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)

Testicular germ cell tumours (TGCT) are the most common solid tumour among young males. Whereas in 1970s, only 5% of patients with a metastatic testicular tumours survived their disease, these days 80% of patients treated by modern cisdiamminedichloroplatinum (cisplatin, CDDP)-based chemotherapy are cured. Although data are accumulating on the effect of the mitogen-activated protein kinase (MAPK) family on the CDDP-induced apoptosis in tumour cells, the mechanisms by which CDDP initiates apoptosis in TGCT are not completely understood. Applying Western blot and phosphorylated kinase-specific ELISA analyses, flow cytometry, blocking experiments, and morphological methods we sought here to define the MAPK pathway(s) involved in the CDDP-induced apoptosis in the human TGCT cell line NCCIT. Our experiments showed that within hours of CDDP application only the extracellular signal-regulated kinase (ERK) was dually phosphorylated and caspase-3 became active. Functional assays using chemical inhibitors demonstrated that the phosphorylation of ERK was mediated by reactive oxygen species in an Raf-1-independent manner and required the activation of caspase-3. Thus, our data suggest that CDDP mediates its apoptosis-inducing effect on the human malignant testicular germ cells, at least partially, through activation of the MEK-ERK signaling pathway in a ROS-dependent, Raf-1-independent manner.
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PMID:The role of reactive oxygen species in cisplatin-induced apoptosis in human malignant testicular germ cell lines. 1554 4

Repression of activation of c-Jun N-terminal kinase (JNK) participates in the anti-apoptotic effect of nuclear factor-kappaB (NF-kappaB) in TNFalpha-treated Ewing sarcoma cells. As oxidative stress is one of the most prominent activators of JNK, we investigated the relationship between TNFalpha-induced NF-kappaB activation and the control of oxidative stress. Inhibition of NF-kappaB activation resulted in an increase in TNFalpha-induced ROS production, lipid peroxidation and protein oxidation. Those ROS and lipid peroxides were both involved in TNFalpha-induced apoptosis, whereas only ROS elevation triggered sustained JNK activation. TNFalpha increased the level of two antioxidant enzymes, thioredoxin and manganese superoxide dismutase by an NF-kappaB-dependent mechanism. Inhibition of expression or activity of these enzymes sensitized cells to TNFalpha-induced apoptosis, indicating their functional role in protection from cell death. Thus, agents that inhibit activities of these enzymes may prove helpful in the treatment of Ewing tumors.
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PMID:NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells. 1558 26

An environmental pollutant, tetrachloro dibenzo dioxin (TCDD) is known to illicit the cognitive disability and motor dysfunction in the developing brain. TCDD induced effects leading to neurodevelopmental and neurobehavioral deficit may have been defined, however underlying molecular mechanism and possible intracellular targets remain to be elucidated. In this study, we attempted to analyze TCDD-induced neurotoxic effects in the granule cells from cerebellum where certain cognitive abilities and motor function command are known to be excuted. [3H]PDBu, (phorbol 12,13-dibutyrate) binding assay indicated that TCDD induced a dose-dependent increase of total PKC activity and its induction was the aryl hydrocarbon receptor (AhR) dependent and N-methyl-D-aspartate receptor (NMDAR) independent. TCDD also caused the translocation of both PKC-alpha and -epsilon in a dose-dependent manner but associated with different receptors; PKC-alpha via AhR but not PKC-epsilon indicating an isozyme-specific pattern of the induction. Increase of the ROS formation was also observed in the cells treated with TCDD in a dose-dependent and an AhR-dependent manner. The treatment of the cells with the diamino dicyano-bis(2-aminophenylthio) butadiene (U0126, MEK-1/2 inhibitor), dizocilpine maleate (MK-801, non-competitive N-methyl-D-aspartate glutamate receptor antagonist) and vitamin E attenuated the TCDD-induced ROS production indicating that TCDD-induced ROS formation may be associated with activation of ERK-1/2 in the MAP kinase pathway or the NMDA receptor. TCDD also increased [Ca2+]i, which is associated with ROS formation and PKC activation in the cerebellar granule cells. It is suggested that TCDD activates the NMDA receptor, which may induce a sustained increase of [Ca2+]i in neurons followed by the ROS formation. Our findings may contribute to understanding the mechanism of TCDD-related neurotoxicity, thereby improving the health risk assessment of neurotoxic compounds in humans.
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PMID:Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells. 1576 Dec 53

