Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MAPK pathways transduce a broad variety of extracellular signals into cellular responses. Despite their pleiotropic effects and their ubiquitous distribution, surprisingly little is known about their involvement in the communication network of nerve cells. As a first step to elucidate the role of MAPK pathways in neuronal signalling, we studied the distribution of SAPK alpha/JNK2, SAPK beta/JNK3, and SAPK gamma/JNK1, three isoforms of SAPK/JNK, a stress-activated MAPK subfamily. We compared the mRNA localisation of the three main isoforms in the adult and developing rat brain using in situ hybridisation. In the adult brain, SAPK alpha and beta were widely but heterogeneously distributed, reproducing the pattern of a probe that does not discriminate the isoforms. Differently, high labelling for the SAPK gamma probe was exclusively localised in the endopiriform nucleus and medial habenula. Intermediate staining was detected in the hippocampus. During post-natal development, SAPK beta showed the same localisation as in the adult. Nevertheless, the semi-quantitative analysis of optical densities showed significantly different mRNA levels. In the adult, SAPK gamma signal was weak, whereas in newborn rats the labelling was intense and widely distributed. SAPK gamma mRNA levels decreased during development, to reach the low signals detected in the adult. These results suggest that in the central nervous system SAPK-type MAP kinases perform significant physiological functions which are particularly relevant during post-natal development. The distinct distribution patterns of SAPK isoforms in the adult rat brain support the hypothesis that separate functions are performed by the products of the three SAPK genes.
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PMID:Differential expression of SAPK isoforms in the rat brain. An in situ hybridisation study in the adult rat brain and during post-natal development. 974 3

c-Jun NH2-terminal kinases (JNKs) are protein kinases that are activated by a wide variety of extracellular signals. This study investigated the expression and regulation of JNKs in isolated gastric canine parietal cells. Western blot analysis of cell lysates from highly purified (>95%) parietal cells with an antibody recognizing JNK1 and to a lesser degree JNK2 revealed the presence of two bands of 46 and 54 kDa, respectively. JNK1 activity was quantitated by immunoprecipitation and in-gel kinase assays. Of the different agents tested, carbachol was the most potent inducer of JNK1 activity, whereas histamine and epidermal growth factor induced weaker responses. The proinflammatory cytokine tumor necrosis factor-alpha stimulated JNK1 but had no effect on extracellular signal-regulated kinase (ERK2) induction, suggesting that activation of JNK1 might represent an important event in mediation of the inflammatory response in the stomach. The action of carbachol was dose (0.1-100 microM) and time dependent, with a maximal stimulatory effect (fourfold) detected after 30 min of incubation and sustained for 2 h. Addition of the specific protein kinase C (PKC) inhibitor GF109203X did not affect the stimulatory action of carbachol. The intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-AM inhibited carbachol induction of JNK1 activity by 60%. Thapsigargin (1 microM), an intracellular Ca2+-rising agent, induced JNK1 activity more than threefold. Carbachol activation of JNK1 resulted in induction of c-Jun (protein) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun. In conclusion, our data indicate that carbachol induces JNK activity in gastric parietal cells via intracellular Ca2+-dependent, PKC-independent pathways, leading to induction of c-jun gene expression via phosphorylation and transcriptional activation of c-Jun.
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PMID:Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells. 975 5

