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)

NF-kappaB is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-kappaB and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1alpha through the adapter protein TRAF2. ER stress-induced NF-kappaB activation is impaired in IRE1alpha knockdown cells and IRE1alpha(-/-) MEFs. We found, however, that inhibiting NF-kappaB significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-alpha) was IRE1alpha and NF-kappaB dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-alpha-induced activation of NF-kappaB and c-Jun N-terminal kinase and turns TNF-alpha from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-alpha induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.
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PMID:Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. 1658 82

Activation of Toll-like receptors (TLRs) on immune surveillance cells in the lung has been implicated in the pathobiology of allergic asthma, a condition associated with altered airway smooth muscle (ASM) contractility. Because ASM is known to directly respond to various proasthmatic stimuli, the potential role of TLR signaling in ASM in regulating airway expression of the proasthmatic phenotype was investigated. Cultured human ASM cells were found to express TLR4 and TLR9 mRNA transcripts and, whereas TLR9 stimulation had little effect, TLR4 activation with LPS elicited significant increases in IL-6 release and evoked proasthmatic-like changes in the constrictor and relaxation responsiveness of isolated rabbit ASM tissues. Complementary studies further demonstrated that the ASM responses to LPS were associated with activation of the ERK1/2 and p38 MAPK signaling pathways, IKK-mediated activation of NF-kappaB, and coupling of phosphorylated ERK1/2 with the p65 subunit of NF-kappaB. Moreover, the induced NF-kappaB activity and changes in ASM responsiveness were prevented in LPS-exposed ASM that were pretreated with inhibitors of ERK1/2 signaling, whereas inhibition of p38 MAPK augmented the proasthmatic responses to LPS. Finally, activation of p38 MAPK with anisomycin prevented both the LPS-induced stimulation of ERK1/2-mediated NF-kappaB activity and associated changes in ASM responsiveness. Collectively, these data support the novel concept that TLR4 activation in ASM elicits changes in ASM function that are regulated by opposing effects of MAPK signaling, wherein LPS-induced ERK1/2 activation mediates NF-kappaB-dependent proasthmatic-like changes in ASM function, whereas coactivation of p38 MAPK serves to homeostatically downregulate the proasthmatic effects of ERK1/2 activation.
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PMID:Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling. 1667 80

Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. We investigated the production of the CXC chemokine growth-related oncogene protein-alpha (GRO-alpha) from ASMC induced by cytokines and the role of MAPK and NF-kappaB pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1beta and TNF-alpha after growth arrest. GRO-alpha release, measured by ELISA, was increased by >50-fold after IL-1beta (0.1 ng/ml) or 5-fold after TNF-alpha (1 ng/ml) in a dose- and time-dependent manner. GRO-alpha release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1beta and TNF-alpha also induced GRO-alpha mRNA expression. Supernatants from IL-1beta-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO-alpha blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO-alpha release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO-alpha release without effect on mRNA expression. SB-203580, an inhibitor of p38 MAPK, had no effect. AS-602868 but not PD-98059 or SP-600125 inhibited p65 DNA-binding induced by IL-1beta and TNF-alpha. By chromatin immunoprecipitation assay, IL-1beta and TNF-alpha enhanced p65 binding to the GRO-alpha promoter, which was inhibited by AS-602868. IL-1beta- and TNF-alpha-stimulated expression of GRO-alpha from ASMC is regulated by independent pathways involving NF-kappaB activation and ERK and JNK pathways. GRO-alpha released from ASMC participates in neutrophil chemotaxis.
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PMID:GRO-alpha regulation in airway smooth muscle by IL-1beta and TNF-alpha: role of NF-kappaB and MAP kinases. 1661 94

