Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate receptor activation of mitogen-activated protein (MAP) kinase signalling cascades has been implicated in diverse neuronal functions such as synaptic plasticity, development and excitotoxicity. We have previously shown that Ca2+-influx through NMDA receptors in cultured striatal neurones mediates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt/protein kinase B (PKB) through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. Exposing neurones to the Src family tyrosine kinase inhibitor PP2, but not the inactive analogue PP3, inhibited NMDA receptor-induced phosphorylation of ERK1/2 and Akt/PKB in a concentration-dependent manner, and reduced cAMP response element-binding protein (CREB) phosphorylation. To establish a link between Src family tyrosine kinase-mediated phosphorylation and PI 3-kinase signalling, affinity precipitation experiments were performed with the SH2 domains of the PI 3-kinase regulatory subunit p85. This revealed a Src-dependent phosphorylation of a focal adhesion kinase (FAK)-p85 complex on glutamate stimulation. Demonstrating that PI3-kinase is not ubiquitously involved in NMDA receptor signal transduction, the PI 3-kinase inhibitors wortmannin and LY294002 did not prevent NMDA receptor Ca2+-dependent phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2). Further, inhibiting Src family kinases increased NMDA receptor-dependent JNK1/2 phosphorylation, suggesting that Src family kinase-dependent cascades may physiologically limit signalling to JNK. These results demonstrate that Src family tyrosine kinases and PI3-kinase are pivotal regulators of NMDA receptor signalling to ERK/Akt and JNK in striatal neurones.
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PMID:Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones. 1500 68

Bovine type I collagen (Col-I) is utilized for medical purposes such as cosmetic surgery and wrinkle removal. Cyclooxygenase-2 (COX-2) plays roles in pathophysiological processes including inflammation and tumorigenesis. This study examines the effects of Col-I on the COX-2 expression and the signaling pathways in macrophages. Col-I increased the levels of COX-2 protein and mRNA in serum-stimulated Raw264.7 cells in a time- and concentration-dependent manner. Treatment of cells with Col-I increased CCAAT/enhancer binding protein (C/EBP) DNA binding. Antibody supershift experiments revealed that C/EBP DNA binding activity induced by Col-I depended largely on C/EBPbeta and C/EBPdelta. Immunocytochemistry showed that Col-I induced nuclear translocation of C/EBPbeta and C/EBPdelta, whose activation contributes to COX-2 induction. Overexpression of the dominant-negative mutant form of C/EBP abolished COX-2 induction by Col-I. Col-I also increased cyclic-AMP response element binding protein (CREB) binding to DNA. Inhibition of focal adhesion kinase (FAK) or downstream phosphoinositide 3-kinase and p70S6 kinase by specific chemical inhibitors prevented COX-2 induction by Col-I, and C/EBP and CREB from binding to their consensus DNA oligonucleotides. Experiments using chemical inhibitors or dominant-negative mutant vectors showed that the mitogen-activated protein (MAP) kinase pathways including p38-kinase and extracellular signal-regulated kinase (ERK1/2), but not c-Jun N-terminal kinase (JNK1), simultaneously regulated COX-2 induction by Col-I. This was in agreement with inhibition of Col-I-inducible C/EBP and CREB DNA binding by concomitant treatment with SB203580 and PD98059. These results provide evidence that Col-I induces COX-2 in serum-stimulated macrophages and that the multiple cell signaling pathways involving Src-focal adhesion kinase, phosphoinositide 3-kinase, and MAP kinases regulate COX-2 induction by Col-I via C/EBP and CREB activation.
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PMID:Induction of cyclooxygenase-2 by bovine type I collagen in macrophages via C/EBP and CREB activation by multiple cell signaling pathways. 1516 55

Polycyclic aromatic hydrocarbons (PAHs) and their derivatives, such as benzo[a]pyrene (B[a]P), (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), and 5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE), are complete carcinogens. However, the tumor promotion effects of PAHs remain unclear. We therefore investigated the possible activation of activator protein-1 (AP-1) and nuclear factor-kappaB (NFkappaB) in mouse epidermal Cl41 cells after different PAHs treatments, including B[a]P, B[a]PDE, chrysene-1,2-diol-3,4-epoxid (CDE), and 5-MCDE. The results showed that B[a]PDE and 5-MCDE were able to activate AP-1 and NF-kappaB, whereas B[a]P showed only marginal effect on AP-1 activation, and B[a]P and CDE had no effect on NF-kappaB activation. Treatment with either B[a]PDE or 5-MCDE also resulted in mitogen-activated protein kinases (MAPKs) activation as well as inhibitory subunit kappa-B (IkappaBalpha) phosphorylation and degradation, whereas B[a]P and CDE had no effect. Pretreatment with PD98059, a specific inhibitor for extracellular signal-regulated protein kinases (ERKs) upstream kinase MEK1/2, or SB202190, a p38 kinase inhibitor, resulted in a dramatic inhibition of B[a]PDE-induced AP-1 transactivation. In addition, B[a]PDE-induced AP-1 activation was also inhibited by overexpressing a dominant negative mutant of JNK1 in the cells. All these suggest ERKs, c-jun N-terminal kinases (JNKs), and p38 kinase signal transduction pathways are required for AP-1 induction by B[a]PDE. Taken together, B[a]PDE and 5-MCDE are the active compounds of PAHs to initiate signaling pathways. Considering the important roles of AP-1 and NF-kappaB in tumor promotion, we speculated the activation of AP-1 and NF-kappaB by B[a]PDE and 5-MCDE may involve in their or their parent compounds' tumor promotion effects. This study may help in better understanding the tumor promotion effects of PAHs.
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PMID:Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP-1 and NF-kappaB in mouse epidermal cl41 cells. 1517 Aug 15