B cell antigen receptor (BCR) cross-linking activates three distinct families of nonreceptor protein tyrosine kinases (PTKs): src-family kinases, Syk, and Btk; these PTKs are responsible for initiating downstream events. BCR cross-linking in the chicken DT40 B cell line also activates three distinct mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK)2, c-jun NH2-terminal kinase (JNK)1, and p38 MAPK. To dissect the functional roles of these PTKs in MAPK signaling, activation of MAPKs was examined in various PTK-deficient DT40 cells. BCR-mediated activation of ERK2, although maintained in Lyn-deficient cells, was abolished in Syk-deficient cells and partially inhibited in Btk-deficient cells, indicating that BCR-mediated ERK2 activation requires Syk and that sustained ERK2 activation requires Btk. BCR-mediated JNK1 activation was maintained in Lyn-deficient cells but abolished in both Syk- and Btk-deficient cells, suggesting that JNK1 is activated via a Syk- and Btk-dependent pathway. Consistent with this, BCR-mediated JNK1 activation was dependent on intracellular calcium and phorbol myristate acetate-sensitive protein kinase Cs. In contrast, BCR-mediated p38 MAPK activation was detected in all three PTK-deficient cells, suggesting that no single PTK is essential. However, BCR-mediated p38 MAPK activation was abolished in Lyn/Syk double deficient cells, demonstrating that either Lyn or Syk alone may be sufficient to activate p38 MAPK. Our data show that BCR-mediated MAPK activation is regulated at the level of the PTKs.
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PMID:Different protein tyrosine kinases are required for B cell antigen receptor-mediated activation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase 1, and p38 mitogen-activated protein kinase. 976 9

Paclitaxel (Taxol) is a novel anti-cancer drug that has shown efficacy toward several malignant tumors, particularly ovarian tumors. We reported previously that paclitaxel can induce interleukin (IL)-8 promoter activation in subgroups of ovarian cancer through the activation of both AP-1 and nuclear factor kappaB. Further analysis of paclitaxel analogs indicates that the degree of IL-8 induction by analysis correlates with the extent of cell death; however, IL-8 itself is not the cause of cell death. This suggests that pathways that lead to IL-8 and cell death may overlap, although IL-8 per se does not kill tumor cells. To decipher the upstream signals for paclitaxel-induced transcriptional activation and cell death, we studied the involvement of protein kinases that lead to the activation of AP-1, specifically the c-Jun NH2-terminal kinase (JNK1), p38, and the extracellular signal-regulated kinase 1 (ERK1). The role of IkappaB in paclitaxel-induced cell death was also analyzed. Paclitaxel activated JNK, and to a lesser degree p38, but not ERK1. Paclitaxel-induced IL-8 promoter activation was inhibited by dominant-inhibitory mutants of JNK, p38, and the super-repressor form of IkappaBalpha, but not by dominant-inhibitory forms of ERK1. Dominant-inhibitory mutants of JNK1 also greatly reduced paclitaxel-induced cell death, and the kinetics of JNK induction was closely followed by DNA fragmentation. These results indicate (i) that paclitaxel activates the JNK signaling pathway and (ii) that JNK activation is a common point of paclitaxel-induced gene induction and cell death.
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PMID:Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). 977 47

The inflammatory cytokine interleukin-1beta (IL-1beta) induces cyclooxygenase-2 (Cox-2) expression with a concomitant release of prostaglandins from glomerular mesangial cells. We reported previously that IL-1beta rapidly activates the c-Jun NH2-terminal/stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-2 expression and prostaglandin E2 (PGE2) production. The current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 JNK2/SAPKbeta reduces Cox-2 expression and PGE2 production stimulated by IL-1beta. Similarly, overexpression of the kinase-dead form of p38 MAPK also inhibits IL-1beta-induced Cox-2 expression and PGE2 production. These results suggest that activation of both JNK/SAPK and p38 MAPK is required for Cox-2 expression after IL-1beta activation. Furthermore, our experiments confirm that IL-1beta activates MAP kinase kinase-4 (MKK4)/SEK1, MKK3, and MKK6 in renal mesangial cells. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1beta- induced Cox-2 expression with inhibition of both JNK/SAPK and p38 MAPK phosphorylation. Overexpression of the kinase-dead form of MKK3 or MKK6 demonstrated that either of these two mutant kinases inhibited IL-1beta-induced p38 MAPK phosphorylation and Cox-2 expression but not JNK/SAPK phosphorylation and activation. This study suggests that the activation of both JNK/SAPK and p38 MAPK signaling cascades is required for IL-1beta-induced Cox-2 expression and PGE2 synthesis.
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PMID:Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. 978 61