ApoB is an important determinant of atherosclerosis susceptibility and a potential pharmaceutical target for lowering atherogenic lipoproteins. In the present study, we used a lentiviral vector to express short hairpin RNAs for inhibition of apoB production in HepG2 cells. We first demonstrated that lentivirus could efficiently deliver transgene into HepG2 cells by using GFP lentivirus. We then made three lentiviral siApoB constructs, two of which were highly efficient for silencing apoB expression in HepG2 cells. We showed that siApoB lentivirus specifically knocked down apoB but had no effects on other proteins such as apoAI and albumin. Consequently, the secretion of apoB was reduced markedly. The silencing effect of siApoB lentivirus appeared to be permanent. Knocking down apoB did not alter the expression of cytoplasmic stress proteins (HSP70 and HSP90) and their ER homologues (GRP78 and GRP94). Furthermore, neither IKKalpha and JNK nor phosphorylated IKK and JNK were increased in long-term apoB-deficient hepatocytes as compared to the control cells. Consistent with these findings, apoB-deficient hepatocytes responded to insulin to a similar extent as the control cells as determined by measuring insulin-induced phosphorylation of IRS and ERK. Our studies indicate that lentiviral siRNAs provide an excellent approach for delivering siRNA into HepG2 cells and may be used for gene therapy for hyperlipidemia.
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PMID:Knockdown of apolipoprotein B, an atherogenic apolipoprotein, in HepG2 cells by lentivirus-mediated siRNA. 1662 Jul 82

Osteopontin (OPN) is a secreted, non-collagenous, sialic-acid rich, glycosylated adhesive phospho- protein. Several highly metastatic transformed cells synthesized a higher level of OPN compared with non-tumorigenic cells. We have recently reported that OPN induces nuclear factor-kappaB (NF-kappaB)-mediated promatrix metalloproteinase-2 activation through IkappaBalpha/IKK signaling pathways. However, the molecular mechanism(s) by which OPN regulates pro-matrix metalloproteinase-9 (pro-MMP-9) activation and involvement of upstream kinases in regulation of these processes that ultimately control cell motility and tumor growth in murine melanoma cells are not well defined. Here we report that OPN induces alphavbeta3 integrin-mediated phosphorylation and activation of nuclear factor inducing kinase (NIK) and enhances the interaction between phosphorylated NIK and IkappaBalpha kinase alpha/beta (IKKalpha/beta) in B16F10 cells. Moreover, NIK is involved in OPN-induced phosphorylations of MEK-1 and ERK1/2 in these cells. OPN induces NIK-dependent NF-kappaB activation through ERK/IKKalpha/beta-mediated pathways. Furthermore, OPN enhances NIK-regulated urokinase-type plasminogen activator (uPA) secretion, uPA-dependent pro-MMP-9 activation, and cell motility. Pretreatment of cells with anti-MMP-2 antibody along with anti-MMP-9 antibody drastically inhibited the OPN-induced cell migration and chemoinvasion, whereas cells pretreated with anti-MMP-2 antibody had no effect on OPN-induced pro-MMP-9 activation suggesting that OPN induces pro-MMP-2 and pro-MMP-9 activations through two distinct pathways. Taken together, NIK acts as crucial regulator in OPN-induced MAPK/IKK-mediated NF-kappaB-dependent uPA secretion and MMP-9 activation thereby controlling melanoma cell motility and chemoinvasion.
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PMID:Nuclear factor inducing kinase: a key regulator in osteopontin- induced MAPK/IkappaB kinase dependent NF-kappaB-mediated promatrix metalloproteinase-9 activation. 1669 5

