Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol increases human and animal susceptibility to opportunistic lung infections in part by suppression of endotoxin (LPS) and bacteria-mediated upregulation of inducible nitric oxide synthase (iNOS) in alveolar macrophages (AM). LPS and cytokine-induced NOS mRNA are dependent on NF-kappaB/Rel (NFkappaB) and Activator Protein-1 (AP-1), which are regulated in turn by protein kinase C and tyrosine kinase-dependent phosphorylation. ETOH does not directly inhibit NFkappaB or AP-1, in vivo, but rather inhibits LPS-induced activation of the MEKK/MAP kinase system and inhibition of inhibitory protein IkappaBalpha required for formation of AP-1 and NFkappaB, respectively. in AM. Both transcription factors are involved iNOS mRNA transcription. LPS-induced upregulation of MEKK/MAP tyrosine kinase upregulates NADPH oxidase activity and oxygen free radical formation required for activation of NFkappaB and AP-1 and phosphorylation of IkappaBalpha. LPS downregulates endogenous calcium-sensitive PKC isozymes (PKCdelta), which repress iNOS mRNA expression. ETOH inhibits LPS-induced upregulation of iNOS mRNA by preventing its ability to decrease PKCdelta and upregulate tyrosine kinase-mediated phosphorylation. This effect of ETOH is prevented by inhibitors of PKC and tyrosine kinase. The data support the hypothesis that ETOH inhibits LPS-induced upregulation of iNOS mRNA by interfering with the phosphorylation processes involved in activation of the nuclear transcription factors NFkappaB and AP-1.
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PMID:Role of PKC and tyrosine kinase in ethanol-mediated inhibition of LPS-inducible nitric oxide synthase. 966 19

Recent studies suggest that sodium arsenite downregulates NF-kappaB activity by inhibiting phosphorylation and subsequent degradation of IkappaBalpha. Many effects of sodium arsenite are secondary to induction of heat shock proteins. The role of the heat shock response in arsenite-induced inhibition of NF-kappaB, however, is not known. We examined the involvement of the heat shock response in arsenite-induced inhibition of NF-kappaB activity in IL-1beta-stimulated Caco-2 cells, a human colorectal adenocarcinoma cell line with enterocytic properties. Treatment of the cells with IL-1beta resulted in increased IkappaB kinase activity, reduced levels of IkappaBalpha and increased NF-kappaB DNA binding activity. Sodium arsenite blocked all of these responses to IL-1beta without inducing changes in heat shock factor activity or heat shock protein levels. Results from additional experiments showed that the protective effect of sodium arsenite on IkappaBalpha was not influenced by the oxygen radical scavenger catalase or by inhibitors of the MAP-kinase signaling pathway. The present results suggest that sodium arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1beta-stimulated Caco-2 cells independent of the heat shock response. In addition, stabilization of IkappaBalpha by sodium arsenite does not require oxygen radical formation or activation of the MAP kinase signaling pathway.
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PMID:Arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1 beta-stimulated Caco-2 cells independent of the heat shock response. 1183 94

The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein's function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the alpha isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.
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PMID:Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. 1452 58

In the present study, the signal pathways involved in NO formation and iNOS expression in RAW 264.7 macrophages stimulated by LTA were investigated. We also compared the relative inhibitory activities and mechanisms of PMC, a novel potent antioxidant of alpha-tocopherol derivatives, with those of YC-1, an sGC activator, on the induction of iNOS expression by LTA in cultured macrophages in vitro and LTA-induced hypotension in vivo. LTA induced concentration (0.1-50 microg/mL)- and time (4-24 hr)-dependent increases in nitrite (an indicator of NO biosynthesis) in macrophages. Both PMC (50 microM) and YC-1 (10 microM) inhibited NO production, iNOS protein, mRNA expression, and IkappaBalpha degradation upon stimulation by LTA (20 microg/mL) in macrophages. On the other hand, PMC (50 microM) almost completely suppressed JNK/SAPK activation, whereas YC-1 (10 microM) only partially inhibited its activation in LTA-stimulated macrophages. Moreover, PMC (10 mg/kg, i.v.) and YC-1 (5 mg/kg, i.v.) significantly inhibited the fall in MAP stimulated by LTA (10 mg/kg, i.v.) in rats. In conclusion, we demonstrate that YC-1 shows more-potent activity than PMC at abrogating the expression of iNOS in macrophages in vitro and reversing delayed hypotension in rats with endotoxic shock stimulated by LTA. The inhibitory mechanisms of PMC may be due to its antioxidative properties, with a resulting influence on JNK/SAPK and NF-kappaB activations. YC-1 may be mediated by increasing cyclic GMP, followed by, at least partly, inhibition of JNK/SAPK and NF-kappaB activations, thereby leading to inhibition of iNOS expression.
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PMID:Inhibitory mechanisms of YC-1 and PMC in the induction of iNOS expression by lipoteichoic acid in RAW 264.7 macrophages. 1501 57

