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)

The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1beta and TNF-alpha can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. Salicylate inhibited the IL-1beta and TNF-alpha-induced COX-2 expressions, regulated the activation of ERK, IKK and IkappaB degradation, and the subsequent activation of NF-kappaB, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1beta and TNF-alpha-induced COX-2 and PGE2 release. The antioxidant, N-acetyl-cysteine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1beta and TNF-alpha-treated cells. This antioxidant also inhibited the activation of ERK and NF-kappaB in neonatal rat cardiomyocytes. In addition, IL-1beta and TNF-alpha stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IkappaB and NF-kappaB, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.
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PMID:Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-kappaB activation in rat ventricular cardiomyocytes. 1293 47

Nuclear factor kappaB (NF-kappaB) plays a pivotal role in numerous cellular processes, including stress response, inflammation, and protection from apoptosis. Therefore, the activity of NF-kappaB needs to be tightly regulated. We have previously identified a novel gene, named CIKS (connection to IkappaB-kinase and SAPK), able to bind the regulatory sub-unit NEMO/IKKgamma and to activate NF-kappaB. Here, we demonstrate that CIKS forms homo-oligomers, interacts with NEMO/IKKgamma, and is recruited to the IKK-complex upon cell stimulation. In addition, we identified the regions of CIKS responsible for these functions. We found that the ability of CIKS to oligomerize, and to be recruited to the IKK-complex is not sufficient to activate the NF-kappaB. In fact, a deletion mutant of CIKS able to oligomerize, to interact with NEMO/IKKgamma, and to be recruited to the IKK-complex does not activate NF-kappaB, suggesting that CIKS needs a second level of regulation to efficiently activate NF-kappaB.
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PMID:Role of the adaptor protein CIKS in the activation of the IKK complex. 1294 67

MAPK/ERK kinase kinase 1 (MEKK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) of the stress-induced JNK pathway. Once activated, MEKK1 phosphorylates the MAP2K MKK4, which in turn phosphorylates JNK. MEKK1 also has the capacity to activate IKK, the central protein kinase of the NF-kappa B pathway. The molecular determinants responsible for the ability of MEKK1 to recognize specific substrates are poorly understood. We report here that select point mutations in subdomain VIII of the protein kinase domain of MEKK1 (MEKK1 Delta) differentially affect its ability to activate MKK4 and IKK, and consequently AP1 and NF-kappa B reporter genes. Moreover, binding of MKK4 to MEKK1 Delta protects the latter from cleavage at an engineered protease target site in subdomain VIII. Collectively these results provide evidence that subdomain VIII of MEKK1 is involved not only in binding to, but also in discrimination of, protein substrates.
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PMID:Subdomain VIII is a specificity-determining region in MEKK1. 1450 Jul 27

1. Although capsaicin analogs might be a potential strategy to manipulate inflammation, the mechanism is still unclear. In this study, the effects and action mechanisms of vanilloid analogs on iNOS and COX-2 expression were investigated in RAW264.7 macrophages. 2. Capsaicin and resiniferatoxin (RTX) can inhibit LPS- and IFN-gamma-mediated NO production, and iNOS protein and mRNA expression with similar IC50 values of around 10 microm. 3. Capsaicin also transcriptionally inhibited LPS- and PMA-induced COX-2 expression and PGE2 production. However, this effect exhibited a higher potency (IC50: 0.2 microm), and RTX failed to elicit such responses at 10 microm. 4. Interestingly, we found that capsazepine, a competitive TRPV1 antagonist, did not prevent the inhibition elicited by capsaicin or RTX. Nevertheless, it mimicked vanilloids in inhibiting iNOS/NO and COX-2/PGE2 induction with an IC50 value of 3 microm. RT-PCR and immunoblotting analysis excluded the expression of TRPV1 in RAW264.7 macrophages. 5. The DNA binding assay demonstrated the abilities of vanilloids to inhibit LPS-elicited NF-kappaB and AP-1 activation and IFN-gamma-elicited STAT1 activation. The reporter assay of AP-1 activity also supported this action. 6. The kinase assay indicated that ERK, JNK, and IKK activation by LPS were inhibited by vanilloids. 7. In conclusion, vanilloids can modulate the expression of inflammatory iNOS and COX-2 genes in macrophages through interference with upstream signalling events of LPS and IFN-gamma. These findings provide new insights into the potential benefits of the active ingredient in hot chilli peppers in inflammatory conditions.
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PMID:Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages. 1453 Feb 14

TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38alpha at Ser423, Thr431 and Ser438 in vitro. TAB1 became phosphorylated at all three sites when cells were exposed to cellular stresses, or stimulated with tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or lipopolysaccharide (LPS). The phosphorylation of Ser423 and Thr431 was prevented if cells were pre-incubated with SB 203580, while the phosphorylation of Ser438 was partially inhibited by PD 184352. Ser423 is the first residue phosphorylated by SAPK2a/p38alpha that is not followed by proline. The activation of TAK1 was enhanced by SB 203580 in LPS-stimulated macrophages, and by proinflammatory cytokines or osmotic shock in epithelial KB cells or embryonic fibroblasts. The activation of TAK1 by TNF-alpha, IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38alpha-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38alpha-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38alpha but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).
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PMID:Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. 1459 77

