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)

The profound neuroprotection observed in poly(ADP-ribose) polymerase-1 (PARP-1) null mice to ischemic and excitotoxic injury positions PARP-1 as a major mediator of neuronal cell death. We report here that apoptosis-inducing factor (AIF) mediates PARP-1-dependent glutamate excitotoxicity in a caspase-independent manner after translocation from the mitochondria to the nucleus. In primary murine cortical cultures, neurotoxic NMDA exposure triggers AIF translocation, mitochondrial membrane depolarization, and phosphatidyl serine exposure on the cell surface, which precedes cytochrome c release and caspase activation. NMDA neurotoxicity is not affected by broad-spectrum caspase inhibitors, but it is prevented by Bcl-2 overexpression and a neutralizing antibody to AIF. These results link PARP-1 activation with AIF translocation in NMDA-triggered excitotoxic neuronal death and provide a paradigm in which AIF can substitute for caspase executioners.
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PMID:Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. 1557 46

R-flurbiprofen, a non cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID), has been found to inhibit tumor growth in various animal models. In vitro experiments have shown that this effect is based on the induction of a cell cycle block and apoptosis. Cell cycle inhibition has been explained by activation of the c-Jun-N-terminal kinase (JNK) and downregulation of cyclin D1 expression. However, the molecular mechanism leading to apoptosis is unknown. Here, we show that treatment of the human colon carcinoma cell line HCT116 with different concentrations of R-flurbiprofen leads to an accumulation of p53 protein which is accompanied by an increase in phosphorylated p53 at serine 15. Mutation of serine 15 to alanine by site directed mutagenesis and overexpression of the mutated p53 gene in HCT116 cells, revealed that these cells are significantly less sensitive to apoptosis induced by R-flurbiprofen than pcDNA control cells, as measured by PARP-cleavage and flow cytometry. By contrast, no difference was detected between HCT116p53ser15ala cells and HCT116 pcDNA cells with respect to induction of a cell cycle block after R-flurbiprofen treatment. Moreover, in nude mice HCT116p53ser15ala overexpressing xenografts were significantly less sensitive to R-flurbiprofen than HCT116 pcDNA control xenografts. In conclusion, we were able to show that induction of apoptosis in HCT116 cells after R-flurbiprofen treatment is at least partly dependent on the tumor suppressor gene p53 and that mutation of p53 at serine 15 impairs the apoptotic potency of R-flurbiprofen.
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PMID:Induction of apoptosis by R-flurbiprofen in human colon carcinoma cells: involvement of p53. 1571 Mar 60

The cytoskeleton is critical to neuronal functioning and survival. Cytoskeletal alterations are involved in several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We studied the possible pathways involved in colchicine-induced apoptosis in cerebellar granule neurons (CGNs). Although colchicine evoked an increase in caspase-3, caspase-6 and caspase-9 activation, selective caspase inhibitors did not attenuate apoptosis. Inhibitors of other cysteine proteases such as PD150606 (a calpain-specific inhibitor), Z-Phe-Ala fluoromethyl ketone (a cathepsins-inhibitors) and N(alpha)-p-tosyl-l-lysine chloromethyl ketone (serine-proteases inhibitor) also had no effect on cell death/apoptosis induced by colchicine. However, BAPTA-AM 10 microM (intracellular calcium chelator) prevented apoptosis mediated by cytoskeletal alteration. These data indicate that calcium modulates colchicine-induced apoptosis in CGNs. PARP-1 inhibitors did not prevent apoptosis mediated by colchicine. Finally, colchicine-induced apoptosis in CGNs was attenuated by kenpaullone, a cdk5 inhibitor. Kenpaullone and indirubin also prevented cdk5/p25 activation mediated by colchicine. These findings indicate that cytoskeletal alteration can compromise cdk5 activation, regulating p25 formation and suggest that cdk5 inhibitors attenuate apoptosis mediated by cytoskeletal alteration. The present data indicate the potential therapeutic value of drugs that prevent the formation of p25 for the treatment of neurodegenerative disorders.
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PMID:Evaluation of the neuronal apoptotic pathways involved in cytoskeletal disruption-induced apoptosis. 1595 Sep 51

