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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD72, a 45-kDa type II transmembrane glycoprotein carrying an ITIM motif, is believed to be an inhibitory coreceptor of the BCR. Mature B cells lacking CD72 show enhanced Ca(2+) mobilization and are hyperproliferative in response to BCR ligation. However, the signal transduction pathways downstream of BCR signaling that transmit the inhibitory effect of CD72 in mature B cells remain unknown. To address this question, we used hen egg lysozyme-specific BCR transgenic mice to elucidate the differential cell signaling between wild-type and CD72-deficient B cells in response to hen egg lysozyme Ag stimulation. Our results demonstrate that CD72 predominantly down-regulates the major signal transduction pathways downstream of the BCR, including NF-AT, NF-kappaB, ERK, JNK, p38-MAPK, and PI3K/Akt in mature B cells. CD72 ligation with anti-CD72 Ab (K10.6), which mimics the binding of CD100 (a natural ligand for CD72) to release the inhibitory function of CD72, augments cell proliferation, Ca(2+) flux, IkappaBalpha activation, and ERK MAPK activity upon Ag stimulation in wild-type B cells. In addition, we show direct evidence that CD72 promotes cell cycle arrest and apoptosis after Ag stimulation in mature B cells. Taken together, our findings conclude that CD72 plays a dominant role as a negative regulator of BCR signaling in primary mature B lymphocytes.
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PMID:CD72 down-modulates BCR-induced signal transduction and diminishes survival in primary mature B lymphocytes. 1662 99

Lnk, with APS and SH2-B (Src homology 2-B), belongs to a family of SH2-containing proteins with potential adaptor functions. Lnk regulates growth factor and cytokine receptor-mediated pathways implicated in lymphoid, myeloid, and platelet homeostasis. We have previously shown that Lnk is expressed and up-regulated in vascular endothelial cells (ECs) in response to tumor necrosis factor-alpha (TNFalpha). In this study, we have shown that, in ECs, Lnk down-regulates the expression, at both mRNA and protein levels, of the proinflammatory molecules VCAM-1 and E-selectin induced by TNFalpha. Mechanistically, our data indicated that, in response to TNFalpha, NFkappaB/p65 phosphorylation and translocation as well as IkappaBalpha phosphorylation and degradation were unchanged, suggesting that Lnk does not modulate NFkappaB activity. However, Lnk activates phosphatidylinositol 3-kinase (PI3K) as reflected by Akt phosphorylation. Our results identify endothelial nitric-oxide synthase as a downstream target of Lnk-mediated activation of the PI3K/Akt pathway and HO-1 as a new substrate of Akt. We found that sustained Lnk-mediated activation of PI3K in TNFalpha-activated ECs correlated with the inhibition of ERK1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was unchanged. ERK1/2 inhibition decreases VCAM-1 expression in TNFalpha-treated ECs. Collectively, our results identify the adaptor Lnk as a negative regulator in the TNFalpha-signaling pathway mediating ERK inhibition and suggest a role for Lnk in the interplay between PI3K and ERK triggered by TNFalpha in ECs.
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PMID:The adaptor molecule Lnk negatively regulates tumor necrosis factor-alpha-dependent VCAM-1 expression in endothelial cells through inhibition of the ERK1 and -2 pathways. 1664 35

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

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

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.
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PMID:Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-kappaB activation by the HDAC inhibitor apicidin. 1687 Jan 49

Haemorrhagic shock leads to decreased proinflammatory cytokine response which is associated with an increased susceptibility to bacterial infections. In the present study, the effect of GM-CSF on lipopolysaccharide (LPS)-induced TNF-alpha release and MAPkinase activation was analysed on the background of a possible immunostimulating activity of this substance. Male BALB/c mice were bled to a mean arterial blood pressure of 50 mmHg for 45 min followed by resuscitation. Peritoneal macrophages were isolated 20 h after haemorrhage and incubated with 10 ng/ml GM-CSF for 6h before LPS stimulation. TNF-alpha synthesis was studied in the culture supernatants using ELISA. Phosphorylation of ERK, p38MAPK and IkappaBalpha was detected by Western blotting. LPS-induced TNF-alpha production of peritoneal macrophages was significantly decreased 20 h after haemorrhage in comparison to the corresponding cells of sham-operated mice. In parallel the phosphorylation of IkappaBalpha was less in LPS-stimulated peritoneal macrophages from haemorrhagic mice. LPS-induced phosphorylation of ERK1/2 was also decreased in peritoneal macrophages isolated after haemorrhagic shock. In contrast, p38MAPK was phosphorylated more intensely after LPS-stimulation in macrophages collected from shocked mice. GM-CSF incubation elevated LPS-induced TNF-alpha response of macrophages from both sham-operated and shocked mice which was accompanied by an elevated IkappaB and ERK phosphorylation. In general, GM-CSF treatment in vitro enhanced peritoneal macrophages LPS-response both in terms of TNF-alpha synthesis and IkappaB and MAPK signalling, but the levels always stayed lower than those of GM-CSF-treated cells from sham-operated animals. In conclusion, GM-CSF preincubation could partly reactivate the depressed functions of peritoneal macrophages and may therefore exert immunostimulating properties after shock or trauma.
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PMID:Haemorrhagic shock in mice--intracellular signalling and immunomodulation of peritoneal macrophages' LPS response. 1701 46

