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)

Dopamine dose-dependently reduced the viable cell number of both human salivary gland tumor HSG and oral squamous cell carcinoma HSC-2, HSC-4, and NA cells. CoCl2 significantly reduced both the cytotoxic activity and radical intensity of dopamine (determined by ESR spectroscopy). Dopamine produced DNA fragments (demonstrated by TUNEL method) and induced degradation of cytokeratin by activated caspase in HSG cells (detected by an immunocytochemical method, using a specific M30 monoclonal antibody). FACS analysis demonstrated that dopamine induced DNA fragmentation, a biochemical hallmark of apoptosis, in human promyelocytic leukemia HL-60 cells. The addition of catalase did not prevent the apoptosis-inducing activity of dopamine, reducing the possibility of the involvement of H2O2 for dopamine-induced apoptosis. Dopamine transiently induced p38 mitogen-activated protein kinase (MAP kinase) phosphorylation. However, an inhibitor of p38 MAP kinase phosphorylation, SB203680, failed to inhibit the dopamine-induced apoptosis. These data suggest that p38 phosphorylation at an early stage may not be a causative event for apoptosis.
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PMID:Induction of apoptosis by dopamine in human oral tumor cell lines. 1076 62

HIV-tat protein, like TNF, activates a wide variety of cellular responses, including NF-kappa B, AP-1, c-Jun N-terminal kinase (JNK), and apoptosis. Whether HIV-tat transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an isogeneic lck-deficient T cell line. Treatment with HIV-tat protein activated NF-kappa B, degraded I kappa B alpha, and induced NF-kappa B-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56lck kinase. These effects were specific to HIV-tat, as activation of NF-kappa B by PMA, LPS, H2O2, and TNF was minimally affected. p56lck was also found to be required for HIV-tat-induced but not TNF-induced AP-1 activation. Similarly, HIV-tat activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. HIV-tat also induced cytotoxicity, activated caspases, and reactive oxygen intermediates in Jurkat cells, but not in JCaM1 cells. HIV-tat activated p56lck activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56lck tyrosine kinase reversed the HIV-tat-induced NF-kappa B activation and cytotoxicity. Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-kappa B, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF.
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PMID:Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosis. 1079 74

As a result of identifying the regulatory proteins of thioredoxin (TRX), a murine homologue for human vitamin D3 up-regulated protein 1 (VDUP1) was identified from a yeast two-hybrid screen. Cotransfection into 293 cells and precipitation assays confirmed that mouse VDUP1 (mVDUP1) bound to TRX, but it failed to bind to a Cys32 and Cys35 mutant TRX, suggesting the redox-active site is critical for binding. mVDUP1 was ubiquitously expressed in various tissues and located in the cytoplasm. Biochemical analysis showed that mVDUP1 inhibited the insulin-reducing activity of TRX. When cells were treated with various stress stimuli such as H2O2 and heat shock, mVDUP1 was significantly induced. TRX is known to interact with other proteins such as proliferation-associated gene and apoptosis signal-regulating kinase 1. Coexpression of mVDUP1 interfered with the interaction between TRX and proliferation-associated gene or TRX and ASK-1, suggesting its roles in cell proliferation and oxidative stress. To investigate the roles of mVDUP1 in oxidative stress, mVDUP1 was overexpressed in NIH 3T3 cells. When cells were exposed to stress, cell proliferation was declined with elevated apoptotic cell death compared with control cells. In addition, c-Jun N-terminal kinase activation and IL-6 expression were elevated. Taken together, these results demonstrate that mVDUP1 functions as an oxidative stress mediator by inhibiting TRX activity.
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PMID:Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. 1084 82

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic effects. How this chemical produces these effects is not known, but it may work by suppressing NF-kappaB, a nuclear transcription factor that regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratrol on NF-kappaB activation induced by various inflammatory agents. Resveratrol blocked TNF-induced activation of NF-kappaB in a dose- and time-dependent manner. Resveratrol also suppressed TNF-induced phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB, and NF-kappaB-dependent reporter gene transcription. Suppression of TNF-induced NF-kappaB activation by resveratrol was not restricted to myeloid cells (U-937); it was also observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resveratrol also blocked NF-kappaB activation induced by PMA, LPS, H2O2, okadaic acid, and ceramide. The suppression of NF-kappaB coincided with suppression of AP-1. Resveratrol also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases.
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PMID:Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. 1084 9

