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)

Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) induce apoptosis in many different cell types. Jurkat T cells die rapidly by apoptosis after treatment with either ligand. We have previously shown that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) can act as a negative regulator of apoptosis mediated by the Fas receptor. In this study we examined whether MAPK/ERK can also act as a negative regulator of apoptosis induced by TRAIL. Activated Jurkat T cells were efficiently protected from TRAIL-induced apoptosis. The protection was shown to be MAPK/ERK dependent and independent of protein synthesis. MAPK/ERK suppressed TRAIL-induced apoptosis upstream of the mitochondrial amplification loop because mitochondrial depolarization and release of cytochrome c were inhibited. Furthermore, caspase-8-mediated relocalization and activation of Bid, a proapoptotic member of the Bcl family, was also inhibited by the MAPK/ERK signaling. The protection occurred at the level of the apoptotic initiator caspase-8, as the cleavage of caspase-8 was inhibited but the assembly of the death-inducing signaling complex was unaffected. Both TRAIL and Fas ligand have been suggested to regulate the clonal size and persistence of different T cell populations. Our previous results indicate that MAPK/ERK protects recently activated T cells from Fas receptor-mediated apoptosis during the initial phase of an immune response before the activation-induced cell death takes place. The results of this study show clearly that MAPK/ERK also participates in the inhibition of TRAIL-induced apoptosis after T cell activation.
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PMID:Mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in activated T cells abrogates TRAIL-induced apoptosis upstream of the mitochondrial amplification loop and caspase-8. 1221 97

Prolonged activation of the c-Jun N-terminal kinase (JNK) has been suggested as a signal for apoptosis in response to a wide variety of stimuli. Using three cytocidal RNA or protein synthesis inhibitors (actinomycin D, anisomycin, and emetine), the potential role of JNK in activation of the mitochondrial apoptotic cascade was investigated in A549-S cells. Protein synthesis inhibition per se was not the cause of cell death as cycloheximide induced only growth arrest. All the cytocidal inhibitors induced cytochrome c release and caspases 9 activation within hours, but only anisomycin caused persistent JNK activation. Although, the JNK inhibitor, SP600125, inhibited JNK-dependent anisomycin-induced c-Jun phosphorylation, it was ineffective in preventing anisomycin-induced caspase activation and cell death. Thus, all three lethal macromolecule synthesis inhibitors can activate the mitochondrial apoptotic machinery independent of JNK activation, demonstrating that the mitochondrial apoptotic pathway can be activated independently of the JNK pathway in the absence of protein synthesis.
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PMID:Activation of the mitochondrial caspase cascade in the absence of protein synthesis does not require c-Jun N-terminal kinase. 1222 May 37

Alpha-synuclein (alpha-SN) is a ubiquitous protein that is especially abundant in the brain and has been postulated to play a central role in the pathogenesis of Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders. However, little is known about the neuronal functions of alpha-SN and the molecular and cellular mechanisms underlying neuronal loss. Here, we show that alpha-SN plays dual roles of neuroprotection and neurotoxicity depending on its concentration or level of expression. At nanomolar concentrations, a-SN protected neurons against serum deprivation, oxidative stress, and excitotoxicity through the PI3/Akt signaling pathway, and its protective effect was increased by Bcl-2 overexpression. Conversely, at both low micromolar and overexpressed levels in the cell, alpha-SN resulted in cytotoxicity. This might be related to decreased Bcl-xL expression and increased bax expression, which is subsequently followed by cytochrome c release and caspase activation and also by microglia-mediated inflammatory responses via the NFkappaB and mitogen-activated protein kinase pathways.
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PMID:Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. 1222 45

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.
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PMID:Prevention of bile acid-induced apoptosis by betaine in rat liver. 1229 30

Nur77 is an orphan receptor. Although Nur77 affects cell proliferation and apoptosis through its capability of binding to a variety of response elements and regulating their transactivation activities, the intrinsic function of Nur77 is not yet fully understood; in particular, its regulation of apoptosis and proliferation has been characterized as cell type-dependent and agent context-dependent. In this study, Nur77 can be seen to regulate apoptosis via its expression and translocation, rather than its transactivation activity in gastric cancer cells. Nur77 was constitutively expressed in BGC-823 cells. The tetradecanoylphorbol-1,3-acetate (TPA) treatment not only resulted in up-regulation of the Nur77 mRNA level, but also led to translocation of Nur77 protein from the nucleus to the mitochondria, and caused the release of cytochrome c. This TPA-induced translocation of Nur77 was in association with the initiation of apoptosis in gastric cancer cells. Although all-trans retinoic acid (ATRA) could not induce apoptosis in BGC-823 cells due to failure of stimulating Nur77 translocation, expression of Nur77 in the nucleus was required for cell growth inhibition by ATRA. Transfection of antisense Nur77 receptor into BGC-823 cells resulted in resistance of cell growth against ATRA inhibition, and the cells were still arrested in the S phase. Furthermore, the action of Nur77 in TPA-induced apoptosis was mediated through a protein kinase C signaling pathway, while mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways were responsible for the regulation of Nur77 mRNA expression. Taken together, the data revealed the dual functioning mechanisms of Nur77 in gastric cancer cells in response to TPA and ATRA.
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PMID:Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells. 1237 65

