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)

Exposure to irradiation leads to detrimental changes in several cell types. In this study we assessed the changes induced in hippocampus by exposure of rats to whole body irradiation; the findings reveal that irradiation leads to apoptotic cell death in hippocampus, and as a consequence, long term potentiation in perforant path-granule cell synapses is markedly impaired. The evidence is consistent with the view that irradiation induced an increase in reactive oxygen species and that this leads to stimulation of the stress-activated protein kinase, JNK, and activation of the transcription factor, c-Jun. Consequent upon activation of JNK, a cascade of cell signaling events was stimulated that ultimately resulted in apoptosis, as suggested by parallel increases in cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end labeling staining. Treatment of rats with eicosapentaenoic acid inhibited the irradiation-induced increase in reactive oxygen species production and the subsequent cellular signaling events, suggesting that oxidative stress triggered apoptotic cell death in the hippocampus of rats exposed to irradiation. Significantly, when the compromise in cell viability induced by irradiation was prevented by eicosapentaenoic acid, long term potentiation was sustained in a manner similar to that in the sham-treated control group.
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PMID:Neuroprotective effect of eicosapentaenoic acid in hippocampus of rats exposed to gamma-irradiation. 1191 18

Hepatocyte resistance to tumor necrosis factor alpha (TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor kappaB (NF-kappaB). To determine the mechanism by which NF-kappaB protects against TNF toxicity, the effect of NF-kappaB inactivation on the proapoptotic c-Jun NH(2)-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-kappaB inactivation led to a prolonged activation of JNK and increased activating protein-1 (AP-1) transcriptional activity in response to TNF treatment. Inhibition of the function of the JNK substrate and AP-1 subunit c-Jun blocked cell death from NF-kappaB inactivation and TNF as determined by measures of cell survival, numbers of apoptotic and necrotic cells, and DNA hypoploidy. Inhibition of c-Jun function blocked mitochondrial cytochrome c release and activation of caspase-3 and -7. NF-kappaB therefore blocks the TNF death pathway through down-regulation of JNK and c-Jun/AP-1. In conclusion, sustained JNK activation that occurs in the absence of NF-kappaB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.
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PMID:NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. 1191 22

The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or pro-apoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.
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PMID:The proteasome: a novel target for cancer chemotherapy. 1196 Mar 20

Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS.
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PMID:Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. 1198 68

In this study, the role of V12-Rac1 in the cisplatin-induced apoptosis was investigated. Cisplatin-induced apoptosis is associated with cytochrome c release, which can be inhibited by V12-Rac1 expression. The analysis of mitogen-activated protein kinase activity indicated that V12-Rac1 expression led to a decrease in p38 activity after exposure to cisplatin but not c-jun N-terminal kinase and extracellular signal-regulated kinase. Using pharmacological inhibitors, it was found that only p38 is a critical mediator in the cisplatin-induced apoptosis of NIH3T3 cells. This suggests that V12-Rac1 can stimulate the anti-apoptotic signaling pathway in response to cisplatin, and that decreased p38 activity caused by V12-Rac1 expression in cisplatin-treated NIH3T3 cells is crucial for V12-Rac1-dependent cell survival.
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PMID:Rac1 prevents cisplatin-induced apoptosis through down-regulation of p38 activation in NIH3T3 cells. 1199 32

Microsomal epoxide hydrolase (mEH), an epoxide detoxifying enzyme and putative cell surface autoantigen, is inducible by xenobiotics and by certain pathophysiological conditions (e.g., tumorigenesis and protein-calorie malnutrition). The present study was designed to determine mEH expression in H4IIE cells during cell death initiated by sulfur amino acid deprivation (SAAD) and to identify the signaling pathway for the enzyme induction. SAAD induced cell death at 48-72 h with translocation of Bax to mitochondria and increased mitochondrial permeability with cytochrome c release, both of which were prevented by SB203580 or by dominant-negative JNK1 [JNK1(-)] stable transfection. Caspase-3 activity was only marginally increased by SAAD. Neither genomic DNA fragmentation nor poly(ADP-ribose) polymerase cleavage was observed during SAAD-induced cell death. Thus, SAAD induced cell death independent of caspase activation. This was supported by the observation that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a general caspase inhibitor, did not prevent cell death. The levels of mEH mRNA and protein were notably increased in cells under SAAD for 48-72 h. The induction of mEH occurred in parallel with cell death. Whereas SAAD-induced cell death resulted from both JNK1 and p38 kinase activation, mEH induction was decreased only by JNK1(-) transfection. Immunocytochemistry revealed that mEH protein was intensely stained in dying cells, cellular fragments and cell debris. Furthermore, the number of cells positive for surface mEH substantially increased by SAAD, as evidenced by flow cytometry analysis. These results demonstrated that SAAD induced nonapoptotic cell death with Bax translocation to mitochondria and mitochondrial cytochrome c release, but not through caspase-3 activation, and that mEH was induced by SAAD via the pathway of JNK1, but not ERK1/2 or p38 kinase, in parallel with cell death.
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PMID:Induction of microsomal epoxide hydrolase by sulfur amino acid deprivation via the pathway of C-Jun N-terminal kinase and its extracellular exposure during cell death. 1200 17