Multiple myeloma is a clonal malignancy of plasma cells that invariably progresses to a chemoresistant state. The PI3K/Akt pathway mediates signals downstream of several growth factors involved in myeloma pathogenesis, and constitutive activation of Akt was observed in myeloma cells. We now report that a staurosporine derivative, N-benzoylated staurosporine or PKC412, induces cell death in myeloma cell lines (RPMI8226S, U266, MM1S and MM1R) with loss of mitochondrial membrane potential Delta psi m, caspase 3 and PARP cleavage. ZVAD.fmk, but not interleukin-6, rescued these cells from PKC412 effects. Upstream of the mitochondria, PKC412 inhibited Bad phosphorylation and attenuated Akt kinase activity by suppressing its phosphorylation on serine residue in its activation loop. Reduced phosphorylation of downstream Akt substrates GSK3 alpha/beta and FKHR was also noted. Stable transfection of 8226S cells with constitutively active Akt (8226S-myAkt) partially protected against PKC412 cytotoxicity. Primary myeloma cells isolated from refractory myeloma patients (n=4), were equally sensitive to PKC412 treatment. More importantly, PKC412 did not affect CFU-GM or BFU-E colony formation. In summary, our results demonstrate that PKC412 suppresses Akt kinase activation and induces apoptosis in myeloma cell lines, as well as primary resistant cells. PKC412 is an appropriate candidate for novel treatment protocols for multiple myeloma.
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PMID:N-benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells. 1601 36

We recently observed an interaction between poly(ADP-ribose) polymerase-1 (PARP-1) and the tumor suppressor p53 protein. However, more extensive studies on both proteins, especially those on characterization of their domains involved in the interaction were difficult due to very low expression levels of p53 in mammalian cells. Therefore, we generated recombinant proteins for such studies. To clarify which domains of human PARP-1 and of human wild-type (wt) p53 were involved in this protein-protein interaction, we generated baculoviral constructs encoding full length or distinct functional domains of both proteins. Full length PARP-1 was simultaneously coexpressed in insect cells with full length wt p53 protein or its distinct truncated fragments and vice versa. Reciprocal immunoprecipitation of Sf9 cell lysates revealed that the central and carboxy-terminal fragments of p53 each were sufficient to confer binding to PARP-1, whereas the amino-terminal part harbouring the transactivation functional domain was dispensable. On the other hand, the amino-terminal and central fragments of PARP-1 were both necessary for complex formation with p53 protein. Since the most important features of p53 protein are regulated by phosphorylation, we addressed the question whether its phosphorylation is essential for the binding between the two proteins. Baculovirally expressed wt p53 was post-translationally modified. At least six distinct p53 isomers were resolved by immunoblotting following two-dimensional separation of baculovirally expressed wt p53 protein. Using specific phospho-serine antibodies, we identified phosphorylation of baculovirally expressed p53 protein at five distinct sites. To define the role of p53 phosphorylation, pull-down assays using untreated and dephosphorylated p53 protein were performed. Dephosphorylated p53 failed to bind PARP-1, indicating that complex formation between the two proteins was regulated by phosphorylation of p53. The marked phosphorylation of p53 at Ser392 observed in unstressed cells suggests that the phosphorylated carboxy-terminal part of p53 undergoes complex formation with PARP-1 resulting in masking of the NES and thereby preventing its export.
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PMID:Advantage of a baculovirus expression system for protein-protein interaction studies. Involvement of posttranslational phosphorylation in the interaction between wt p53 protein and poly(ADP-ribose) polymerase-1. 1608 9

Microtubule active drugs are used in the treatment of malignancies and their mechanism of action in cycling cells is to produce mitotic arrest followed by apoptosis. In this study, we investigate in detail the specificity and mechanism by which a microtubule de-polymerising agent, nocodazole, induces apoptosis in non-cyclingm, i.e. G(0)/G(1), chronic lymphocytic leukaemia (CLL) B-cells. The majority of cases of CLL are sensitive (IC(50)<or=16 microM) but normal peripheral blood B-cells, which are also in G(0)/G(1), are resistant to the maximum in vitro concentration of this agent. Taxol, a microtubule stabilising drug does not kill CLL cells suggesting a specific effect of nocodazole. The mechanism of apoptosis involves mitochondrial membrane depolarisation, activation of caspases and cleavage of PARP. Nocodazole causes two patterns of change to Bcl-2 expression. In one there is increase in expression of the serine-70 phosphorylated form of Bcl-2 and in the other total Bcl-2 expression is reduced. Collectively the data shows that sensitivity to nocodazole-induced apoptosis is a feature of chronic lymphocytic leukaemia and suggests that newer microtubule active agents be systematically investigated for their effectiveness in this condition.
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PMID:Nocodazole, a microtubule de-polymerising agent, induces apoptosis of chronic lymphocytic leukaemia cells associated with changes in Bcl-2 phosphorylation and expression. 1616 58