Brief exposure to ozone, a potent cross-inducer of plant stress responses, leads within minutes to activation of an ERK-type MAP kinase (approximately 46 kDa) in tobacco. This activation process is calcium-dependent and can be blocked both by free radical quenchers and by a specific inhibitor of MEK-1 (MAPKK). Hydrogen peroxide and superoxide anion radicals can substitute for ozone as the activation stimulus, which does not appear to require salicylate as an intermediary. The properties of the ozone-induced MAPK suggest that it may be SIPK (salicylate-induced protein kinase), a tobacco MAPK that is activated by a variety of stress treatments. The ability of ozone to activate SIPK indicates that this protein kinase acts as a very early transducer of redox stress signals in plant cells.
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PMID:Ozone treatment rapidly activates MAP kinase signalling in plants. 1084 53

Stimulation of human lung fibroblast cells with TGF-beta1 resulted in a transient burst of reactive oxygen species with maximal increase at 5 min after treatment. This reactive oxygen species increase was inhibited by the antioxidant, N-acetyl-l -cysteine (NAC). TGF-beta1 treatment stimulated IL-6 gene expression and protein synthesis in human lung fibroblast cells. Antioxidants including NAC, glutathione, and catalase reduced TGF-beta1-induced IL-6 gene expression, and direct H2O2 treatment induced IL-6 expression in a dose-dependent manner. NAC also reduced TGF-beta1-induced AP-1 binding activity, which is involved in IL-6 gene expression. It has been reported that Ca2+ influx is stimulated by TGF-beta1 treatment. EGTA suppressed TGF-beta1- or H2O2-induced IL-6 expression, and ionomycin increased IL-6 expression, with simultaneously modulating AP-1 activity in the same pattern. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-related kinase kinase 1, suppressed TGF-beta1- or H2O2-induced IL-6 and AP-1 activation. In addition, TGF-beta1 or H2O2 increased MAPK activity which was reduced by EGTA and NAC, suggesting that MAPK is involved in TGF-beta1-induced IL-6 expression. Taken together, these results indicate that TGF-beta1 induces a transient increase of intracellular H2O2 production, which regulates downstream events such as Ca2+ influx, MAPK, and AP-1 activation and IL-6 gene expression.
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PMID:Requirement of hydrogen peroxide generation in TGF-beta 1 signal transduction in human lung fibroblast cells: involvement of hydrogen peroxide and Ca2+ in TGF-beta 1-induced IL-6 expression. 1092 6

To elucidate mechanisms underlying glutathione S-transferase p (GSTp)-mediated cellular protection against oxidative stress-induced cell death, the effect of GSTp on stress signaling pathways was investigated before and after H2O2 treatment. Under nonstressed conditions, increased expression of GSTp via a tet-off-inducible GSTp in NIH 3T3 cells increased the phosphorylation of mitogen-activated protein (MAP) kinase kinase 4, p38, extracellular receptor kinase (ERK), and inhibitor of kappa-kinase (IKK), and reduced phosphorylation of MAP kinase kinase 7 and Jun NH2-terminal kinase (JNK). Whereas H2O2 treatment of cells induced JNK, p38, and IKK activities, in the presence of H2O2 and elevated GSTp expression there was an additional increase in ERK, p38, and IKK activities and a decrease in JNK activity. GSTp-mediated protection from H2O2-induced death was attenuated upon inhibition of p38, nuclear factor KB, or MAP kinase by dominant negative or pharmacological inhibitors. Conversely, expression of a dominant negative JNK protected cells from H2O2-mediated death. These data suggest that the coordinated regulation of stress kinases by GSTp, as reflected by increased p38, ERK, and nuclear factor kappaB activities together with suppression of JNK signaling, contributes to protection of cells against reactive oxygen species-mediated death.
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PMID:Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. 1094 8