In previous reports we demonstrated that glucose deprivation induces metabolic oxidative stress in drug-resistant human breast carcinoma MCF-7/ADR cells (Lee, Y. J., Galoforo, S. S., Berns, c. M., Chen, J. C., Davis, B. H., Swim, J. E., Corry, P. M., and Spitz, D. R. (1998) J. Biol. Chem. 273, 5294-5299). In the study described here, we investigated intracellular responses to metabolic oxidative stress. Northern blots show an increase in the level of HSP70 and HSP28 mRNA in cells exposed to glucose-free medium for 1 h. One- and two-dimensional polyacrylamide gel analyses confirmed that glucose deprivation induced a family of HSPs, particularly an inducible HSP70. Overexpression of bcl-2 suppressed glucose deprivation-induced HSP70 gene expression, heat shock transcription factor-heat shock element binding activity, as well as c-Jun NH2-terminal kinase (JNK1) activation. Expression of a dominant-negative mutant of JNK1 also suppressed glucose deprivation-induced JNK1 activation as well as HSP70 gene expression. Taken together, the stress-activated protein kinase signal transduction pathway is involved in glucose deprivation-induced heat shock gene expression.
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PMID:Metabolic oxidative stress-induced HSP70 gene expression is mediated through SAPK pathway. Role of Bcl-2 and c-Jun NH2-terminal kinase. 979 2

Phorone, a glutathione (GSH) depletor, induces the expression of mRNAs of heme oxygenase-1 (HO-1) and c-jun by mediating the activation of activated protein-1 (AP-1) in rat livers. We have shown that phorone activates c-Jun N-terminal kinase (JNK), thus leading to c-Jun phosphorylation, and transactivation of AP-1 and HO-1 gene expression in the rat liver in response to oxidative stress. The in-gel kinase assay showed that phorone activated JNK1 predominantly in the rat liver nuclear extract. The JNK activation by phorone was slightly observed at 1 hr after administration and gradually increased with time. Ser73-phosphorylation of c-Jun catalyzed by JNK was significantly altered by changing hepatic GSH levels based on the results observed by the combined injection of buthionine sulfoximine (BSO) or GSH isopropyl ester (GIP) with phorone. Namely, BSO, an inhibitor of GSH biosynthesis, enhanced phorone-mediated c-Jun phosphorylation as well as AP-1 binding activity. However, GSH isopropyl ester prevented GSH depletion and abolished both c-Jun phosphorylation and the activation of AP-1 binding evoked by phorone. GSH isopropyl ester also suppressed phorone-produced HO-1 and c-jun gene expressions to 25 and 30% of the induced level. Perfluorodecanoic acid (PFDA) reduced GSH S-transferase activity, prevented phorone-mediated GSH depletion and abolished either HO-1 or c-jun mRNA induction by phorone. These results indicated that oxidative stress under GSH depletion produced by phorone could activate preferentially JNK and lead to the transcriptional activation of AP-1 and consequently to HO-1 gene expression. This study suggests that JNK activation could be one of the major signaling pathways to transmit intracellular events to the nuclei during oxidative stress via GSH depletion by phorone in rat livers.
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PMID:The expression of heme oxygenase-1 gene responded to oxidative stress produced by phorone, a glutathione depletor, in the rat liver; the relevance to activation of c-jun n-terminal kinase. 980 9

