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)

Excessive oxidative stress has been implicated in the induction of cell death in a variety of neurodegenerative diseases. In the present study, hydrogen peroxide (H2O2)-induced cell death in rat C6 glioma cells was used as a model system for studying the molecular events associated with oxidative stress-induced cell death in glial cells. We demonstrate that exposure of C6 glioma cells to H2O2 results in apoptotic cell death in a concentration-dependent manner, and caused activation of a member of the caspase-3-like family of proteases resulting in cleavage of the DNA repair enzyme poly(ADP-ribose)polymerase, PARP. Furthermore, H2O2 induced a transient activation of the transcription factor, nuclear factor kappa B (NF(Kappa)B). Pre-treatment of cells with the antioxidant N-acetylcysteine, (NAC), prevented both the activation of NF(Kappa)B and the induction of apoptosis by H2O2, suggesting a possible role for this transcription factor in oxidant-induced apoptosis in glial cells. Exposure of the cells to H2O2 led to transient activation of both c-Jun N-terminal kinase (JNK) and p38 kinase but has no effect on extracellular regulated kinase (ERK) activity. Inhibition of p38 by SB203580 did not protect the cells against H2O2-induced apoptosis suggesting that activation of p38 is not essential for H2O2-mediated cell death in C6 glioma cells.
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PMID:Oxidative stress induces apoptosis in C6 glioma cells: involvement of mitogen-activated protein kinases and nuclear factor kappa B. 1471 69

Taxotere is a cytotoxin effective in treating breast and prostate cancer. It stabilizes microtubules and causes catastrophic cell cycle arrest in G2/M. Taxanes also initiate apoptosis by activating signal pathways, such as the jun N-terminal kinase (JNK) pathway. Strategies aimed at potentiating cell death signaling may improve their efficacy while lessening the potential side effects. We reported that all-trans retinoic acid (ATRA) potentiated taxane-mediated cell death. Here we investigated whether ATRA potentiates cell death signaling through the JNK pathway. Activation of JNK by Taxotere 0.01, 0.1 and 1.0 microM was observed at 24 h in adherent cells and increased at 48 h. Taxotere 0.001 microM-induced JNK activation started after 48 h and increased at 72 h. The timing and intensity of PARP cleavage was similar to that of JNK activation. JNK activation and PARP cleavage induced by 30 nM Taxotere at 48 h were reversed by curcumin, PD169316 and SP600125, JNK inhibitors in order of progressive specificity. None of these inhibitors had an effect on p38 or ERK phosphorylation. All three inhibitors reversed Taxotere-induced phosphorylation of Bcl-2. ATRA induced JNK activation at 24, 48 and 72 h. Incubating cells with ATRA 0.01 microM for 3 days prior to Taxotere treatment potentiated Taxotere-induced JNK activation 24 and 48 h later, an effect sustained for 72 h. Cytotoxicities from 3-day ATRA 0.01 microM incubations were synergistic with subsequent 1-h Taxotere 0.01, 0.1 and 1.0 microM incubations in breast cancer cell lines MCF-7 and MDA-MB-231 and in prostate cancer cell lines LNCaP and PC-3, and additive in breast cancer cell line SK-Br-3. These data demonstrate the potentiation of Taxotere-induced cell death by ATRA pretreatment in breast and prostate cancer cells, and support a mechanism through accentuated and sustained JNK activation.
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PMID:All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells. 1472 71

ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.
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PMID:ZBP-89-induced apoptosis is p53-independent and requires JNK. 1496 12