Tumor necrosis factor (TNF) is a multipotential cytokine that induces apoptosis and activates nuclear factor-kappa B (NF-kappaB), activation protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). Several mechanisms have been suggested to explain these effects of TNF, one of them being the involvement of reactive oxygen intermediates (ROI). Because Bcl-2 family members are known to affect the redox status of the cell, we examined the effect of Bcl-x(L) expression on TNF signaling. Overexpression of Bcl-x(L) in human promyelocytic lymphoma HL-60 cells downregulated TNF-induced cytotoxicity. Cleavage of poly (ADP-ribose) polymerase by caspases, an early indicator of apoptosis, was also blocked by Bcl-x(L) overexpression. Activation of NF-kappaB was significantly suppressed in cells overexpressing Bcl-x(L), as was degradation of IkappaBalpha, the inhibitory subunit of NF-kappaB. NF-kappaB activation induced by serum-activated lipopolysaccharide (SALPS), ceramide, and okadaic acid was also inhibited by overexpression of Bcl-x(L), whereas that by phorbol myristate acetate (PMA) and H2O2 was unaffected. Besides NF-kappaB, the activation of AP-1 by TNF also was blocked by Bcl-x(L). The activation of JNK and MAPK kinase, which regulate these transcription factors, was reduced in Bcl-x(L)-transfected cells. Overall, our results demonstrate that Bcl-x(L) inhibits TNF signaling at an early step common to induction of activation of apoptosis, NF-kappaB, AP-1, MAPK, and JNK.
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PMID:Bcl-x(L) suppresses TNF-mediated apoptosis and activation of nuclear factor-kappaB, activation protein-1, and c-Jun N-terminal kinase. 1095 16

Reactive oxygen species (ROS) have been proposed to mediate vascular hypertrophy induced by angiotensin II (Ang II). Recently, we and others have shown that growth-promoting signals by Ang II involve protein tyrosine kinase (PTK) and extracellular signal-regulated kinase (ERK). However, whether ROS contribute to the Ang II-induced PTK and/or ERK activation in vascular smooth muscle cells (VSMCs) remains largely unclear. Here, we have investigated the possible involvement of ROS in Ang II-induced PTK and ERK activation. In the presence of a NADH/NADPH oxidase inhibitor, diphenyleneiodonium (DPI) or an antioxidant, alpha-tocopherol, Ang II-induced protein tyrosine phosphorylation of two major proteins (p120, p70) and ERK activation were markedly reduced, whereas ERK activation by epidermal growth factor was unaffected. DPI also inhibited Ang II-induced H2O2 production and PTK activation. In this regard, H2O2 and a membrane permeable thiol-oxidizing agent, diamide, stimulated protein tyrosine phosphorylation of p120 and p70, and ERK activation in VSMCs. H2O2 also enhanced PTK activity. From these data, we conclude that ROS play a critical role in the Ang II-induced PTK and ERK activation in VSMCs, thereby contributing to vascular growth associated with enhanced Ang II activity.
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PMID:Involvement of reactive oxygen species in the activation of tyrosine kinase and extracellular signal-regulated kinase by angiotensin II. 1096 82

We studied mechanisms by which senescent cells acquire resistance to UV-induced cellular insults. Human primary foreskin fibroblast culture was used since it undergoes cellular senescence in vitro after a limited number of passages. Senescence was induced by a brief treatment of the early passage cells with 100 microM of H2O2 for 1 h, and subsequent culture for 3 weeks. Hydrogen peroxide-treated cells showed an enhancement of senescence-associated beta-galactosidase activity. In the senescent cells, DNA fragmentation in response to UV-irradiation was found to decrease significantly compared with that in the young cells. The SAPK/JNK activation by UV irradiation was reduced in both non-treated senescent cells and the hydrogen peroxide-induced senescent cells, suggesting that a reduced DNA fragmentation by UV-irradiation in the senescent cells is closely related to the decreased SAPK/JNK activity. Since a cell cycle inhibitor, p21Waf1, has been implicated in protecting cells against apoptotic cell death, we determined p21Waf1 to assess whether its elevation has any impact on the reduction of UV-induced activation of SAPK/JNK in the senescent cells. The expression of p21Waf1 increased in both the nontreated and the hydrogen peroxide-treated senescent cells. Our study also revealed that the blockage of SAPK/JNK activation in the senescent cells was closely related to the increased level of p21Waf1. Our observation might provide clues about molecular mechanism of resistance to DNA fragmentation and the consequent cell death by UV-irradiation.
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PMID:Reduction of UV-induced cell death in the human senescent fibroblasts. 1098 39


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