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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We conducted our study to assess the antiproliferative and proapoptotic potential of hecogenin and tigogenin, two saponins which are structurally similar to diosgenin. We particularly focused our attention on mitogen-activated protein kinase (MAPK) activation in relation to apoptosis but also with the COX-2 expression and activity. Rheumatoid arthritis (RA) synoviocytes were isolated from fresh synovial biopsies obtained from five RA patients undergoing hip arthroplasty. Measurement of cell proliferation was determined using the MTT assay. Apoptosis was evaluated by studying caspase-8, caspase-9 and caspase-3 activities but also by quantification of DNA fragmentation. Quantification of human phospho-MAPKs was realized by ELISA. COX-2 expression was demonstrated by Western blot analysis and COX-2 activity by assay of endogenous prostaglandin E2 (PGE2) production. Tigogenin was more effective than hecogenin in inducing apoptosis in human RA fibroblast-like synoviocytes (FLS) which was caspase dependent but poly(ADP-ribose) polymerase independent and characterized by DNA fragmentation. Our results demonstrated hecogenin- and tigogenin-induced apoptosis through activation of p38 without affecting the JNK and ERK pathways. Indeed, pretreatment with a p38 inhibitor decreased saponin-induced apoptosis with a significant decrease in DNA fragmentation. Furthermore, the rate of apoptosis induced by hecogenin or tigogenin was associated with overexpression of COX-2 correlated with overproduction of endogenous PGE2. These new results provide strong evidence that a family of structurally similar plant steroids is capable of inducing apoptosis in human RA FLS with different rates and different signalling pathways. This study also confirms the discussed appearance of the downregulation or upregulation of COX-2 in cell apoptosis as a function of cell type.
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PMID:Inhibition of human rheumatoid arthritis synovial cell survival by hecogenin and tigogenin is associated with increased apoptosis, p38 mitogen-activated protein kinase activity and upregulation of cyclooxygenase-2. 1778 75

CD54 is a cell surface adhesive glycoprotein, which is expressed in most cells. Interaction between CD54 and its ligands is involved in several cellular events including activation, proliferation, and cell death and also cell-to-cell adhesion. In the present study, we found that cross-linking of CD54 on Burkitt lymphoma cell lines, Raji and Ramos, induced apoptosis. We investigated that cross-linking of CD54 on Raji and Ramos using immobilized anti-CD54 mAb (clone 6.5B5) leads to apoptosis. CD54-induced apoptosis took place in association with an increase of intracellular reactive oxygen species (ROS) and a loss of the mitochondrial membrane potential and also the activation of caspases 3 and 9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase. Pretreatment of each N-acetyl cystein and N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (a broad caspase inhibitor) blocked apoptosis. Cross-linking of CD54 immediately induced expression of fasL, which was inhibited by pretreatment of N-acetyl cystein. NOK-1 (antagonistic anti-fasL), ZB4 (antagonistic anti-fas), and N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketon (caspase 8 inhibitor) effectively rescued cells from apoptosis via adjacent fas-fasL interaction but did not block ROS generation. Taken together, it is concluded that engagement of CD54 on B lymphoma cell lines by anti-CD54 mAb may trigger fasL expression through ROS generation and may subsequently induce apoptosis in adjacent fas-fasL interaction.
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PMID:Cross-linking of CD54 on Burkitt lymphoma cell line Raji and Ramos induces FasL expression by reactive oxygen species and apoptosis of adjacent cells in Fas/FasL interaction. 1789 65

The present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor-related-apoptosis-inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French-American-British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib-sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase-8 and caspase-3 and decreased cellular FLICE [Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme]-inhibitory protein (c-FLIP) levels in AML blasts; (ii) high c-FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an anti-leukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.
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PMID:M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis. 1789 95

CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-kappaB (nuclear factor kappaB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.
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PMID:Characterization of cancer stem cells in chronic myeloid leukaemia. 1795 48