The p75 neurotrophin receptor (p75NTR) mediates signaling events leading to activation of the JNK pathway and cell death in a variety of cell types. We recently identified NRAGE, a protein that directly interacts with the p75NTR cytosolic region and facilitates p75NTR-mediated cell death. For the present study, we developed an inducible recombinant NRAGE adenovirus to dissect the mechanism of NRAGE-mediated apoptosis. Induced NRAGE expression resulted in robust activation of the JNK pathway that was not inhibited by the pharmacological mixed lineage kinase (MLK) inhibitor CEP1347. NRAGE induced cytosolic accumulation of cytochrome c, activation of Caspases-3, -9 and -7, and caspase-dependent cell death. Blocking JNK and c-Jun action by overexpression of the JNK-binding domain of JIP1 or dominant-negative c-Jun ablated NRAGE-mediated caspase activation and NRAGE-induced cell death. These findings identify NRAGE as a p75NTR interactor capable of inducing caspase activation and cell death through a JNK-dependent mitochondrial apoptotic pathway.
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PMID:NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. 1237 48

The effects of combined exposure to the checkpoint abrogator UCN-01 and pharmacologic MEK1/2 inhibitors were examined in human multiple myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase activation, an effect that was blocked by coadministration of the MEK1/2 inhibitor PD184352. These events were accompanied by enhanced activation of p34(cdc2) and a marked increase in mitochondrial damage (loss of DeltaPsim; cytochrome c and Smac/DIABLO (direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis. PD184352/UCN-01 also dramatically reduced clonogenic survival in each of the MM cell lines. In contrast to As(2)0(3), apoptosis induced by PD184352/UCN-01 was not blocked by the free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented dexamethasone-induced lethality in MM cells, it was unable to protect them from PD184352/UCN-01-induced apoptosis despite enhancing Akt activation. Insulinlike growth factor 1 (IGF-1) also failed to diminish apoptosis induced by this drug regimen. MM cell lines selected for a high degree of resistance to doxorubicin, melphalan, or dexamethasone, or displaying resistance secondary to fibronectin-mediated adherence, remained fully sensitive to PD184352/UCN-01-induced cell death. Finally, primary CD138(+) MM cells were also susceptible to UCN-01/MEK inhibitor-mediated apoptosis. Together, these findings suggest that simultaneous disruption of cell cycle and MEK/MAP kinase signaling pathways provides a potent stimulus for mitochondrial damage and apoptosis in MM cells, and also indicate that this strategy bypasses the block to cell death conferred by several other well-described resistance mechanisms.
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PMID:Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. 1238 35

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

Members of the Bcl-2 family of proteins function either to promote or to repress apoptosis. Bcl-2 has been mainly localised to the mitochondria and acts predominantly upstream of cytochrome c release in its prevention of apoptosis. Little is known about the function of Bcl-2 independent of an apoptotic stimulus. Here we demonstrate that inducible overexpression of the anti-apoptotic protein Bcl-2 in a PC12 Tet-on- cell line up-regulates mRNA expression and leads to phosphorylation of c-Jun at Ser73 via the ERK pathway in a time and concentration dependent manner. Phosphorylation of c-Jun was inhibited by the addition of the selective ERK inhibitor PD 98059. No activation of the stress-activated protein kinases JNK and p38 could be detected. This is the first evidence of a direct activation of the Ras-Raf-MAPK cascade by an anti-apoptotic protein. We propose that the selective activation of Ras, the ERK pathway and the subsequent phosphorylation of c-Jun contribute to the anti-apoptotic action of Bcl-2.
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PMID:Bcl-2 up-regulates ha-ras mRNA expression and induces c-Jun phosphorylation at Ser73 via an ERK-dependent pathway in PC 12 cells. 1249 45

1 Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects, but little is known about its molecular mechanisms of action. 2 Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 microM), and induced apoptosis at high concentrations (80-100 microM). 3 Treatment with 80 microM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. 4 Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. 5 Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the protein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. 6 These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis.
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PMID:Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. 1252 90


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