To better predict the consequences of blocking signal transduction pathways as a means of controlling intestinal inflammation, we are characterizing the pathways up-regulated by IL-1 in intestinal epithelial cells (IEC). IL-1beta induced increased mRNA levels of MIP-2, MCP-1, RANTES, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) in the IEC-18 cell line. IL-1beta activated NF-kappaB but not ERK or p38. Infecting cells with adenovirus expressing a mutated gene for IkappaBalpha (IkappaBAA) blocked IL-1-induced mRNA increases in MIP-2, MCP-1, and iNOS but not COX-2 or RANTES. Expression of IkappaBAA attenuated the IL-1-induced increase in COX-2 protein. Unexpectedly, RANTES mRNA increased, and protein was secreted by cells expressing IkappaBAA in the absence of IL-1. Adenovirus-expressing IkappaBAA, blocking protein synthesis, and IL-1beta all resulted in activation of JNK. The JNK inhibitor SP600125 prevented the RANTES increases by all three stimuli. A human enterocyte line was similarly examined, and both NF-kappaB and JNK regulate IL-1-induced RANTES secretion. We conclude that in IEC-18, IL-1beta-induced increases in mRNA for MIP-2, MCP-1, and iNOS are NF-kappaB-dependent, whereas regulation of RANTES mRNA is independent of NF-kappaB but is positively regulated by JNK. IL-1beta-induced mRNA increases in COX-2 mRNA are both NF-kappaB- and MAPK-independent but the translation of COX-2 protein is NF-kappaB-dependent. This pattern of signaling due to a single stimulus exposed the complexities of regulating inflammatory genes in IEC.
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PMID:Differential pattern of inflammatory molecule regulation in intestinal epithelial cells stimulated with IL-1. 1701 48

Mitogen-activated protein/ERK kinase kinase 3 (MEKK3) is a Ser/Thr protein kinase belonging to the MEKK/STE11 subgroup of the MAP3K family. Recently, we found that MEKK3 plays a critical role in interleukin-1 (IL-1) receptor and Toll-like receptor 4 signalling using established primary mouse embryonic fibroblast (MEF) cell lines. However, the function of MEKK3 in immune cells has not been studied because germ-line MEKK3 knockout mice are embryonically lethal between embryonic days 10 and 11. In this study, we used small interference RNA to the mouse Mekk3 gene to specifically knock down MEKK3 expression in the macrophage line Raw264.7. We found that the lipopolysaccharide-induced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production was dramatically decreased in MEKK3 knockdown cells whereas the tumour necrosis factor-alpha and IL-1beta production were not affected. We also observed that the ERK1/2, p38 and JNK MAPK induction in MEKK3 knockdown cells were moderately inhibited within the first 60 min of stimulation, while the ERK and p38 were more severely inhibited after 2-4 hr of stimulation. Degradation of IkappaBalpha was also partially blocked in MEKK3 knockdown cells. Notably, the impairment in IL-6 and GM-CSF production in the MEKK3 knockdown cells was restored by reintroducing a human Mekk3 cDNA that could not be targeted by mouse Mekk3-siRNAs. In conclusion, this study showed that MEKK3 is a crucial and specific regulator of the proinflammatory cytokines IL-6 and GM-CSF in macrophages and provided a novel method for investigating MEKK3 function in other immune cells.
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PMID:MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages. 1711 70

In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.
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PMID:Kushen flavonoids induce apoptosis in tumor cells by inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities. 1718 93

Keratinocyte growth factor (KGF)/fibroblast growth factor-7 (FGF-7) is a paracrine- and epithelium-specific growth factor produced by cells of mesenchymal origin. It acts exclusively through FGF-7 receptor (FGFR2/IIIb), which is expressed predominantly by epithelial cells, but not by fibroblasts, suggesting that it might function as a paracrine mediator of mesenchymal-epithelial interactions. KGF/FGF-7 plays an essential role in the growth of epithelial cells and is frequently overexpressed in cancers of epithelial origin such as pancreatic cancer, switching paracrine stimulation of KGF/FGF-7 to an autocrine loop. Less is known, however, about the signaling pathways by which KGF/FGF-7 regulates the response of epithelial cells. To delineate the signaling pathways activated by KGF/FGF-7 and examine cellular response to KGF/FGF-7 stimulation, we performed functional analysis of KGF/FGF-7 action. In this report, we show that KGF/FGF-7 activated nuclear factor kappaB (NF-kappaB), which in turn induced expression of VEGF, MMP-9, and urokinase-type plasminogen activator and increased migration and invasion of KGF/FGF-7-stimulated human pancreatic ductal epithelial cells. Expression of phosphorylation-defective IkappaBalpha (IkappaBalphaS32A,S36A), which blocked NF-kappaB activation, inhibited KGF/FGF-7-induced gene expression and cell migration and invasion. Our results demonstrate for the first time that KGF/FGF-7 induces NF-kappaB activation and that NF-kappaB plays an essential role in regulation of KGF/FGF-7-inducible gene expression and KGF/FGF-7-initiated cellular responses. Thus, these findings identify one signaling pathway for KGF/FGF-7-regulated cell migration and invasion and suggest that paracrine sources of KGF/FGF-7 are one of the malignancy-contributing factors from tumor stroma.
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PMID:Keratinocyte growth factor/fibroblast growth factor-7-regulated cell migration and invasion through activation of NF-kappaB transcription factors. 1720 Jan 10


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