UV light, a paradigmatic initiator of cell stress, invokes responses that include signal transduction, activation of transcription factors, and changes in gene expression. Consequently, in epidermal keratinocytes, its principal and frequent natural target, UV regulates transcription of a distinctive set of genes. Hypothesizing that UV activates distinctive epidermal signal transduction pathways, we compared the UV-responsive activation of the JNK and NFkappaB pathways in keratinocytes, with the activation of the same pathways by other agents and in other cell types. Using of inhibitors and antisense oligonucleotides, we found that in keratinocytes only UVB/UVC activate JNK, while in other cell types UVA, heat shock, and oxidative stress do as well. Keratinocytes express JNK-1 and JNK-3, which is unexpected because JNK-3 expression is considered brain-specific. In keratinocytes, ERK1, ERK2, and p38 are activated by growth factors, but not by UV. UVB/UVC in keratinocytes activates Elk1 and AP1 exclusively through the JNK pathway. JNKK1 is essential for UVB/UVC activation of JNK in keratinocytes in vitro and in human skin in vivo. In contrast, in HeLa cells, used as a control, crosstalk among signal transduction pathways allows considerable laxity. In parallel, UVB/UVC and TNFalpha activate the NFkappaB pathway via distinct mechanisms, as shown using antisense oligonucleotides targeted against IKKbeta, the active subunit of IKK. This implies a specific UVB/UVC responsive signal transduction pathway independent from other pathways. Our results suggest that in epidermal keratinocytes specific signal transduction pathways respond to UV light. Based on these findings, we propose that the UV light is not a genetic stress response inducer in these cells, but a specific agent to which epidermis developed highly specialized responses.
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PMID:Specificity in stress response: epidermal keratinocytes exhibit specialized UV-responsive signal transduction pathways. 1461 88

Stress signals activate both inhibitor of nuclear factor-kappaB kinase (IKKbeta) and c-Jun NH(2)-terminal kinase (JNK). It was shown recently that IKK-dependent nuclear factor kappaB activation results in attenuation of tumor necrosis factor alpha-induced JNK activation. How that negative cross-talk between nuclear factor kappaB and JNK occurs is not well-understood. By using wild-type and Ikkbeta gene knockout (Ikkbeta(-/-)) mouse embryo fibroblasts, we found that IKKbeta deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45beta or X-linked Inhibitor of Apoptosis (XIAP), as suggested previously for RelA(-/-) cells treated with tumor necrosis factor alpha. This enhanced JNK activation was largely associated with an oxidative stress response as indicated by elevated expression of heme oxygenase-1 and the accumulation of H(2)O(2) in Ikkbeta(-/-) cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in Ikkbeta(-/-) cells compared with wild-type cells. Inhibition of CYP1B1 reduced both oxidative stress and arsenic-stimulated JNK activation. Thus, increased CYP1B1 expression is central to and seems to be responsible for sensitizing Ikkbeta(-/-) cells to stress-induced JNK activation.
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PMID:Inhibitor of nuclear factor kappaB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. 1463 91

Although c-Jun NH(2)-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells.
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PMID:Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines. 1464 74

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-kappaB. However, production and secretion of the proinflammatory cytokine TNF-alpha in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-alpha-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-kappaB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-kappaB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-kappaB but rather reflected diminished degradation of IkappaB-alpha. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-kappaB activation and associated TNF-alpha expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.
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PMID:Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression. 1465 21

TRAF2 is a RING finger protein that regulates the cellular response to stress and cytokines by controlling JNK, p38 and NF-kappaB signaling cascades. Here, we demonstrate that TRAF2 ubiquitination is required for TNFalpha-induced activation of JNK but not of p38 or NF-kappaB. Intact RING and zinc finger domains are required for TNFalpha-induced TRAF2 ubiquitination, which is also dependent on Ubc13. TRAF2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of JNK. Inhibition of Ubc13 expression by RNAi resulted in inhibition of TNFalpha-induced TRAF2 translocation and impaired activation of JNK but not of IKK or p38. TRAF2 aggregates in the cytoplasm, as seen in Hodgkin-Reed-Sternberg lymphoma cells, resulting in constitutive NF-kappaB activity but failure to activate JNK. These findings demonstrate that the TRAF2 RING is required for Ubc13-dependent ubiquitination, resulting in translocation of TRAF2 to an insoluble fraction and activation of JNK, but not of p38 or NF-kappaB. Altogether, our findings highlight a novel mechanism of TRAF2-dependent activation of diverse signaling cascades that is impaired in Hodgkin-Reed-Sternberg cells.
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PMID:Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-kappaB. 1471 52


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