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)

In this study, we used subtractive suppression hybridization to compare gene expression between an ALK-positive anaplastic large cell lymphoma (ALCL)-derived cell line and a clinical case of ALK-negative ALCL. Construction and screening of a subtracted library resulted in the cloning of 29 cDNAs which were differentially expressed. Most of these clones corresponded to novel genes with unknown function (EST) or to genes implicated in the differentiation, activation or signalling of T cells such as Ran/TC4, interleukin 1-receptor, thymosin beta4, thymosin beta10, moesin and cytohesin-1. Other genes involved in the regulation of apoptosis, such as human inhibitor of apoptosis-1 (HIAP-1), Bax inhibitor-1 and MCL-1, or DNA repair, such as poly (ADP-ribose) polymerase 1 (PARP-1), X-associated protein-1 (XAP-1), SUMO-1 (sentrin-1) and RanGTPase-activating protein 1 (RanGAP-1), were isolated. Interestingly, we found that both RNA and protein levels of human sterol isomerase (hSI), also referred to as emopamil binding protein (EBP), were overexpressed in ALK+ tumours. This protein is involved in the biosynthesis of cholesterol and may be activated by NPM-ALK. Overall, our results suggest that all the genes described above are upregulated in the NPM-ALK-driven transformation process, and that moesin and cytohesin-1 may be more specifically implicated in a signalling pathway involving PLCgamma and PI3K.
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PMID:Isolation of differentially expressed genes in NPM-ALK-positive anaplastic large cell lymphoma. 1218 Oct 47

Aplidin, a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of Aplidin induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by Aplidin demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C delta (PKC-delta) mediates the cytotoxic effect of Aplidin and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-delta show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-delta thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process.
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PMID:Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. 1238 16

We investigated the signal transduction pathway to low-dose radiation-induced apoptosis in vitro in the human peripheral primitive neuroectodermal tumor (pPNET) cell line with wild-type p53 established in our laboratory. Apoptosis was induced by 2Gy irradiation in an almost p53-dependent manner in this model except for a deficiency of the cleavage of caspase-9. It was detected 3 hours after irradiation by fragmentation assay. The expressions of p53, p21WAF-1 and Bax increased, in contrast to the gradually decreasing expression of Bcl-2, as observed by immunoblotting. Following this, cleavages of caspase-3 and PARP reached peak levels. There were no detectable increases in ERK expression and caspase-9 cleavage. In respect of the probability of other pathways to apoptosis, this cell line will provide a useful model both for investigating low-dose radiation-induced signal transduction pathway and for analyzing the biological characteristics of pPNET.
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PMID:Signal transduction pathway to low-dose radiation-induced apoptosis in peripheral PNET cells. 1252 90

Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.
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PMID:Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. 1258 73

Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53, and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context-dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function.
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PMID:The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide. 1290 45

Therapeutic options to inhibit growth of human NETs of the GEP system are limited. Since NSAIDs might provide an antiproliferative treatment alternative with acceptable toxicity, we examined the effects of different NSAIDs on growth and survival in a representative set of human GEP NET cell lines. Growth and apoptosis were determined based on cell numbers, cell-cycle analyses, kinase assays, DNA fragmentation and PARP cleavage. Expression of COX and cell cycle-regulatory molecules was examined by immunoblotting and reporter gene assays. Depending on the drug and cell line investigated, NSAID treatment resulted in profound growth inhibition of GEP NET cells. Growth-inhibitory effects were achieved with either COX-2 selective (NS398) or unselective (indomethacin, sulindac) compounds. Cell-cycle analyses documented a G1 arrest in NSAID-treated GEP NET populations. In addition, 100 microM sulindac or indomethacin induced apoptosis. All 3 COX inhibitors prevented CDK-2 activation. In parallel to the NSAID-mediated reduction of CDK-2 activity, p21(cip-1) promoter activity and cellular p21(cip-1) levels increased and p21(cip-1) was sequestered into CDK-2 complexes. Thus, the G1 arrest likely resulted from p21(cip-1)-dependent inhibition of CDK-2 activity. At therapeutically relevant concentrations, sulindac significantly reduced GEP NET cell numbers, whereas IFN-alpha and octreotide remained ineffective. The extent of growth inhibition in GEP NETs was comparable to the antiproliferative effects of sulindac in established NSAID-sensitive cell models. NSAIDs acted as potent antiproliferative agents in GEP NET cells via G1 cell-cycle arrest and might therefore offer a therapeutic alternative to current treatment modalities.
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PMID:Nonsteroidal anti-inflammatory drugs inhibit growth of human neuroendocrine tumor cells via G1 cell-cycle arrest. 1456 37

