-alpha induced varying amounts of cytosolic accumulation of cytochrome c either prior to or concurrent with PARP cleavage while vinblastine and BHPP did not. Taken together, the present results suggest that cytochrome c accumulation in the cytosol during apoptosis is a cell type- and inducer-dependent phenomenon.
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PMID:Apoptosis in the absence of cytochrome c accumulation in the cytosol. 944 3

Aging is characterized by increased T cell lymphopenia, T cell dysfunction, and increased serum TNF levels. In this study, we have examined the role of TNF-induced apoptosis in T cell deficiency in lymphocytes from aged humans. The constitutive expression of TNF receptors (TNFRI and TNFRII) and the adapter molecules, including TNFR-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF-2), and receptor interacting protein (RIP), were analyzed both at the protein level by flow cytometry or Western blotting, and at the mRNA level using quantitative PCR or Northern blotting in lymphocytes from aged and young subjects. The susceptibility of T cells to undergo TNF-induced apoptosis was analyzed using terminal deoxynucleotidyltransferase-mediated UTP-end-labeling (TUNEL) and DNA ladder assays. Caspase (caspase-8 and caspase-3) activation was compared between aged and young subjects using Western blotting and colorimetric assays. In lymphocytes from aged humans, there was an increased susceptibility of CD4+ and CD8+ T cells to undergo TNF-alpha-induced apoptosis, as observed by TUNEL assay and DNA fragmentation ladder assay. Increased TNF-alpha-induced apoptosis was also observed in both CD45RA+ and CD45RO+ T cells from aging subjects. An increased constitutive expression of TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were observed in lymphocytes from aged as compared with young controls. In addition, there was an early and increased activation of caspases (caspase-8 and caspase-3) involved in TNFR/TNF signaling pathway, as evident by early cleavage of caspase-8, poly(ADP-ribose) polymerase (PARP), and caspase-3 substrate DEVD-p-nitroamilide NA. These data suggest that an increased TNF-alpha-induced apoptosis may play a role in T cell deficiency associated with human aging.
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PMID:Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. 997 90

Cholangiocarcinoma (CCA), a tumour of the bile duct epithelium, occurs with a higher incidence in South-east Asian countries than in Europe and North America. The prognosis is poor, due to the unavailability of early diagnosis and the tumours being relatively resistant to chemotherapy. In the present study one of the fatal routes of this tumour was studied. This death was stimulated by TNF-alpha. TNF-alpha at a concentration of 760 pg/ml and 100 pg/ml in the presence of 1 microgram/ml actinomycin D induced 50% cell death of the two established human cholangiocarcinoma cell lines HuCCA-1 and HuCCA-INu, respectively. Preincubation of both cell lines with MoAb to TNF-RI or TNF-RII before TNF-alpha treatment showed that only the MoAb specific to TNF-RI inhibited death. The death of these two cell lines was proved to be apoptosis. Western blot analysis of extracts from both cell lines demonstrated a cleavage of poly (ADP-ribose) polymerase (PARP) within 6-8 h following TNF-alpha treatment. The degradation of PARP was prevented by a MoAb to TNF-RI indicating that the TNF-RI but not TNF-RII was involved in TNF-induced apoptosis in these two human cholangiocarcinoma cell lines. Moreover, peptide inhibitor for caspase II subfamily, Ac-DEVD-CHO, reduced the cytolysis of TNF-alpha-treated cholangiocarcinoma cells. The inhibitor also prevented degradation of PARP. These results indicate that the interaction between TNF-alpha and TNF-RI alone generated a sufficient signal to activate a caspase II subfamily-dependent apoptosis in human cholangiocarcinoma cell lines.
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PMID:Binding of tumour necrosis factor-alpha (TNF-alpha) to TNF-RI induces caspase(s)-dependent apoptosis in human cholangiocarcinoma cell lines. 1020 3

PED/PEA-15 is a recently cloned 15 kDa protein possessing a death effector domain (DED). In MCF-7 and HeLa cells, a fivefold overexpression of PED/PEA-15 blocked FasL and TNFalpha apoptotic effects. This effect of PED overexpression was blocked by inhibition of PKC activity. In MCF-7 and HeLa cell lysates, PED/PEA-15 co-precipitated with both FADD and FLICE. PED/PEA-15-FLICE association was inhibited by overexpression of the wild-type but not of a DED-deletion mutant of FADD. Simultaneous overexpression of PED/PEA-15 with FADD and FLICE inhibited FADD-FLICE co-precipitation by threefold. Based on cleavage of the FLICE substrate PARP, this inhibitory effect was paralleled by a threefold decline in FLICE activation in response to TNF-alpha. TNFalpha, in turn, reduces PED association with the endogenous FADD and FLICE of the cells. Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis. At least in part, this function may involve displacement of FADD-FLICE binding through the death effector domain of PED/PEA-15.
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PMID:PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. 1044 31