The mechanisms of ultraviolet-B (UV-B)-induced apoptosis and the role of p38 mitogen-activated protein kinase (MAPK) were investigated in murine peritoneal macrophages. Exposure of murine peritoneal macrophages to UV-B irradiation induced rapid apoptosis concurrent with DNA fragmentation and activation of caspase-3 but did not activate caspase-1. UV-B irradiation (100 mJ/cm2) also induced expression of phospho-p38 and -c-Jun N-terminal kinase (JNK) MAPK; however, no significant expression of phospho-p42/44 was observed 120 min after exposure. Pretreatment of macrophages with a p38 MAPK inhibitor, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190), and a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-CHO, suppressed UV-B irradiation-induced apoptosis as observed by DNA laddering and DNA fragmentation estimation quantitatively. Pretreatment with caspase-1 inhibitor, N-acetyl-Tyr-Val-Ala-Asp-CHO, had no effect. UV-B-induced caspase-3 activation resulted in the cleavage of poly-(ADP-ribose) polymerase (PARP), which was inhibited by the caspase-3 inhibitor. SB202190 pretreatment also prevented activation of caspase-3 and the cleavage of PARP. However, the caspase-3 and -1 inhibitors did not affect UV-B-induced expression of phospho-p38 and -JNK. These results suggest that activation of p38 MAPK upstream of caspases might play an important role in the apoptotic process of macrophages exposed to UV-B irradiation.
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PMID:Role of p38 mitogen-activated protein kinase and caspases in UV-B-induced apoptosis of murine peritoneal macrophages. 1497 15

We investigated the ceramide-induced apoptosis and potential mechanism in A-431 cells. Ceramide treatment causes the round up and the death of A-431 cells that is associated with p38 activation and can be observed in 10 h. Short-time ceramide treatment-induced cell death is not associated with the typical apoptotic phenotypes, such as the translocation of phosphatidylserine (PS) from inner layer to outer layer of the plasma membrane, loss of mitochondrial membrane potential, DNA fragmentation, caspase activation, and PARP or PKC-delta degradation. SB202190, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, but not caspase inhibitor, blocks the cell death induced by short-time ceramide treatment (within 12 h). Whereas neither inhibition of p38 MAP kinase nor inhibition of caspases blocks cell death induced by prolonged ceramide treatment. Moreover, incubation of cells with ceramide for a long time (over 12 h) results in the reduction of proportion of S phase accompanied with typical apoptotic cell death phenotypes that are different from the cell death induced by short-time ceramide treatment. Our data demonstrated that ceramide-induced apoptotic cell death involves both caspase-dependent and caspase-independent signaling pathways. The caspase-independent cell death that occurred in relatively early stage of ceramide treatment is mediated via p38 MAP kinase, which can progress into a stage that is associated with changes of cell cycle events and involves both caspase-dependent and -independent mechanisms.
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PMID:Ceramide induces caspase-dependent and -independent apoptosis in A-431 cells. 1497 34

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is involved in numerous pathophysiological conditions. Because PARP-1 knockout mice are resistant to endotoxin-induced shock and inhibitors of the enzyme were reported to have similar beneficial properties, we investigated the effect of 4-hydroxyquinazoline (4-HQN), a potent PARP-1 inhibitor, on the modulation of kinase cascades and the regulation of transcription factors in a rodent septic shock model. T2-weighted magnetic resonance imaging showed the pattern of anatomical localization of the inflammatory response in bacterial lipopolysaccharide (LPS)-treated mice and the anti-inflammatory effect of the PARP-1 inhibitor. We have found that 4-HQN activated the phosphatidylinositol 3 (PI3)-kinase/Akt pathway in lung, liver, and spleen, and down-regulated two elements of the MAP kinase system. Namely, it dramatically attenuated the activation of the LPS-induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase in a tissue-specific manner. Furthermore, phosphorylation of p90RSK, a downstream target of ERK1/2, showed a similar pattern of down-regulation as did the phosphorylation of ERK1/2 and p38 after LPS and 4-HQN treatment. As a consequence of the aforementioned effects on the kinase pathways, 4-HQN decreased the activation of transcription factor nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) in LPS-induced endotoxic shock. Our results provide evidence for the first time that the beneficial effects of PARP inhibition in endotoxic shock, such as attenuation of NF-kappaB- and AP-1 transcription factor activation, are mediated, at least partially, through the regulation of the PI3-kinase/Akt pathway and MAP kinase cascades.
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PMID:Regulation of kinase cascades and transcription factors by a poly(ADP-ribose) polymerase-1 inhibitor, 4-hydroxyquinazoline, in lipopolysaccharide-induced inflammation in mice. 1499 56