A role for pro-inflammatory cytokines in inflammation-related cancers has been suggested, but mechanisms are not defined. Here, we demonstrate that treatment of HeLa cells with TNFalpha increases chromosomal aberration. In contrast, IL-1beta did not increase, but rather decreased chromosomal aberration. TNFalpha and IL-1beta increased the production of H2O2 to similar levels in cells, suggesting that increased production of reactive oxygen species might not be the premier factor involved. Reducing H2O2 through overexpression of catalase or treatment of cells with NAC or BHA did not have an effect on TNF-induced chromosomal aberration. TNFalpha-induced NO production has been implicated in DNA damage. Inhibiting NO did not reduce TNF-induced chromosomal aberration. Inhibiting IKK, JNK, and p38 kinase as well as caspases decreased TNF-induced chromosomal aberration, and a correlation between TNF-induced apoptosis and CA generation was not found. Single-strand DNA breaks give rise to double-strand breaks, which then results in chromosomal breaks, when replication forks reach the single-strand breaks during S-phase. In cells progressing through S-phase, TNFalpha activation of IKK, JNK, and p38 is significantly reduced. However, these kinases were activated by IL-1beta in S-phase. The possibility that these pathways, in a TNF-specific manner, may regulate either the generation of single- and double-strand breaks or their repair, thereby resulting in increased chromosomal aberration, is discussed.
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PMID:TNFalpha induces chromosomal abnormalities independent of ROS through IKK, JNK, p38 and caspase pathways. 1672 55

Baicalin is a flavonoid isolated from Scutellaria baicalensis and is known to affect multiple biological functions, including the inhibition of aldose reductase, HIV infection, and nitric oxide producing activity. Oxidative stress is considered a major cause of aging and various age-related diseases, and among the key cellular components exquisitely sensitive to oxidative stress is the transcription factor, nuclear factor-kappaB (NF-kappaB). In the present study, we attempted to elucidate the mechanisms underlying the suppression of age-related NF-kappaB activation by baicalin in kidney tissue from old rats. Results showed NF-kappaB activation and the upregulation of NF-kappaB targeting genes, hemoxygenase-1, inducible nitric oxide synthase (iNOS), and COX-2 with age. In contrast, the increased expression of these NF-kappaB targeting genes was effectively inhibited by baicalin. Baicalin was shown to inhibit the NF-kappaB cascade via three signal transduction pathways, NIK/IKK, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK). Our results clearly indicated the anti-oxidative effects of baicalin on age-related redox imbalance. Thus, the significance of the current study is the new information revealing the anti-oxidative properties of baicalin and the role it plays in the regulation of age-related alterations.
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PMID:Short-term feeding of baicalin inhibits age-associated NF-kappaB activation. 1676 19

The polysaccharides of Ganoderma lucidum (Reishi) possess immunomodulation activities; however, their mode of molecular action in regulating each cellular subset in the immune system is still not clear. Here, we investigate the function of the main polysaccharide fraction of Reishi (Reishi-F3) in B lymphocyte activation/differentiation. We find that Reishi-F3 causes mouse splenic B cell activation and differentiation to IgM-secreting plasma cells, and the process depends on Reishi-F3-mediated induction of Blimp-1, a master regulator capable of triggering the changes of a cascade of gene expression during plasmacytic differentiation. In human peripheral B lymphocytes, although Reishi-F3 fails to induce their activation, it is able to enhance antibody secretion, which is associated with Blimp-1 mRNA induction. The function of Reishi-F3 depends on the Toll-like receptors TLR4/TLR2 as neutralizing antibodies against TLR4/TLR2 block Reishi-F3-mediated induction of Blimp-1 mRNA and Ig secretion. We have shown that interaction of Reishi-F3 with TLR4/TLR2 followed by signaling through p38 MAPK is involved in the induction of Blimp-1 mRNA, whereas signaling through ERK, p38 MAPK, JNK, and IKK complex is involved in Reishi-F3-mediated Ig secretion. Furthermore, the differential mechanism of Reishi-F3 in mouse and human B cell activation is probably due to the presence of Blimp-1 regulatory site in human CD86 promoter. These results establish the signaling and molecular mechanisms of Reishi-F3 on promoting antibody secretion.
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PMID:Reishi polysaccharides induce immunoglobulin production through the TLR4/TLR2-mediated induction of transcription factor Blimp-1. 1679 41