The NF-kappaB/iNOS pathway stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway and diverse antioxidants block muscle differentiation. Therefore, we here investigated whether Nox 2 links those two myogenic pathways in H9c2 and C2C12 myoblasts. Compared with the proliferation stage, ROS generation was enhanced from the early stage of differentiation and gradually increased as differentiation progressed. Antioxidants suppressed the activated NF-kappaB/iNOS pathway during muscle differentiation. Nox 2 activity was also increased during muscle differentiation. Treatment with DPI and apocynin, two inhibitors of NADPH oxidase, and suppression of Nox 2 expression using siRNA, but not Nox 1, inhibited NADPH oxidase activity, muscle differentiation, and the NF-kappaB/iNOS pathway. Inhibition of PI 3-kinase and p38 MAPK suppressed the Nox 2/NF-kappaB/iNOS pathway. Nitric oxide restored muscle differentiation blocked by treatment with antioxidants or suppression of the Nox 2/NF-kappaB/iNOS pathway. In conclusion, Nox 2 stimulates muscle differentiation downstream of the PI 3-kinase/p38 MAPK pathway by activating the NF-kappaB/iNOS pathway via ROS generation.
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PMID:Nox 2 stimulates muscle differentiation via NF-kappaB/iNOS pathway. 1578 Jul 57

We reported recently that (-)epigallocatechin gallate and quercetin inhibited H2O2-induced apoptosis through modulation of the expression of apoptosis-related Bcl-2 and Bax in endothelial cells. This study attempted to identify possible regulatory sites and mechanisms of antiapoptotic flavonoids, focusing on ROS-mediated signaling in HUVEC. The effects of apigenin on the signaling pathway downstream were compared. Submillimolar H2O2 caused >30% cell killing with intracellular oxidant generation. H2O2-induced oxidant generation markedly decreased total intracellular glutathione (GSH) levels. Micromolar (-)epigallocatechin gallate and quercetin partially eliminated the dichlorodihydrofluorescein (DCF) and phospho-p53 staining, suggesting that these flavonoids inhibited the accumulation of intracellular oxidants and nuclear transactivation of p53 in H2O2-exposed cells. In contrast, cells treated with apigenin remained DCF and phospho-p53 staining positive in response to H2O2. (-)Epigallocatechin gallate significantly raised the total GSH level that had been depleted by H2O2. Caspase-3 activity was enhanced by H2O2, and this increase was inhibited by (-)epigallocatechin gallate and quercetin. Additionally, the upregulation of caspase-3 activation was reversed by these flavonoids at > or =10 micromol/L; these inhibitory effects were dose dependent. Western blot data revealed that H2O2 upregulated phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), which was rapidly reversed by quercetin within 30 min; H2O2 activation of c-Jun was downregulated. (-)Epigallocatechin gallate inhibited H2O2-induced phosphorylation of JNK and p38 MAPK after 60 min. These results reveal that quercetin blocks JNK- and p38 MAPK-related signaling triggered by the oxidant and may regulate expression of apoptotic downstream genes, preventing apoptosis and promoting cell survival. (-)Epigallocatechin gallate may function as an antiapoptotic agent through other antiapoptotic pathways.
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PMID:(-)Epigallocatechin gallate and quercetin enhance survival signaling in response to oxidant-induced human endothelial apoptosis. 1579 22

Chlorogenic acid, the ester of caffeic acid with quinic acid, is one of the most abundant polyphenols in the human diet. The antioxidant and anticarcinogenic properties of chlorogenic acid have been established in animal studies. However, little is known about the molecular mechanisms through which chlorogenic acid inhibits carcinogenesis. In this study, we found that chlorogenic acid inhibited the proliferation of A549 human cancer cells in vitro. The results of the soft agar assay indicated that chlorogenic acid suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells in a dose-dependent manner. Pretreatment of JB6 cells with chlorogenic acid blocked UVB- or TPA-induced transactivation of AP-1 and NF-kappaB over the same dose range. At low concentrations, chlorogenic acid decreased the phosphorylation of c-Jun NH2-terminal kinases, p38 kinase, and MAPK kinase 4 induced by UVB/12-O-tetradecanoylphorbol-13-acetate, yet higher doses were required to inhibit extracellular signal-regulated kinases. Chlorogenic acid also increased the enzymatic activities of glutathione S-transferases (GST) and NAD(P)H: quinone oxidoreductase. Further studies indicated that chlorogenic acid could stimulate the nuclear translocation of Nrf2 (NF-E2-related factor) as well as subsequent induction of GSTA1 antioxidant response element (ARE)-mediated GST activity. The phosphatidylinositol 3-kinase pathway might be involved in the activation of Nrf2 translocation. These results provide the first evidence that chlorogenic acid could protect against environmental carcinogen-induced carcinogenesis and suggest that the chemopreventive effects of chlorogenic acid may be through its up-regulation of cellular antioxidant enzymes and suppression of ROS-mediated NF-kappaB, AP-1, and MAPK activation.
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PMID:Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. 1594 51