Dehydroepiandrosterone (DHEA) is synthesized in the brain, but whether DHEA is involved in modulating neuronal cell survival is not yet fully understood. Herein we show that when deprived of trophic support, GT1-7 hypothalamic neurons undergo apoptosis following exposure to DHEA, as demonstrated both by morphological and biochemical criteria. This proapoptotic effect appeared to be specific to DHEA itself, and not through conversion of DHEA to other steroids such as androgen or estrogen. Importantly, we determined that IGF-I protects GT1-7 neurons from DHEA-induced cell death. DHEA-induced apoptosis was associated with increased activation of caspase 3 and decreased PARP, which were both attenuated with addition of IGF-I. Addition of DHEA prevented phosphorylation of both Akt and glycogen synthase kinase-3 beta (GSK-3beta), downstream effector molecules of the phosphatidylinositol 3-kinase (PI3K) pathway. Further IGF-I was able to sustain Akt activity and thus preventing GSK-3beta activation in the presence of DHEA. On the other hand, the MAP kinases, ERK, p38, and JNK, were not affected by DHEA. These findings suggest that in GT1-7 hypothalamic neurons, DHEA acts detrimentally to induce cell death and IGF-I is able to rescue the neurons by preserving the activity of Akt, and therefore maintaining the proapoptotic kinase GSK-3beta, in a phosphorylated catalytically inactive state.
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PMID:IGF-I signaling prevents dehydroepiandrosterone (DHEA)-induced apoptosis in hypothalamic neurons. 1506 51

The human ether-a-go-go-related gene (HERG) encodes a delayed rectifier K(+) channel, which is expressed in a variety of tissues and cells. Besides its well-recognized function in cellular electrophysiology, HERG channels have also been implicated in neuronal differentiation and cell cycle regulation. We have recently found that HERG regulates apoptosis. To elucidate the signaling pathways, we performed studies in HEK293 cells stably expressing HERG channels. ELISA was used to quantify DNA fragmentation, a biochemical hallmark of apoptosis. In HERG-transfected HEK cells, the degree of DNA fragmentation was found consistently higher (approximately 4-times) than in non-transfected cells. Correspondingly, remarkable activation of caspase 3, caspase 9 and cleavage of PARP were seen in HERG-expressing cells, which were otherwise minimal in non-transfected cells. Exposure of cells to H(2)O(2) (10 hrs) at concentrations up to 1 mM, which is known to induce apoptosis in a variety of cells, caused minimal DNA fragmentation in non-transfected cells. HERG expression facilitates DNA fragmentation induced by H(2)O(2) at a concentration-dependent fashion, starting at 200 microM and reaching maximum at 1 mM. Selective HERG channel inhibitors, dofetilide or E-4031 (5 microM) prevented DNA fragmentation. Inhibition of p38 by SB-203580 alleviated DNA-F and PD-98059, which inhibited activation of ERKs, nearly abolished DNA-F. Immunoblotting analysis demonstrated that p38, SAPKs and ERKs MAP kinases were all substantially activated (>10-fold higher) in HERG-expressing cells vs. non-transfected cells. Akt activity was approximately 4-fold lower in HERG cells vs. non-transfected cells in the absence of H(2)O(2) and was slightly increased (approximately 2-fold) after H(2)O(2) exposure. We conclude that HERG channels facilitate cellular DNA fragmentation in HEK cells via concomitant activation of MAP kinases and inactivation of Akt.
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PMID:HERG K channel conductance promotes H2O2-induced apoptosis in HEK293 cells: cellular mechanisms. 1510 89