The development of specific inhibitors for the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) has been a recent research focus because of the association of JNK with cell death in conditions such as stroke and neurodegeneration. We have demonstrated previously the presence of critical inhibitory residues within an 11-mer peptide (TI-JIP) based on the sequence of JNK-interacting protein-1 (JIP-1). However, the corresponding region of JNK bound by this JIP-1-based peptide was unknown. To identify this region, we used a novel reverse two-hybrid approach with TI-JIP as bait. We screened a library of JNK1 mutants that had been generated by random PCR mutagenesis and found three mutants of JNK1 that failed to interact with TI-JIP. The mutations in JNK1 were L131R, R309W, and Y320H. Of these mutated residues, Leu-131 and Tyr-320 were located on a common face of the JNK protein close to other residues implicated previously in the interactions of MAPKs with substrates, phosphatases, and scaffolds. To test whether these JNK1 mutants were thus affected in their regulation, we evaluated their activation in mammalian cells in response to hyperosmolarity or cotransfection with a constitutively active upstream kinase or their direct phosphorylation by either MAPK kinase (MKK)4 or MKK7. In each situation, all three JNK mutants were not activated or phosphorylated to the same level as wild-type JNK. Therefore, the results of our unbiased reverse two-hybrid screening approach have identified residues of JNK responsible for binding JIP-1-based peptides as well as MKK4 or MKK7.
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PMID:Reverse two-hybrid screening identifies residues of JNK required for interaction with the kinase interaction motif of JNK-interacting protein-1. 1527 95

We monitored cyclooxygenase-2 (COX-2) expression in the insulin-like growth factor-II (IGF-II) treated human keratinocytes and explored the IGF-II signaling pathways with respect to the expression of COX-2. IGF-II induced COX-2 mRNA and protein levels, and the up-regulation of COX-2 expression by IGF-II was reduced by pretreatment with inhibitors of tyrosine kinase, Src and PI3-kinase. The inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) 1 also reduced the increased expression of COX-2 by IGF-II, but the inhibition of p38 did not. To further examine the roles of these mitogen-activated protein kinases (MAPKs) in IGF-II-induced COX-2 expression, we performed COX-2 promoter analysis using dominant negative plasmids of MEK1 (DN-MEK1), p38 (DN-p38) and JNK1 (DN-JNK1). Although IGF-II increased COX-2 promoter activity approximately 2.5-fold, this increase was blocked by cotransfection with DN-MEK1 or DN-JNK1. However, DN-p38 did not block the IGF-II-induced COX-2 promoter activity. In addition, inhibition of ERK or JNK1 reduced the increase of IGF-II-induced prostaglandin E(2) synthesis or cell proliferation. These results suggest that IGF-II induces COX-2 expression through the tyrosine kinase-Src-ERK and tyrosine kinase-PI3-kinase pathways, but not via p38 MAPK pathway, and that the basal JNK activity is required for the upregulation of COX-2 by IGF-II, as well.
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PMID:IGF-II-mediated COX-2 gene expression in human keratinocytes through extracellular signal-regulated kinase pathway. 1530 95

The c-Jun NH(2)-terminal kinase (JNK) group of mitogen-activated protein kinases is activated in response to a wide array of cellular stresses and proinflammatory cytokines. Roles for JNK in the developing nervous system and T-cell-mediated immunity have been established by detailed studies of mice with compound mutations in the Jnk genes. However, little is known concerning the roles of JNK in other mammalian tissues. Mice lacking both of the ubiquitously expressed isoforms (JNK1 and -2) die during midgestation with neural tube closure defects and brain abnormalities. Here we show that JNK-deficient mice exhibit delayed epithelial development in the epidermis, intestines, and lungs. In addition, JNK-deficient mice exhibit an eyelid closure defect associated with markedly reduced epidermal growth factor (EGF) receptor function, and loss of expression of the ligand EGF. We further demonstrate that adult mice lacking either JNK1 or -2 display striking differences in epidermal proliferation and differentiation, indicative of distinct roles for these kinases in the skin. We conclude that JNK is necessary for epithelial morphogenesis and is an essential regulator of signal transduction by the EGF receptor in the epidermis.
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PMID:The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis. 1537 16