The cell cycle-regulated Aurora-B kinase is a chromosomal passenger protein that is implicated in fundamental mitotic events, including chromosome alignment and segregation and spindle checkpoint function. Aurora-B phosphorylates serine 10 of histone H3, a function that has been associated with mitotic chromatin condensation. We find that activation of poly(ADP-ribose) polymerase (PARP) 1 by DNA damage results in a rapid block of H3 phosphorylation. PARP-1 is a NAD(+)-dependent enzyme that plays a multifunctional role in DNA damage detection and repair and maintenance of genomic stability. Here, we show that Aurora-B physically and specifically associates with the BRCT (BRCA-1 C-terminal) domain of PARP-1. Aurora-B becomes highly poly(ADP-ribosyl)ated in response to DNA damage, a modification that leads to a striking inhibition of its kinase activity. The highly similar Aurora-A kinase is not regulated by PARP-1. We propose that the specific inhibition of Aurora-B kinase activity by PARP-1 contributes to the physiological response to DNA damage.
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PMID:Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. 1617 89

The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20microM) and ARA (20microM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia.
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PMID:Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. 1621 66

N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid effective in cancer chemoprevention and therapy, is thought to act via apoptosis induction resulting from increased reactive oxygen species (ROS) generation. As ROS can activate MAP kinases and protein kinase C (PKC), we examined the role of such enzymes in 4HPR-induced apoptosis in HNSCC UMSCC22B cells. 4HPR increased ROS level within 1 h and induced activation of caspase 3 and PARP cleavage within 24 h. Activation of MKK3/6 and MKK4, JNK, p38 and ERK was detected between 6 and 12 h, increased up to 24 h and preceded apoptosis. 4HPR-induced activation of these kinases was abrogated by the antioxidants BHA and vitamin C. SP600125, a JNK inhibitor, suppressed 4HPR-induced c-Jun phosphorylation, cytochrome c release from mitochondria and apoptosis. Suppression of JNK1 and JNK2 using siRNA decreased, whereas overexpression of wild type-JNK1 enhanced 4HPR-induced apoptosis. PD169316, a p38, inhibitor suppressed phosphorylation of Hsp27 and apoptosis. PD98059, an MEK1/2 inhibitor, also suppressed ERK1/2 activation and apoptosis induced by 4HPR. Likewise, PKC inhibitor GF109203X suppressed ERK and p38 phosphorylation and PARP cleavage. These data indicate that 4HPR-induced apoptosis is triggered by ROS increase, leading to the activation of the mitogen-activated protein serine/threonine kinases JNK, p38, PKC and ERK, and subsequent apoptosis.
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PMID:N-(4-hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells. 1640 47

Ultraviolet light (UV) inhibits translation initiation through activation of kinases that phosphorylate the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha). Two eIF2alpha kinases, PERK and GCN2, are known to phosphorylate the Serine-51 of eIF2alpha in response to UV-irradiation. In this report, we present evidence that phosphorylation of eIF2alpha plays a role in UV-induced apoptosis. Our data show that wild-type mouse embryo fibroblasts (MEF(s/s)) are less sensitive to UV-induced apoptosis than MEF(A/A) cells in which the phosphorylation site, Ser51, of eIF2alpha is replaced with a non-phosphorylatable Ala (Ser51Ala). PARP expression in MEF(A/A) cells is reduced without being cleaved after UV-irradiation. In contrast, PARP is cleaved without a significant decrease in parental PARP in MEF(S/S) cells after UV-irradiation. Our data also show that MEF(GCN2-/-) cells, in which GCN2 is knocked out, are more sensitive to UV-irradiation, agreeing with the observation from MEF(A/A) cells. However, MEF(PERK-/-) cells, in which PERK is knocked out, are less sensitive to UV-irradiation. In addition, MCF-7-PERKDeltaC cells, which are stably transfected with a kinase domain deleted mutant of PERK (PERKDeltaC), are more resistant to UV-induced apoptosis than parental MCF-7 cells. Overexpression of wild-type PERK sensitizes MCF-7 cells to UV-induced apoptosis without directly inducing cell death. These results suggest that the level of eIF2alpha phosphorylation impacts PARP expression upon UV-irradiation. The eIF2alpha kinases may mediate UV-induced apoptosis via an eIF2alpha dependent or independent signaling pathway.
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PMID:The roles of translation initiation regulation in ultraviolet light-induced apoptosis. 1678 87


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