The mitogen-activated protein kinase (MAPK) cascades represent one of the important signalling mechanisms in response to environmental stimuli. We report the identification of a human MAPK kinase kinase, MAPKKK4, via sequence similarity with other MAPKKKs. When truncated MAPKKK4 (DeltaMAPKKK4) was overexpressed in HEK293 cells, it was constitutively active and induced the activation of endogenous p38alpha, c-Jun N-terminal kinase (JNK)1/2 and extracellular signal-regulated kinase (ERK)2 in vivo. Kinase-inactive DeltaMAPKKK4 partly inhibited the activation of p38alpha, JNK1/2 and ERK2 induced by stress, tumour necrosis factor alpha or epidermal growth factor, suggesting that MAPKKK4 might be physiologically involved in all three MAPK cascades. Co-expressed MAP kinase kinase (MKK)-1, MKK-4, MKK-3 and MKK-6 were activated in vivo by DeltaMAPKKK4. All of the above MKKs purified from Escherichia coli were phosphorylated and activated by DeltaMAPKKK4 immunoprecipitates in vitro. When expressed by lower plasmid doses, DeltaMAPKKK4 preferentially activated MKK-3 and p38alpha in vivo. Overexpression of DeltaMAPKKK4 did not activate the NF-kappaB pathway. Immunoprecipitation of endogenous MAPKKK4 by specific antibodies showed that MAPKKK4 was activated after the treatment of K562 cells with various stress conditions. As a broadly distributed kinase, MAPKKK4 might serve as a stress responder. MAPKKK4 is 91% identical with the recently described murine MEKK-4beta and might be its human homologue. It is also identical with the recently cloned human MAP three kinase 1 except for the lack of an internal sequence homologous to the murine MEKK-4alpha isoform. Differences in the reported functional activities of the three kinases are discussed.
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PMID:Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. 984 71

Mitogen-activated protein kinases (MAPKs) mediate many of the cellular effects of growth factors, cytokines and stress stimuli. Their activation requires the phosphorylation of a threonine and a tyrosine residue located in a Thr-X-Tyr motif (where X is any amino acid) [1]. This phosphorylation is catalysed by MAPK kinases (MKKs), which are all thought to be 'dual specificity' enzymes that phosphorylate both the threonine and the tyrosine residue of the Thr-X-Tyr motif [2]. Here, we report that the MAPK family member known as stress-activated protein kinase-1c (SAPK1c, also known as JNK1) [3] is activated synergistically in vitro by MKK4 ([4] [5] [6]; also called SKK1 and JNKK1) and MKK7 ([7] [8] [9]; also called SKK4 and JNKK2). We found that MKK4 had a preference for the tyrosine residue, and MKK7 for the threonine residue, within the Thr-X-Tyr motif. These observations suggest that the full activation of SAPK1c in vivo may sometimes require phosphorylation by two different MKKs, providing the potential for integrating the effects of different extracellular signals. They also raise the possibility that other MAPK family members may be activated by two or more MKKs and that some MKKs may have gone undetected because they phosphorylate the tyrosine residue only, and therefore do not induce any activation unless the threonine has first been phosphorylated by another MKK.
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PMID:Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. 988 2

Epidermal growth factor (EGF) is produced in the ovary and influences proliferation of the malignant ovarian surface epithelium (OSE); yet its role in malignancy or in regulating the normal surface epithelium is unclear. In human OSE cells derived from primary cultures of normal tissue transfected with SV40 large T antigen (IOSE cells), EGF promoted survival but not proliferation. This survival effect was reversed by acute treatment with the phorbol ester, 12-0-tetradecanoyl-13-phorbol acetate (TPA) which alone markedly inhibited IOSE proliferation. We tested whether the activities of the mitogen-activated protein kinases (ERK1/2 and JNK1) varied in response to EGF, TPA, or combinations of these agonists and if the same treatments altered patterns of immediate early gene expression. Alone, EGF activated ERK1/2, increased and sustained levels of c-jun mRNA, but had almost no effect on JNK1 activation. Conversely, PKC activation resulted in a rapid, but transient induction of c-fos RNA and of both kinases, JNK1 and ERK2. When combined, EGF and TPA further enhanced the phosphorylation of both enzymes despite inhibiting survival. Though JNKs and ERKs are thought to transduce opposing cellular responses, in IOSE cells, robust costimulation of the JNK and ERK pathways may redirect the survival message.
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PMID:Regulation of proliferation and apoptosis by epidermal growth factor and protein kinase C in human ovarian surface epithelial cells. 992 63


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