Excessive exposure of solar ultraviolet (UV) radiation, particularly its UV-B component, to humans causes many adverse effects that include erythema, hyperplasia, hyperpigmentation, immunosuppression, photoaging and skin cancer. In recent years, there is increasing use of botanical agents in skin care products. Pomegranate derived from the tree Punica granatum contains anthocyanins (such as delphinidin, cyanidin and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose) and possesses strong antioxidant and anti-inflammatory properties. Recently, we have shown that pomegranate fruit extract (PFE) possesses antitumor promoting effects in a mouse model of chemical carcinogenesis. To begin to establish the effect of PFE for humans in this study, we determined its effect on UV-B-induced adverse effects in normal human epidermal keratinocytes (NHEK). We first assessed the effect of PFE on UV-B-mediated phosphorylation of mitogen-activated protein kinases (MAPK) pathway in NHEK. Immunoblot analysis demonstrated that the treatment of NHEK with PFE (10-40 microg/mL) for 24 h before UV-B (40 mJ/cm(2)) exposure dose dependently inhibited UV-B-mediated phosphorylation of ERKl/2, JNK1/2 and p38 protein. We also observed that PFE (20 microg/mL) inhibited UV-B-mediated phosphorylation of MAPK in a time-dependent manner. Furthermore, in dose- and time-dependent studies, we evaluated the effect of PFE on UV-B-mediated activation of nuclear factor kappa B (NF-kappaB) pathway. Using Western blot analysis, we found that PFE treatment of NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated degradation and phosphorylation of IkappaBalpha and activation of IKKalpha. Using immunoblot analysis, enzyme-linked immunosorbent assay and electrophoretic mobility shift assay, we found that PFE treatment to NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated nuclear translocation and phosphorylation of NF-kappaB/p65 at Ser(536). Taken together, our data shows that PFE protects against the adverse effects of UV-B radiation by inhibiting UV-B-induced modulations of NF-kappaB and MAPK pathways and provides a molecular basis for the photochemopreventive effects of PFE.
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PMID:Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes paragraph sign. 1549 60

Previously, studies reported that depletion of cellular GSH by sulfur amino acid deprivation (SAAD) potentiated arsenic (As)-induced cytotoxicity through activation of mitogen-activated protein (MAP) kinases. Deprenyl (selegiline), a selective inhibitor of monoamine oxidase B that is responsible for oxidative metabolism of dopamine, has been used as a therapeutic agent for the treatment of Parkinson's disease. This study investigated (1) whether deprenyl inhibited As-induced toxicity or As toxicity that was potentiated by glutathione (GSH) depletion and (2) whether deprenyl affected MAP kinase activation. Deprenyl protected H4IIE cells against the toxicity induced by As + SAAD in a concentration-dependent manner, but not by As alone. Activation of JNK by SAAD or As, but not that of p38 kinase or ERK1/2, was inhibited by treatment of cells with deprenyl. The cells that had been exposed to As or SAAD exhibited decreases in mitochondrial permeability to rhodamine 123, which was restored by deprenyl treatment or transfection with the plasmid encoding a dominant negative mutant of JNK [JNK1( )]. Transfection of H4IIE cells with the JNK1( ) plasmid, however, failed to protect cells against As toxicity. These results showed that deprenyl inhibits As toxicity potentiated by cellular GSH depletion, but not the toxicity induced by As alone. The cytoprotective effect of deprenyl may be mediated with restoration of mitochondrial function via its inhibition of JNK1.
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PMID:Deprenyl, a therapeutic agent for Parkinson's disease, inhibits arsenic toxicity potentiated by GSH depletion via inhibition of JNK activation. 1551 99

Cisplatin is a potent anti-cancer chemotherapeutic agent but has the undesirable side effect of hepatotoxicity at high doses. In a previous study, abrogation of cisplatin-induced hepatotoxicity by pretreatment with xanthorrhizol was observed in mice, but the mechanism has not yet been studied. We therefore investigated whether the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity is associated with the mitogen-activated protein (MAP) kinase-signaling pathway. Cisplatin caused phosphorylation of both c-Jun N-terminal kinases 1/2 (JNK1/2) and the extracellular signal-regulated kinase 1/2 (ERK1/2), but not that of p38. However, cisplatin-induced phosphorylation of JNKs, especially JNK1, was highly attenuated by pretreatment with xanthorrhizol in a dose-dependent manner. This study suggested that the phosphorylation of JNKs could be involved in the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity and it also affects gene transcription by regulating the expression of transcription factor subunits such as c-fos and p50 in part. In addition, considering that the expression of both cytochrome c and caspase-9 were not changed in this model, its mechanism might be independent of mitochondria-related apoptosis. This is the first report giving evidence that the physiological function of xanthorrhizol is linked to regulation of the phosphorylation of JNK(s).
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PMID:Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity. 1553 42

Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-alpha signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1-/-) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1-/-, hTNFtg, JNK1-/-hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1-/-hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1-/-hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1-/-hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis.
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PMID:JNK1 is not essential for TNF-mediated joint disease. 1564 37


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