The dual Ser/Thr kinase MKK4 and its downstream targets JNK and p38 regulate critical cellular functions during embryogenesis and development. MKK4 has been identified as a putative tumor-suppressor gene in human solid tumors of breast, prostate and pancreas. To clarify the mechanisms underlying the transforming potential of molecular defects targeting MKK4, we have generated totipotent embryonic stem (ES) cells expressing the dominant-negative mutant DN-MKK4(Ala), S257A/T261A. Stably transfected DN-MKK4-ES cells exhibit a transformed fibroblast-like morphology, reduced proliferation rate, were no more submitted to cell contact inhibition, were growing in soft agar, and were much more tumorigenic than parental ES cells in athymic nude mice. These phenotypic changes: (i) are consistent with the protection of DN-MKK4-transfected ES cells from spontaneous, cell density-dependent, and stress-induced apoptosis (DAPI staining and poly (ADP-ribose) polymerase (PARP) cleavage) and (ii) correlated with alterations in JNK, p38, and Erk-1/-2 MAPK/SAPK signaling. Taken together, our data provide a new mechanism linking the MKK4 signaling pathways to cancer progression and identify MKK4 as a tumor-suppressor gene implicated in several transforming functions.
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PMID:Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. 1512 34

Rat neonatal ventricular myocytes exposed to simulated ischaemia and reperfusion (SI/R) were used as an in vitro model to delineate the role(s) of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal protein kinase (JNK), as well as PKB in apoptosis. Exposure of the myocytes to SI (simulated ischaemia - energy depletion induced by KCN and 2-deoxy- D-glucose) reduced cell viability, as measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and stimulated apoptosis as evidenced by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage. However, morphological evidence of increased apoptosis, detected by staining with Hoechst 33342, was only seen in response to reperfusion. This suggests that although ischaemic conditions are sufficient to induce cellular markers of apoptosis (PARP cleavage and caspase-3 activation), reperfusion is required to complete the apoptotic pathway in these cells. Furthermore, SI resulted in a rapid, strong, biphasic activation of p38 concomitant with a weak and transient activation of the two ERK isoenzymes, p42/p44-MAPK. Reperfusion for 5 minutes resulted in a strong phosphorylation of p42/p44-MAPK, while no additional p38 activation was seen at this stage. On the other hand, p46/p54-MAPK (JNK) was phosphorylated in response to 5 minutes of reperfusion only and not during SI alone. A peak of PKB/Akt (Ser(473)) activity was seen within 5 minutes of exposure to SI, whereas PKB/Akt (Thr(308)) phosphorylation remained at the baseline level. Both PKB/Akt phosphorylation sites (Ser(473) and Thr(308)) were phosphorylated after 5 minutes of reperfusion. Inhibition of PI-3-kinase activity, using wortmannin, decreased phosphorylation on both sites during SI. However, only SI/R-induced PKB/Akt phosphorylation on Thr(308) was reduced by wortmannin. Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant increase in cell viability [63.67 +/- 1.85 to 84.33 +/- 4.8% (p < 0.05)] and attenuation of the apoptotic index during SI/R [22.6 +/- 2.94% to 9 +/- 0.43% (p < 0.001)], while SP600125, a specific JNK inhibitor, caused a significant increase in caspase-3 activation [1.66 +/- 0.03 fold to 2.56 +/- 0.27 fold (p < 0.001)] and apoptotic index [22.6 +/- 2.94% to 32.75 +/- 6.13% (p < 0.05)]. However, PD98059, an ERK inhibitor, failed to affect apoptosis during SI/R. Inhibition of PI-3-kinase prevented the increase in mitochondrial viability usually observed during reperfusion. Interestingly, wortmannin caused a significant increase in PARP cleavage during reperfusion, but had no effect on caspase-3 activation or the apoptotic index. Our results suggest that p38 has a pro-apoptotic role while JNK phosphorylation is protective in our cell model and that these kinases act via caspase-3 to prevent or promote cell survival in response to SI/R-induced injury.
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PMID:p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes. 1530 13


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