Microvascular endothelial cell (EC) apoptosis or programmed cell death (PCD) during free radical injury may be involved in the development of cerebral ischemic and degenerative diseases. Yet, the cellular mechanisms that mediate cerebral EC injury require further definition. We therefore used the agent nicotinamide as an investigative tool in EC cultures to examine the role of free radical nitric oxide (NO)-induced PCD. EC injury was evaluated by the trypan blue dye exclusion method, DNA fragmentation, membrane phosphatidylserine (PS) exposure, cysteine protease activity, mitochondrial membrane potential, and mitogen-activated protein kinase phosphorylation. We demonstrate that cerebrovascular PCD consists of two distinct pathways that involve the degradation of genomic DNA and the exposure of membrane PS residues. Each of these pathways is reversible in nature and is controlled independently by caspase 8, caspase 1, and caspase 3. As a cytoprotectant, nicotinamide is novel in the vascular system and functions at two levels. Nicotinamide not only maintains the mitochondrial membrane potential and the prevention of cytochrome c release, but also prevents the induction of caspase-8-, caspase-1- and caspase-3-like activities linked to the DNA repair enzyme poly(ADP-ribose) polymerase through mechanisms that are independent from the MAP kinase systems of p38 and JNK. The work begins to identify therapeutic strategies for the protection of the cerebral vasculature during both acute and chronic degenerative disorders.
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PMID:Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. 1201 85

Caspases and c-Jun N-terminal kinase (JNK) are activated in tumor cells during induction of apoptosis. We investigated the signaling cascade and function of these enzymes in cisplatin-induced apoptosis. Treatment of Jurkat T-cells with cisplatin induced cell death with DNA fragmentation and activation of caspase and JNK. Bcl-2 overexpression suppressed activation of both enzymes, whereas p35 and CrmA inhibited only the DEVDase (caspase-3-like) activity, indicating that the activation of these enzymes may be differentially regulated. Cisplatin induced apoptosis with the cytochrome c release and caspase-3 activation in both wild-type and caspase-8-deficient JB-6 cells, while the Fas antibody induced these apoptotic events only in wild-type cells. This indicates that caspase-8 activation is required for Fas-mediated apoptosis, but not cisplatin-induced cell death. On the other hand, cisplatin induced the JNK activation in both the wild-type and JB-6 cells, and the caspase-3 inhibitor Z-DEVD-fmk did not inhibit this activation. The JNK overexpression resulted in a higher JNK activity, AP-1 DNA binding activity, and metallothionein expression than the empty vector-transfected cells following cisplatin treatment. It also partially protected the cells from cisplatin-induced apoptosis by decreasing DEVDase activity. These data suggest that the cisplatin-induced apoptotic signal is initiated by the caspase-8-independent cytochrome c release, and the JNK activation protects cells from cisplatin-induced apoptosis via the metallothionein expression.
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PMID:Signaling and function of caspase and c-jun N-terminal kinase in cisplatin-induced apoptosis. 1201 40

Transforming growth factor (TGF) beta1 is a potent inducer of apoptosis in the liver. During TGF-beta1-induced apoptosis, 3 mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK], and p38 kinase) showed simultaneously sustained activation in FaO rat hepatoma cells. TGF-beta1-induced apoptosis was markedly enhanced when ERK activation was selectively inhibited by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. In contrast, both interfering with p38 activity by overexpression of the dominant negative (DN) MKK6 mutant and inhibition of the JNK pathway by overexpression of the DN SEK1 mutant resulted in suppression of mitochondrial cytochrome c release, abrogating TGF-beta1-induced apoptosis. In addition, antiapoptotic Bcl-2 blocked mitochondrial cytochrome c release, suppressing TGF-beta1-induced activation of JNK and p38. Inhibition of ERK activity enhanced TGF-beta1-induced p38 and JNK activation. However, inhibition of the JNK pathway suppressed p38 but induced transient ERK activation. Similarly, interfering with the p38 pathway also attenuated JNK activation but generated transient ERK activation in response to TGF-beta1. These results indicate that disrupting one MAP kinase pathway affects the TGF-beta1-induced activation of other MAP kinases, suggesting cross-talk among MAP kinase pathways. In conclusion, we propose that the balance and integration of MAP kinase signaling may regulate commitment to TGF-beta1-induced apoptosis modulating the release of cytochrome c from mitochondria.
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PMID:Role of MAP kinases and their cross-talk in TGF-beta1-induced apoptosis in FaO rat hepatoma cell line. 1202 21

Bisindolylmaleimide VIII (Bis VIII) has been previously shown to enhance Fas-mediated apoptosis through a protein kinase C-independent mechanism. In the present study, we examined the effect of Bis VIII on apoptosis induced by DR5 (TRAIL-R2), using an agonistic anti-human DR5 monoclonal antibody, TRA-8. Our results demonstrated that Bis VIII was able to enhance the apoptosis-inducing activity of TRA-8 both in vitro and in vivo. The combination of TRA-8 and Bis VIII led to a synergistic and sustained activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase, which was mediated by MAPK kinase 4 and was caspase-8-dependent. The mitochondrial pathway is involved in the synergistic induction of apoptosis by Bis VIII and TRA-8. Bis VIII alone induced the loss of mitochondrial membrane potential in a caspase-independent fashion without subsequent release of cytochrome c. However, in the presence of Bis VIII, TRA-8 induced more profound loss of mitochondrial membrane potential and release of cytochrome c. These results suggest that the enhanced and persistent activation of the JNK/p38 and the decreased mitochondrial membrane potential play a crucial role in synergistic induction of the death receptor-mediated apoptosis by Bis VIII. The unique ability of Bis VIII to enhance DR5-mediated apoptosis signal transduction discloses a potential utility of this compound in combination with anti-DR5 antibody in cancer therapy.
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PMID:Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4/JNK/p38 kinase and the mitochondrial pathways. 1203 36


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