Poly (ADP-ribose) polymerase-1 is a nuclear DNA-binding protein that participates in the DNA base excision repair pathway in response to genotoxic stress in mammalian cells. Here we show that PARP-1-deficient cells are defective in NF-kappaB-dependent transcription activation, but not in its nuclear translocation, in response to TNF-alpha. Treating mice with lipopolysaccharide (LPS) resulted in the rapid activation of NF-kappaB in macrophages from PARP-1(+/+) but not from PARP-1(-/-) mice. PARP-1-deficient mice were extremely resistant to LPS-induced endotoxic shock. The molecular basis for this resistance relies on an almost complete abrogation of NF-kappaB-dependent accumulation of TNF-alpha in the serum and a down-regulation of inducible nitric oxide synthase (iNOS), leading to decreased NO synthesis, which is the main source of free radical generation during inflammation. These results demonstrate a functional association in vivo between PARP-1 and NF-kappaB, with consequences for the transcriptional activation of NF-kappaB and a systemic inflammatory process.
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PMID:Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. 1044 10

The human prostatic carcinoma cell line LNCaP is sensitive to TNF-alpha treatment and expresses wild-type p53. To analyse the possible role of p53 in TNF-alpha-mediated apoptosis, we generated a derivative of LNCaP, LN-56, expressing a dominant-negative element of p53, GSE56. P53 inactivation in LN-56 was associated with an increased resistance to apoptosis induced by TNF-alpha. Surface expression of TNF-alpha receptors was unchanged in LN-56 compared to LNCaP. TNF-alpha treatment resulted in accumulation of p53 in LNCaP and upregulation of p21/WAF1. Activation of caspase-7 and PARP proteolysis were delayed in LN-56 under TNF-alpha treatment. TNF-alpha-induced apoptosis in LNCaP cells was accompanied by caspase-dependent proteolysis of p21/WAF1 and Rb, which was significantly attenuated in LN-56. Cytochrome c release was induced by TNF-alpha treatment in both cell lines, but caspase-9 was not activated. LNCaP and LN-56 were injected s.c. in nude mice and tumors were identified in all LN-56, but not LNCaP, bearing mice indicating that p53 plays an important role in growth control of prostatic neoplasms. Interestingly, accumulation of p53 in TNF-alpha-treated LNCaP cells was decreased in the presence of the caspase inhibitor Z-VAD-FMK, suggesting a new role of activated caspases in acceleration of p53 response. In summary, these results indicate that p53 is involved in TNF-alpha-mediated apoptosis in LNCaP.
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PMID:p53 is involved in tumor necrosis factor-alpha-induced apoptosis in the human prostatic carcinoma cell line LNCaP. 1077 86

Collapse of the mitochondrial potential (DeltaPsi(m)) during apoptosis has been linked with a release of cytochrome c and apoptosis-inducing factor (AIF) and activation of caspases. Using a laser scanning cytometer (LSC), an instrument that allows one to measure the same cells twice, first when they are alive and subsequently after their permeabilization, we explored whether dissipation of DeltaPsi(m) (measured supravitally) is a prerequisite for the activation of caspases (detected after cell fixation). Apoptosis of HL-60 cells was induced either by TNF-alpha combined with cycloheximide (CHX) or by the DNA topoisomerase I inhibitor camptothecin (CPT) and of U-937 cells by CPT, and DeltaPsi(m) was measured using the carbocyanine fluorochrome DiIC(1) (5). The marker of caspase activation was specific cleavage of poly(ADP) ribose polymerase (PARP) detected immunocytochemically. After 30 or 60 min treatment with TNF-alpha + CHX or 60 or 120 min with CPT a considerable proportion of cells (20-40%) demonstrated PARP cleavage with no evidence of DeltaPsi(m) collapse. Also present in these cultures (3-20%) were cells with collapsed DeltaPsi(m) whose PARP was not cleaved. The results provide direct evidence that in HL-60 and U-937 cells treated with TNF-alpha + CHX or CPT the dissipation of DeltaPsi(m) is not required for activation of caspases and these two events are independent of each other.
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PMID:During apoptosis of HL-60 and U-937 cells caspases are activated independently of dissipation of mitochondrial electrochemical potential. 1083 43

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.
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PMID:Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells. 1131 91

Cholangiocarcinoma (CCA), a malignant tumor derived from bile duct epithelium, occurs with a higher incidence in tropical countires especially in some areas of Southeast Asian countries such as Thailand. This tumor is relatively resistant to chemotherapy. In this study, molecular mechanism of killing of this tumor by TNF-alpha was investigated. Human cholangiocarcinoma cell line (HuCCA-1) was developed and used as a model for treatment. Activation of HuCCA-1 with TNF-alpha in the present of actinomycin D (1 microg/ml) caused death of the tumor cells. Western blotting analysis of the cells extracted demonstrated the cleavage of poly (ADP-ribose) polymerase (PARP) within 6-8 hours following TNF-alpha treatment indicating apoptotic death. The cleavage of PARP was inhibited when the cell line was pretreated with peptide inhibitor, Ac-DEVD-CHO, suggesting that apoptosis induced by TNF-alpha of this cell line involves activation of caspase II subfamily. The procaspase 3 (proCPP-32), one of the caspase group II subfamily was degraded after the HuCCA- I cell line was treated with TNF-alpha. Furthermore, Gelsolin, an 83 kDa protein which is identified as caspase 3 substrate, was cleaved to 43 kDa fragments after the cells were treated with TNF-alpha. These results indicate that apoptosis of human cholangiocarcinoma cell line as induced by TNF-alpha treatment is mediated through caspase 3.
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PMID:TNF-alpha induces caspase 3 (CPP 32) dependent apoptosis in human cholangiocarcinoma cell line. 1141 50


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