Flagellin, a specific ligand for Toll-like receptor 5 (TLR5), is a molecular pattern associated with several bacterial species. Recently, TLR signaling has been intensively studied. However, TLR5-associated signaling in non-transformed colonocytes has not been investigated. Here we studied the expression of cytokines induced by flagellin in non-transformed human colonic NCM460 cells and the signaling mechanisms mediating these responses. Cytokine expression array experiments showed that exposure of the cells to flagellin (100 ng/ml) for 12 h increased the expression of interleukin (IL)-8 and macrophage-inflammatory protein 3alpha (MIP3alpha) in a TLR5-specific manner. Flagellin also activated MAP kinases (ERK1/2, JNK, and p38) and degraded IkappaBalpha. Dominant negative MEK1 (a kinase that activates ERK1/2) blocked flagellin-stimulated IL-8 and MIP3alpha transcriptional activity, while the MEK-specific inhibitors PD98059 and U0126 reduced protein production of these cytokines. Conversely, transfection with a constitutively active MEK1 increased IL-8 and MIP3alpha transcriptional activity in a NFkappaB-independent manner. Furthermore, overexpression of the constitutively active MEK1 induced IL-8 and MIP3alpha protein production. We also demonstrated that C-terminal coiled-coil and TRAF-C domains of TRAF6, unable to mediate NFkappaB activation, are involved in MEK-mediated IL-8 and MIP3alpha expression. Thus, in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFkappaB-independent, IL-8 and MIP3alpha expression.
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PMID:MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. 1506 60

Progressive immunodeficiency in HIV infection is paralleled by a decrease in IL-12 production, a cytokine crucial for cellular immune function. Here we examine the molecular mechanisms by which HIV infection suppresses IL-12 p40 expression. HIV infection of THP-1 myeloid cells resulted in decreased LPS-induced nuclear factor binding to the NF-kappaB, AP-1, and Sp1 sites of the IL-12 p40 promoter. By site-directed mutagenesis we determined that each of these sites was necessary for transcriptional activation of the IL-12 p40 promoter. Binding of NF-kappaB p50, c-Rel, p65, Sp1, Sp3, c-Fos, and c-Jun proteins to their cognate nuclear factor binding sites was somewhat impaired by HV infection, although a role for other as yet unidentified factors cannot be dismissed. The cellular levels of these transcription factors were unaffected by HIV infection, with the exception of a decrease in expression of NF-kappaB p65, consistent with the observed decrease in its binding to the IL-12 p40 promoter following HIV infection. Analysis of regulation of upstream LPS-induced MAP kinases demonstrated impaired phosphorylation of JNK and p38 MAPK, and suppressed phosphorylation and degradation of IkappaBalpha following HIV infection. These results suggest that alterations in nuclear factor binding to numerous sites in the IL-12 p40 promoter, together may contribute to the suppression in IL-12 p40 transcription previously reported. These effects on nuclear factor binding may be a direct effect of HIV infection on the IL-12 p40 promoter, or may occur indirectly as a consequence of altered MAP kinase activation.
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PMID:Disruption of MAP kinase activation and nuclear factor binding to the IL-12 p40 promoter in HIV-infected myeloid cells. 1527 Aug 50

CD44v6 is transiently expressed during T cell activation, and constitutively CD44v4-v7 expressing transgenic T cells show accelerated responses towards nominal antigens. The underlying mechanism is unknown. The mouse thymoma EL4 was transfected with CD44 standard isoform (CD44s) or CD44v6 cDNA (EL4-s, EL4-v6). Only EL4-v6 cells proliferated at an over 10-fold higher rate than untransfected cells, displayed up-regulated expression of CD69, CD25, and IL-2, and were protected from apoptosis by CD44v6 cross-linking. In the absence of any stimulus, ERK1/2 was partly phosphorylated, and phosphorylation was significantly increased by CD44v6 cross-linking. The same accounted for JNK, c-jun, and IkappaBalpha. Moreover, NF-kappaB was partly translocated into the nucleus. Instead, CD44s cross-linking induced ERK1/2, JNK, c-jun, and IkappaBalpha phosphorylation only in the context of TCR engagement. No selectively CD44v6 associated transmembrane proteins were uncovered in EL4 cells. However, CD44v6, as opposed to CD44s, did not colocalise with the TCR/CD3 complex after CD3 cross-linking. Furthermore, a CD44-associated 85-kDa protein became hypophosphorylated only after CD44v6 cross-linking. Threonine hypophosphorylation of this protein coincided with the activation of MAP and SAP kinases, which was prohibited in the presence of a phosphatase inhibitor. Thus, CD44v6, distinct to CD44s, stimulates autonomously growth and IL-2 secretion of a thymoma line and rescues cells from apoptosis.
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PMID:CD44v6 promotes proliferation by persisting activation of MAP kinases. 1589 69