Ghrelin is a 28-amino-acid peptide identified in the stomach as an endogenous ligand of the growth hormone secretagogue receptor (GHS-R) that strongly stimulates the release of growth hormone at the hypothalamus and pituitary level. Although GHS-Rs are expressed in a variety of peripheral tissues, little is known about its effect on bone independent of GH/IGF-1 axis. This study was undertaken to investigate whether ghrelin exerts a direct effect on osteoblasts. We identified mRNA and protein expression of GHS-R in primary osteoblasts as well as a number of osteoblastic cell lines, including MC3T3-E1, ROS 17/2.8, UMR-106, MG63, and SaOS2 cells. Treatment of ghrelin (10(-11) to 10(-7) M) to MC3T3-E1 cells showed dose-dependent stimulation of proliferation, which was abrogated by treatment with [d-Lys]-GHRP-6 (10(-3) M), a selective antagonist of the ghrelin receptor. Ghrelin activated ERK1/2 MAPK and pretreatment with MAPK kinase inhibitors, PD98059 attenuated the ghrelin-induced cell proliferation. Ghrelin also inhibited TNFalpha-induced apoptosis and suppressed caspase-3 activation that occurs in response to TNFalpha as well as during in vitro differentiation process. Moreover, ghrelin treatment enhanced in vitro osteoblast differentiation as evidenced by matrix mineralization, alkaline phosphatase activity, and osteoblast-specific gene expression. These results suggest that ghrelin promotes proliferation and differentiation and inhibits apoptosis of osteoblasts.
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PMID:Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. 1597 80

Ozone induces rapid activation of SIPK, a mitogen-activated protein kinase (MAPK) in tobacco. Through transgenic manipulation it has previously been shown that overexpression of SIPK leads to enhanced ozone-induced lesion formation with concomitant accumulation of ROS. In spite of this hypersensitive phenotype, the effect of this altered SIPK expression on the levels of various hormones that regulate ozone-induced cell death has remained unexplored. The response of both salicylate and ethylene, the major phytohormones that modulate ozone-induced cell death, have now been analysed in SIPK-OX tobacco plants. Ozone treatment strongly induced ethylene formation in the sensitive SIPK-OX plants at ozone concentrations that failed to elicit stress ethylene release in WT plants. By contrast, SIPK-overexpressing plants displayed no ozone-induced SA accumulation, whereas WT plants accumulated SA upon ozone exposure. Epistatic analysis of SIPK-OX function suggests that the ozone-induced cell death observed in SIPK-OX plants is either independent, or upstream, of SA accumulation.
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PMID:Overexpression of SIPK in tobacco enhances ozone-induced ethylene formation and blocks ozone-induced SA accumulation. 1598 10

Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34+ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34+ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21CIP1, Bcr/Abl, and cyclin D1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.
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PMID:Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. 2773 68

Rosmarinic acid (RA) is a naturally occurring polyphenolic and is found in several herbs in the Lamiaceae family, such as, Perilla frutescens. ADR is a potent anti-tumor drug, but is unfortunately potently cardiotoxic. This study was undertaken to investigate the inhibitory effect of RA on ADR-induced apoptosis in H9c2 cardiac muscle cells at a mechanistic level. In vitro, ADR significantly decreased the viabilities of H9c2 cells, and this was accompanied by apoptotic features, such as a change in nuclear morphology and caspase protease activation. RA was found to markedly inhibit these apoptotic characteristics by reducing intracellular ROS generation and by recovering the mitochondria membrane potential (delta psi). In addition, RA reversed the downregulations of GSH, SOD and Bcl-2 by ADR. In the present study, ADR was found to activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), transcriptional factor-activator-protein (AP)-1. We found that c-fos, Jun-B, Jun-D and p-c-Jun were super shifted by ADR, indicating that these proteins have an important role in the ADR-induced AP-1 activation. The inhibitions of JNK and ERK using appropriate inhibitors or dominant negative cell lines reduced ADR-induced apoptosis in H9c2 cardiac muscle cells. Taken together, these results suggest that RA can inhibit ADR-induced apoptosis in H9C2 cardiac muscle cells by inhibiting ROS generation and JNK and ERK activation. Thus, we propose that RA should be viewed as a potential chemotherapeutic that inhibits cardiotoxicity in ADR-exposed patients.
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PMID:Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase. 1610 32


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