Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparing normal human urothelial (NHU) cells to a panel of six representative urothelial cell carcinoma (UCC)-derived cell lines, we showed that while TRAIL receptor expression patterns were similar, susceptibility to soluble recombinant crosslinked TRAIL fell into three categories. 4/6 carcinoma lines were sensitive, undergoing rapid and extensive death; NHU and 253J cells were partially resistant and HT1376 cells, like normal fibroblasts, were refractory. Both normal and malignant urothelial cells underwent apoptosis via the same caspase-8/9-mediated mechanism. Rapid receptor downregulation was a mechanism for evasion by some UCC cells. TRAIL resistance in malignant urothelial cells was partially dependent on FLIP(L) and was differentially mediated by p38(MAPK), whereas in normal cells, resistance was mediated by NF-kappaB. Importantly, extensive killing of UCC cells could be induced using noncrosslinked TRAIL after prolonged exposure, with no damage to their homologous, normal urothelial cell counterparts.
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PMID:Differential susceptibility to TRAIL of normal versus malignant human urothelial cells. 1641 Aug

Inhibition of NF-kappaB activation increases susceptibility to tumor necrosis factor (TNF)alpha-induced cell death, concurrent with caspases and prolonged c-Jun N-terminal kinase (JNK) activation, and reactive oxygen species (ROS) accumulation. However, the detailed mechanisms are unclear. Here we show that cellular FLICE-inhibitory protein (c-FLIP) is rapidly lost in NF-kappaB activation-deficient, but not wild-type fibroblasts upon TNFalpha stimulation, indicating that NF-kappaB normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNFalpha-induced prolonged JNK activation and ROS accumulation in NF-kappaB activation-deficient fibroblasts. Conversely, TNFalpha induces prolonged JNK activation and ROS accumulation in c-Flip-/- fibroblasts. Moreover, c-FLIPL directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-activated kinase 1. This stimuli-dependent interaction of c-FLIPL with MKK7 might selectively suppress the prolonged phase of JNK activation. Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c-FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation.
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PMID:An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. 1711 Sep 30

In most cell types, tumor necrosis factor (TNF) induces a transient activation of the JNK pathway. However, in NFkappaB-inhibited cells, TNF stimulates also a second sustained phase of JNK activation, which has been implicated in cell death induction. In the present study, we have analyzed the relationship of cell death induction, caspase activity, JNK, and NFkappaB stimulation in the context of TNF signaling in four different cellular systems. In all cases, NFkappaB inhibition enhanced TNF-induced cell death and primed most, but not all, cells for sustained JNK activation. The caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-fmk) and overexpression of the antiapoptotic proteins FLIP-L and Bcl2 differentially blocked transient and sustained JNK activation in NFkappaB-inhibited KB and HaCaT cells, indicating that the two phases of TNF-induced JNK activation occur at least in these cellular models by different pathways. Although the broad range caspase inhibitor Z-VAD-fmk and the antioxidant butylated hydroxyanisole interfered with TNF-induced cell death to a varying extent in a cell type-specific manner, inhibition of JNK signaling had no or only a very moderate effect. Notably, the JNK inhibitory effect of neither Z-VAD-fmk nor butylated hydroxyanisole was strictly correlated with the capability of these compounds to rescue cells from TNF-induced cell death. Thus, sustained JNK activation by TNF has no obligate role in TNF-induced cell death and is mediated by caspases and reactive oxygen species in a cell type-specific manner.
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PMID:Sustained JNK activation in response to tumor necrosis factor is mediated by caspases in a cell type-specific manner. 1712 45

The CD95 and TRAIL death receptors can potently stimulate proinflammatory signalling, especially in apoptosis resistant cells. Here, we show that caspases are of cell type-specific relevance for non-apoptotic death receptor signalling in pancreatic tumour cells. Inhibition of caspases by zVAD-fmk strongly enhanced the proinflammatory response in PancTuI, BxPc3 and Panc89 cells, but inhibited this response in Colo357 cells as well as in apoptosis-resistant Colo357-BclxL cells overexpressing BclxL. To characterize the role of caspases in non-apoptotic death receptor signalling, we analysed CD95L- and TRAIL-induced signalling pathways in Colo357-BclxL cells in comparison with PancTuI cells. Both death ligands induced NFkappaB, ERKs, JNK and p38 in Colo357-BclxL cells and except for ERKs also in PancTuI cells. However, inhibition of caspases with zVAD-fmk resulted in strong inhibition of all these signalling pathways in Colo357-BclxL, but enhanced NFkappaB and JNK signalling in PancTuI cells. Caspase-mediated activation of NFkappaB and ERKs were involved in CD95L- and TRAIL-induced up-regulation of proinflammatory genes in Colo357-BclxL cells. At the level of the DISC we did not observe any significant differences in recruitment or processing of FADD, caspase-8, FLIP, TRAF2 and RIP between PancTuI and Colo357-BclxL cells. Consequently, an NFkappaB and ERK stimulating, caspase-dependent factor must operate downstream of the DISC in Colo357-BclxL cells.
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PMID:Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells. 1729 19