We have previously reported that XK469 inhibited topoisomerase (topo) IIbeta, in Waldenstrom's macroglobulinemia cell line (WSU-WM) however the inhibition alone is not sufficient to induce apoptosis. In this study, the apoptotic potential of XK469 and its mechanism in WSU-WM cell line was investigated. Exposure of WSU-WM cells to XK469 caused a decrease in viable cell number in a dose-dependent manner. In addition, XK469 caused the activation of caspase 3 resulting in subsequent cleavage of PARP. These events were preceded by the release of cytochrome c from the mitochondria to the cytosol. Simultaneous exposure of cells to cyclosporin A prevented the release of cytochrome c to cytosol and reduced the loss of viability. XK469 caused the activation of p53 with up-regulation of p53-dependent proteins such as Bax, p21, Gadd 45 and cyclin B1 in association with G2M arrest. The addition of ubiquitin carboxyl terminal hydrolase (UCH-L1) inhibitor (NaBH4) inhibited up-regulation of p53 and p53 related molecules by XK469 and reduced the loss of viability. Pre-incubation with NOK-1, a monoclonal antibody that prevents Fas-Fas ligand interaction and is inhibitory to Fas signaling interfered with XK469 induced activation of caspase 8 and also reduced the loss of viability. Simultaneous exposure of all three inhibitors (cyclosporin A, NaBH4 and NOK-1) abrogated the toxicity of XK469 by 95%. These data define multiple sequences of biochemical events that mediate cell death induced by XK469. Our study suggests a complex mechanistic cascade of XK469-mediated apoptosis that involves Fas signaling pathway, ubiquitination, p53 activation and cytochrome c release.
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PMID:XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways. 1461 35

To examine the roles of PLD (phospholipase D) in the regulation of the apoptotic process, PLD1 and PLD2 were stably overexpressed in S1P3-CHO cells [CHO (Chinese-hamster ovary) cells expressing the S1P (sphingosine 1-phosphate) receptor S1P3]. Treatment of S1P3-CHO cells with ActD (actinomycin D) induced apoptosis, as shown by the occurrence of nuclear fragmentation and the caspase-dependent proteolytic cleavage of PARP [poly(ADP-ribose) polymerase] and protein kinase Cd. Overexpression of either PLD1 or PLD2 protected S1P3-CHO cells from ActD-induced apoptosis, as demonstrated by an increased number of viable cells and inhibition of PARP and protein kinase Cd cleavage. However, in the early phase of apoptosis, ActD induced an increase in PLD activity and activation of key factors in the cell-survival signalling pathways, such as PI3K (phosphoinositide 3-kinase), Akt, p70S6K (p70 S6 kinase) and ERK (extracellular-signal-regulated kinase). Furthermore, the ActD-induced activation of these survival signalling enzymes was potentiated by overexpression of either PLD1 or PLD2. The PI3K inhibitor LY294002 inhibited the ActD-induced activation of Akt and p70S6K, and completely abolished the effects of PLD1 or PLD2, whereas inhibition of ERK activity by the MEK inhibitor U0126 had a milder effect. The ActD-induced activation of p70S6K and ERKs was blocked by 1-butanol, but not by t-butanol; similar to S1P, exogenous PLD suppressed the ActD-induced events in the apoptosis signalling pathways. These results show that, in S1P3-CHO cells, increased expression of PLDs prevents ActD-induced apoptosis by enhanced activation of the PI3K signalling pathways.
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PMID:Overexpression of phospholipase D prevents actinomycin D-induced apoptosis through potentiation of phosphoinositide 3-kinase signalling pathways in Chinese-hamster ovary cells. 1464 Sep 74

Epidermal growth factor receptor [EGFR (HER1, erbB1)] is a receptor with associated tyrosine kinase activity, and is expressed in colorectal cancers and many other solid tumors. We examined the effect of the selective EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib ("Iressa") in combination with the DNA topoisomerase I inhibitor CPT-11 (irinotecan) on human colorectal cancer cells. EGFR mRNA and protein expression were detected by RT-PCR and immunoblotting in all 7 colorectal cancer cell lines studied. Gefitinib inhibited the cell growth of the cancer cell lines in vitro with an IC(50) range of 1.2-160 microM by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Lovo cells exhibited the highest level of protein and autophosphorylation of EGFR and were the most sensitive to gefitinib. The combination of gefitinib and CPT-11 induced supra-additive inhibitory effects in COLO320DM, WiDR and Lovo cells, assessed by an in vitro MTT assay. Administration of gefitinib and CPT-11 had a supra-additive inhibitory effect on WiDR cells and tumor shrinkage was observed in Lovo cell xenografts established in nude mice, whereas no additive effect of combination therapy was observed in COLO320DM cells. To elucidate the mechanisms of synergistic effects, the effect of CPT-11-exposure on phosphorylation of EGFR was examined by immunoprecipitation. CPT-11 increased phosphorylation of EGFR in Lovo and WiDR cells in time- and dose-dependent manners. This EGFR activation was completely inhibited by 5 microM gefitinib and gefitinib-induced apoptosis was enhanced by combination with CPT-11, measured by PARP activation although no PARP activation was induced by 5 microM CPT-11 alone. These results suggested that these modification of EGFR by CPT-11, in Lovo cells, is a possible mechanism for the synergistic effect of CPT-11 and gefitinib. These findings imply that the EGFR-TKI gefitinib and CPT-11 will be effective against colorectal tumor cells that express high levels of EGFR, and support clinical evaluation of gefitinib in combination with CPT-11, in the treatment of colorectal cancers.
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PMID:Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib ("Iressa") and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells. 1464 15

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


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