Quinolones (QNs)-induced arthropathy is an important toxic effect in immature animals leading to restriction of their therapeutic use in pediatrics. However, the exact mechanism still remains unclear. Recently, we have demonstrated that ofloxacin, a typical QN, induces apoptosis of alginate microencapsulated juvenile rabbit joint chondrocytes by disturbing the beta 1 integrin functions and inactivating the ERK/MAPK signaling pathway. In this study, we extend our initial observations to further elucidate the mechanism(s) of ofloxacin-induced apoptosis by utilizing specific caspase inhibitors. Pretreatment with both caspase-9-specific inhibitor zLEHD-fmk and caspase-8 inhibitor zIETD-fmk attenuated ofloxacin-induced apoptosis and activation of caspase-3 of chondrocyte in a concentration-dependent manner, as determined by fluorescent dye staining, enzyme activity assay and immunoblotting. Furthermore, the activation of caspase-9, -8 and -3 stimulated by ofloxacin was significantly inhibited in the presence of zIETD-fmk while pretreatment with zLEHD-fmk only blocked the activation of caspase-9 and -3. Ofloxacin also stimulated a concentration-dependent translocation of cytochrome c from mitochondria into the cytosol and a decrease of mitochondrial transmembrane potential, which was completely inhibited by zIETD-fmk. In addition, ofloxacin was found to increase the level of Bax, tBid, p53 in a concentration- and time-dependent manner. Taken together, The current results indicate that the caspase-8-dependent mitochondrial pathway is primarily involved in the ofloxacin-induced apoptosis of microencapsulated juvenile rabbit joint chondrocytes.
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PMID:Ofloxacin induces apoptosis in microencapsulated juvenile rabbit chondrocytes by caspase-8-dependent mitochondrial pathway. 1796 19

The present studies have determined whether interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza) occur in breast cancer cells. MDA-MB-231 and MCF7 cells were treated with flavopiridol (25-100 nmol/L) and vorinostat (125-500 nmol/L) in vitro, and mechanisms of cell killing were determined. Concurrent treatment of cells with flavopiridol and vorinostat or treatment of cells with flavopiridol followed by vorinostat promoted cell killing in a greater than additive fashion. Similar data were obtained with the CDK inhibitor roscovitine. Flavopiridol suppressed c-FLIP-l/s and BCL-xL expression, whereas vorinostat reduced expression of BCL-xL, and combined exposure to flavopiridol and vorinostat reduced MCL-1 and X-chromosome-linked inhibitor of apoptosis protein (XIAP) levels. Pharmacologic or genetic inhibition of caspase-8 reduced flavopiridol toxicity, but abolished killing by vorinostat and cell death caused by the vorinostat/flavopiridol regimen. Loss of BAX/BAK function or loss of BID function modestly reduced flavopiridol toxicity, but abolished vorinostat-mediated potentiation of flavopiridol toxicity, as did inhibition of caspase-9. Inhibition and/or deletion of cathepsin B function significantly attenuated vorinostat/flavopiridol lethality. Flavopiridol suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT activity and expression of activated forms of AKT and mitogen-activated protein/ERK kinase 1 maintained c-FLIP-l/s, BCL-xL, and XIAP expression and protected cells against flavopiridol/vorinostat lethality. Overexpression of c-FLIP-s and BCL-xL abolished the lethality of flavopiridol/vorinostat. Collectively, these data argue that flavopiridol enhances the lethality of vorinostat in breast cancer cells in part through the inhibition of AKT and ERK1/2 function, leading to reduced expression of multiple inhibitors of the extrinsic and intrinsic apoptosis pathways, as well as activation of cathepsin protease-dependent pathways.
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PMID:Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells. 1806 90

Tissue inhibitor of metalloproteinases (TIMPs) plays an essential role in the regulation of bone metabolism. Here we report that recombinant tissue metalloproteinase inhibitor-3 (TIMP-3) protein induces the apoptosis of MC3T3-E1 osteoblasts. Cell apoptosis was detected by sandwich-enzyme-immunoassay. Fas and Fasl protein levels were determined by Western blot analysis. The enzyme substrate was used to assess the activation of caspase-3 and caspase-8. The phosphorylation of JNK, p38 and ERK1/2 was examined by Western blot analysis. The ELISA suggested that TIMP-3 promoted MC3T3-E1 cell apoptosis. TIMP-3 treatment induced the expression of Fas and Fasl proteins, and the activation of caspase-8 and caspase-3. TIMP-3 treatment induced p38 and ERK phosphorylation. SB203580 and PD98059, the inhibitor of p38 and ERK, respectively, abolished the TIMP-3 effect on osteoblast apoptosis. In conclusion, the signal pathway through which TIMP-3 induces MC3T3-E1 cell apoptosis, mediated by Fas and involves the p38 and ERK signal transduction pathways.
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PMID:Recombinant tissue metalloproteinase inhibitor-3 protein induces apoptosis of murine osteoblast MC3T3-E1. 1815 85