In this report, we describe that NF-kappaB is spontaneously activated in isolated, normal glomeruli. Ex vivo incubation of isolated rat glomeruli triggered expression of a NF-kappaB-dependent gene, monocyte chemoattractant protein-1 (MCP-1), in parallel with downregulation of IkappaBalpha and IkappaBbeta proteins and activation of the p65 NF-kappaB subunit. The induction of MCP-1 was also observed in mesangial cells coincubated with isolated glomeruli or exposed to media conditioned by isolated glomeruli (GCM), which was abrogated by inhibition of NF-kappaB. The activation of NF-kappaB by glomerulus-derived factors was confirmed using reporter mesangial cells that produce secreted alkaline phosphatase (SEAP) under the control of the kappaB enhancer element. When the reporter cells were adoptively transferred into normal glomeruli, expression of SEAP mRNA and activity of SEAP were also upregulated in the explanted glomeruli. The molecular weight of factors responsible for activation of NF-kappaB was >50 kDa, and TNF-alpha was identified as one of glomerulus-derived activators. To examine upstream events involved, we focused on MAP kinases that are spontaneously activated in explanted glomeruli. Selective suppression of ERK or p38 MAP kinase significantly attenuated activation of NF-kappaB in mesangial cells triggered by coculture with isolated glomeruli. Interestingly, the suppressive effects by MAP kinase inhibitors were not observed in mesangial cells treated with GCM. These data suggested that NF-kappaB was spontaneously activated in explanted glomeruli via autocrine/paracrine factors including TNF-alpha and that the production of NF-kappaB activators by glomeruli was, at least in part, through MAP kinase pathways.
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PMID:Spontaneous activation of the NF-kappaB signaling pathway in isolated normal glomeruli. 1670 44

Oscillations in the activation of multiple signaling pathways have never been shown before. Our results presented in the previous accompanying paper showed that TNF induces highly dynamic oscillations in mRNA production in approximately 13% of the mouse genome. Here, we further analyze the TNF time-series microarray data and find that multiple signaling components downstream of the TNF receptor undergo oscillations. Prior studies implicate IkappaBalpha and A-20 as the only oscillatory components in the TNF signaling cascade. We find however, that other components, such as TRAF1, displayed oscillations. This suggested the possibility that all signaling output from the TNF receptor may be oscillatory in nature. Indeed, we show that TNF triggers oscillations in the phosphorylation of three MAP kinases, as well as p65. Because Baltimore and colleagues had proposed that NF-kappaB drives the oscillatory nature of the IkappaBalpha/NF-kappaB feedback loop, we studied the effects of an NF-kappaB super-repressor on oscillations in MAPK phosphorylation; we find that the super-repressor altered the amplitude and frequency of MAP kinase phosphorylation, but failed to abolish oscillations. These results attest to a role for NF-kappaB as a modulator, but not the sole determinant of cyclical activation of signal transduction pathways. These results, together with those of the two accompanying papers, constitute a new paradigm through which cells orchestrate signaling molecules to produce highly dynamic physiological processes such as gene transcription and protein secretion. In view of the discovery that multiple phosphorylation pathways display dynamic oscillations, time-resolved, instead of static, measurements of kinase phosphorylation should become the experimental norm.
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PMID:TNF-induced MAP kinase activation oscillates in time. 1838 51

The metastasis-promoting protein S100A4 stimulates metastatic progression through both intracellular and extracellular functions. Extracellular activities of S100A4 include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which extracellular S100A4 exerts these effects are incompletely elucidated. The aim of the present study was to characterize S100A4-induced signal transduction mechanisms and to identify S100A4 target genes. We demonstrate that extracellular S100A4 activates the transcription factor NF-kappaB in a subset of human cancer cell lines through induction of phosphorylation and subsequent degradation of the NF-kappaB inhibitor IkappaBalpha. Concomitantly, S100A4 induced a sustained activation of the MAP kinase JNK, whereas no increased activity of the MAP kinases p38 or ERK was observed. Microarray analyses identified 136 genes as being significantly regulated by S100A4 treatment, and potentially interesting S100A4-induced gene products include IkappaBalpha, p53, ephrin-A1 and optineurin. Increased expression of ephrin-A1 and optineurin was validated using RT-PCR, Western blotting and functional assays. Furthermore, S100A4-stimulated transcription of these target genes was dependent on activation of the NF-kappaB pathway. In conclusion, these findings contribute to the understanding of the complex molecular mechanisms responsible for the diverse biological functions of extracellular S100A4, and provide further evidence of how S100A4 may stimulate metastatic progression.
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PMID:Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes. 1854 84


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