Mutations in p53 are the most common genetic abnormality in cancers. Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL) and is being tested in phase II studies in various types of cancers. We have shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53 and the extrinsic apoptotic pathway in cells expressing mutant p53. To further establish the differential apoptotic signals of ATO in relation to p53 functional status we studied the activation of the intrinsic and the extrinsic apoptotic pathways in IM9 myeloma cells expressing w.t. p53 following silencing of p53 and p21 with the corresponding SiRNAs-GFP constructs. In untransfected cells or in cells transfected with GFP-empty vector construct we observed weak apoptosis concomitant with mild depolarization of mitochondrial membrane, depletion of reduced glutathione and release of cytochrome c. Following silencing of p53 or p21 we observed extensive apoptosis concomitant with extensive depolarization of mitochondrial membrane and depletion of reduced glutathione. We also observed in these cells activation of the extrinsic apoptotic pathway through upregulation of APO2/TRAIL and APO2/TRAIL-R2, activation of caspase 8, degradation of FLIP-L and release of apoptosis inducing factors from mitochondria, instead of cytochrome c. In addition, we observed marked activation of the MAP kinase pathway and dephosphorylation of Akt in p53 or p21 silenced cells. Hence, silencing of p53 or p21 in IM9 myeloma cells results in diversion of apoptosis to the extrinsic pathway and sensitization of myeloma cells to ATO.
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PMID:Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53. 1733 40

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is capable of inducing apoptosis in non-small cell lung carcinoma (NSCLC). However, many of the human NSCLC cell lines are resistant to TRAIL, and TRAIL treatment of the resistant cells leads to the activation of nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase 1/2 (ERK1/2). TRAIL can induce apoptosis in TRAIL-sensitive NSCLC cells through the induction of death-inducing signaling complex (DISC) assembly in lipid rafts of plasma membrane. In the DISC, caspase-8 is cleaved and initiates TRAIL-induced apoptosis. In contrast, TRAIL-DISC assembly in the nonraft phase of the plasma membrane leads to the inhibition of caspase-8 cleavage and NF-kappaB and ERK1/2 activation in TRAIL-resistant NSCLC cells. Receptor-interacting protein (RIP) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP) mediates the DISC assembly in nonrafts and selective knockdown of either RIP or c-FLIP with interfering RNA redistributes the DISC from nonrafts to lipid rafts, thereby switching the DISC signals from NF-kappaB and ERK1/2 activation to caspase-8-initiated apoptosis. Chemotherapeutic agents inhibit c-FLIP expression, thereby enhancing the DISC assembly in lipid rafts for caspase-8-initiated apoptosis. These studies indicate that RIP and c-FLIP-mediated assembly of the DISC in nonrafts is a critical upstream event in TRAIL resistance and thus targeting of either RIP or c-FLIP may lead to the development of novel therapeutic strategies that can overcome TRAIL resistance in human NSCLC.
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PMID:Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells. 1763 6

A prominent feature of glioblastoma is its resistance to death receptor-mediated apoptosis. In this study, we explored the possibility of modulating death receptor-induced cell death with the c-Jun-NH2-terminal kinase (JNK) activator anisomycin. Anisomycin activates JNK by inactivating the ribosome and inducing "ribotoxic stress." We found that anisomycin and death receptor ligand anti-Fas antibody CH-11 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induce apoptosis in multiple human glioblastoma cell lines. For example, in U87 cells, anisomycin reduced the IC50 of CH-11 by more than 20-fold (from 500 to 25 ng/mL). Cell viability in response to anisomycin, CH-11, and their combination was 79%, 91%, and 28% (P<0.001), respectively. Anisomycin and TRAIL were found to be similarly synergistic in glioblastoma cells maintained as tumor xenografts. The potentiation of death receptor-dependent cell death by anisomycin was specific because emetine, another ribosome inhibitor that does not induce ribotoxic stress or activate JNK, did not have a similar effect. Synergistic cell death was predominantly apoptotic involving both extrinsic and intrinsic pathways. Expression of Fas, FasL, FLIP, and Fas-associated death domain (FADD) was not changed following treatment with anisomycin+CH-11. JNK was activated 10- to 22-fold by anisomycin+CH-11 in U87 cells. Inhibiting JNK activation with pharmacologic inhibitors of JNKK and JNK or with dominant negative mitogen-activated protein kinase (MAPK) kinase kinase 2 (MEKK2) significantly prevented cell death induced by the combination of anisomycin+CH-11. We further found that anisomycin+CH-11 up-regulated the proapoptotic protein Bim by approximately 14-fold. Simultaneously inhibiting Bim expression and JNK activation additively desensitized U87 cells to anisomycin+CH-11. These findings show that anisomycin-induced ribotoxic stress sensitizes glioblastoma cells to death receptor-induced apoptosis via a specific mechanism requiring both JNK activation and Bim induction.
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PMID:Ribotoxic stress sensitizes glioblastoma cells to death receptor induced apoptosis: requirements for c-Jun NH2-terminal kinase and Bim. 1769 4