A major link between inflammation and cancer is provided by NF-kappaB transcription factors. Ikkbeta(Deltahep) mice, which specifically lack IkappaB kinase beta (IKKbeta), an activator of NF-kappaB, in hepatocytes, are unable to activate NF-kappaB in response to proinflammatory stimuli, such as TNF-alpha. Surprisingly, Ikkbeta(Deltahep) mice are hypersusceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Because defective NF-kappaB activation promotes sustained c-Jun N-terminal kinase (JNK) activation in cells exposed to TNF-alpha, whose expression is induced by DEN, and JNK activity is required for normal hepatocyte proliferation, we examined whether increased susceptibility to DEN-induced hepatocarcinogenesis in Ikkbeta(Deltahep) mice requires JNK activation. Hepatocytes express both JNK1 and JNK2, but previous studies indicate that JNK1 is more important for hepatocyte proliferation. We therefore investigated this hypothesis using mice homozygous for a JNK1 deficiency either in wild-type or Ikkbeta(Deltahep) backgrounds. In both cases, mice lacking JNK1 were much less susceptible to DEN-induced hepatocarcinogenesis. This impaired tumorigenesis correlated with decreased expression of cyclin D and vascular endothelial growth factor, diminished cell proliferation, and reduced tumor neovascularization. Whereas hepatocyte-specific deletion of IKKbeta augmented DEN-induced hepatocyte death and cytokine-driven compensatory proliferation, disruption of JNK1 abrogated this response. In addition to underscoring the importance of JNK1-mediated hepatocyte death and compensatory proliferation, these results strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver carcinogenesis.
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PMID:Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. 1680 93

Double-stranded RNA-dependent protein kinase (PKR), a ubiquitously expressed serine/threonine kinase, has been implicated in the regulation or modulation of cell growth through multiple signaling pathways, but how PKR regulates tumor necrosis factor (TNF)-induced signaling pathways is poorly understood. In the present study, we used fibroblasts derived from PKR gene-deleted mice to investigate the role of PKR in TNF-induced activation of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinases (MAPKs) and growth modulation. We found that in wild-type mouse embryonic fibroblast (MEF), TNF induced NF-kappaB activation as measured by DNA binding but deletion of PKR abolished this activation. This inhibition was associated with suppression of inhibitory subunit of NF-kappaB (IkappaB)alpha kinase (IKK) activation, IkappaBalpha phosphorylation and degradation, p65 phosphorylation and nuclear translocation, and NF-kappaB-dependent reporter gene transcription. TNF-induced Akt activation needed for IKK activation was also abolished by deletion of PKR. NF-kappaB activation was diminished in PKR-deleted cells transfected with TNF receptor (TNFR) 1, TNFR-associated death domain and TRAF2 plasmids; NF-kappaB activated by NF-kappaB-inducing kinase, IKK or p65, however, was minimally affected. Among the MAPKs, it was interesting that whereas TNF-induced c-Jun N-terminal kinase (JNK) activation was abolished, activation of p44/p42 MAPK and p38 MAPK was potentiated in PKR-deleted cells. TNF induced the expression of NF-kappaB-regulated gene products cyclin D1, c-Myc, matrix metalloproteinase-9, survivin, X-linked inhibitor-of-apoptosis protein (IAP), IAP1, Bcl-x(L), A1/Bfl-1 and Fas-associated death domain protein-like IL-1beta-converting enzyme-inhibitory protein in wild-type MEF but not in PKR-/- cells. Similarly, TNF induced the proliferation of wild-type cells, but this proliferation was completely suppressed in PKR-deleted cells. Overall, our results indicate that PKR differentially regulates TNF signaling; IKK, Akt and JNK were positively regulated, whereas p44/p42 MAPK and p38 MAPK were negatively regulated.
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PMID:Genetic deletion of PKR abrogates TNF-induced activation of IkappaBalpha kinase, JNK, Akt and cell proliferation but potentiates p44/p42 MAPK and p38 MAPK activation. 1692 32


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