Our study reports that staurosporine induces apoptosis in cultured rat hepatocytes in a dose- and time-dependent fashion. Staurosporine induced apparent cleavage of caspase-8, caspase-9, and caspase-3. The release of cytochrome c from mitochondria, and Bid activation were also detected in staurosporine-treated primary hepatocytes. These results suggest that mitochondria-mediated cell death signaling may be involved in staurosporine-induced hepatocyte apoptosis. Bcl-x(L) overexpression protected from "loss of" mitochondrial transmembrane potential and prevented staurosporine-induced caspase-3 and caspase-8 cleavage. Overexpression of constitutively active ERK and PKB inhibited staurosporine-induced caspase-3 activation and hepatocyte death. PI3K inhibitor (LY294002) and ERK inhibitor (PD98059) significantly reversed the protective effects of Bcl-x(L) on staurosporine-induced hepatocyte death. Our data suggest that Bcl-x(L) prevents staurosporine-induced hepatocyte apoptosis by modulating protein kinase B and p44/42 mitogen-activated protein kinase activity and disrupts mitochondria death signaling.
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PMID:Bcl-xL prevents staurosporine-induced hepatocyte apoptosis by restoring protein kinase B/mitogen-activated protein kinase activity and mitochondria integrity. 1816 94

Desferrioxamine (DFX) induces apoptosis in human lymphocytes, although the mechanism leading to cell death is unclear. Therefore, we investigated the signaling pathways implicated in DFX-induced apoptosis in lymphocytes. DFX treatment activated caspase-9, caspase-3, and caspase-8. DFX-induced apoptosis was inhibited by both z-IETD-fmk and z-DEVD-fmk. DFX treatment also enhanced caspase-8 activity, Bid cleavage, and the conformational activation of Bax. DFX treatment activated two MAPKs, p38 and JNK, and induced the phosphorylation of two proteins in the p38 pathway, MKK3 and MKK6. DFX treatment also increased the phosphorylation of two downstream targets of p38, ATF-2 and MAPKAPK2, indicating that DFX promotes p38 activity. In addition, the selective p38 inhibitor SB203580 suppressed DFX-induced apoptosis and caspase-8 activation, whereas the JNK inhibitor, SP600125, and the ERK inhibitor, PD98059, had no effect. Our results suggest that DFX-induced apoptosis is mediated by the p38 pathway and a caspase-8-dependent Bid-Bax pathway in human lymphocytes.
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PMID:Desferrioxamine (DFX) induces apoptosis through the p38-caspase8-Bid-Bax pathway in PHA-stimulated human lymphocytes. 1818 75

We have shown previously that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, but resistance can be reversed through activation of caspase-4 by inhibition of the MEK/ERK pathway. We report in this study that apoptosis was induced by the ER stress inducer thapsigargin or tunicamycin via a caspase-8-mediated pathway in the melanoma cell line Me1007, although the MEK/ERK pathway was activated in this cell line. The high sensitivity of Me1007 to ER stress-induced apoptosis was associated with low expression levels of the apoptosis repressor with caspase recruitment domain (ARC) protein that was expressed at relatively high levels in the resistant melanoma cell lines. Transfection of cDNA encoding ARC into Me1007 cells inhibited both caspase-8 activation and apoptosis induced by thapsigargin or tunicamycin. In contrast, inhibition of ARC by small interfering RNA knockdown sensitized the resistant melanoma cell lines to ER stress-induced apoptosis, which was inhibitable by blockage of caspase-8 activation. Both exogenous and endogenous ARC seemed to predominantly locate to the cytoplasm and mitochondria and could be coimmunoprecipitated with caspase-8. Taken together, ER stress can potentially activate multiple apoptosis signaling pathways in melanoma cells in a context-dependent manner. Whereas the MEK/ERK signaling pathway plays an important role in inhibiting ER stress-induced caspase-4 activation, ARC seems to be critical in blocking activation of caspase-8 in melanoma cells subjected to ER stress.
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PMID:Inhibition of endoplasmic reticulum stress-induced apoptosis of melanoma cells by the ARC protein. 1824 85


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