Tumor necrosis factor-alpha (TNF-alpha)-activated neutrophils phagocytose and eliminate bacteria by using such oxidants as hydrogen peroxide (H(2)O(2)) and hypochlorous acid (HOCl), which is produced from H(2)O(2) by myeloperoxidase (MPO). Thereafter, neutrophils eventually undergo apoptosis to prevent excessive inflammation. However, it is unclear how this process is regulated. Here, we show that cotreatment of TNF-alpha-resistant neutrophilic HL-60 cells with taurine chloramine (TauCl), a detoxified form of HOCl, and TNF-alpha renders them susceptible to apoptosis, mostly by preventing nuclear factor-kappaB (NF-kappaB) activation. Of several NF-kappaB target genes tested, FLICE inhibitory protein short form (FLIP(S)) was specifically down-regulated by TauCl. TNF-alpha/TauCl cotreatment-induced apoptosis was largely blocked by stable expression of FLIP(S). Cotreatment with TNF-alpha and H(2)O(2) promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIP(S) expression. TNF-alpha priming with H(2)O(2) or bacteria caused MPO-dependent apoptosis in human neutrophils. However, FLIP(S) knock-down by siRNA did not affect the viability of cells treated with TNF-alpha, implying that TauCl may affect another pathway in TNF-alpha-driven apoptosis. Indeed, oxidization of thioredoxin-1 (Trx-1) by TauCl induced the activation of apoptosis signal-regulating kinase 1 (ASK1) and cJun N-terminal kinase (JNK), thereby triggering TNF-alpha-mediated apoptosis. Taken together, these results indicate that the antiapoptotic signaling induced by TNF-alpha via NF-kappaB activation can be altered to promote apoptosis via H(2)O(2)-MPO-mediated FLIP(S) down-regulation and JNK activation.
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PMID:Apoptosis triggered by phagocytosis-related oxidative stress through FLIPS down-regulation and JNK activation. 1770 1

The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) induces apoptosis of cancer cells, enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and exhibits potent anticancer activity in animal models with a favorable pharmacokinetic profile. Thus, CDDO-Me is being tested in Phase I clinical trials. In an effort to understand the mechanism by which CDDO-Me induces apoptosis, particularly in human lung cancer cells, we previously demonstrated that CDDO-Me induces apoptosis involving c-Jun N-terminal kinase (JNK)-dependent upregulation of death receptor 5 (DR5) expression. In the current work, we determined the modulatory effects of CDDO-Me on the levels of c-FLIP, a major inhibitor of death receptor-mediated caspase-8 activation, and its impact on CDDO-Me-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. CDDO-Me rapidly and potently decreased c-FLIP levels including both long (FLIP(L)) and short (FLIP(S)) forms of c-FLIP in multiple human lung cancer cell lines. The presence of the proteasome inhibitor MG132, but not the JNK inhibitor SP600125, prevented CDDO-Me-induced c-FLIP reduction. Moreover, CDDO-Me increased ubiquitination of c-FLIP. Thus, CDDO-Me induces ubiquitin/proteasome-dependent c-FLIP degradation independently of JNK activation. Importantly, overexpression of c-FLIP (e.g., FLIP(L)) protected cells not only from CDDO-Me-induced apoptosis, but also from induction of apoptosis by the combination of CDDO-Me and TRAIL. Accordingly, silencing of c-FLIP with c-FLIP siRNA sensitized cancer cells to CDDO-Me. Collectively, these results indicate that c-FLIP downregulation contributes to CDDO-Me-initiated apoptosis and also to enhancement of TRAIL-induced apoptosis by CDDO-Me.
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PMID:c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells. 1825 90

The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-X(L), Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis.
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PMID:Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells. 1900 38


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