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)

BACKGROUND: Despite IFNalpha has been used extensively in the treatment of multiple myeloma (MM), there are also several reports suggesting that IFNalpha may aggravate isease in some MM patients. That means the effect of IFNalpha on the growth of myeloma cells in vivo may be different. In this study, we selected two human myeloma cell lines that vary remarkably in response to IFNalpha and focused on elucidating the mechanism of differential IFNalpha responsiveness. RESULTS: Sko-007 is a myeloma cell line whose growth is arrested by IFNalpha; however, IFNalpha promoted the proliferation of the other myeloma cell line U266. We observed that the growth-stimulation effect of IFNalpha on U266 cells did not result from up-regulation of the IL-6 receptors on cell surface; while IFNalpha treatment on Sko-007 cells significantly reduced gp130 expression. Moreover, the transcription factors STAT3 and STAT1, which are involved in the JAK/STAT signal transduction pathway, can be activated in both IFNalpha-stimulated and -inhibited myeloma cell lines; while the activation of the protein kinase ERK, which is involved in the Ras/MAPK signal transduction pathway, can be down-regulated in IFNalpha-arrested Sko-007 cells and up-regulated in IFNalpha-stimulated U266 cells. In addition, both IFNalpha-induced growth-stimulation effect and the up-regulated activation of ERK in U266 cells were efficiently inhibited by PD98059, the specific inhibitor of MAPK/ERK kinase (MEK). CONCLUSION: Myeloma cells responsiveness to IFNalpha is heterogeneous and the activation state of ERK in the Ras/MAPK signalling pathway mainly contributed to this difference.
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PMID:Protein kinase ERK contributes to differential responsiveness of human myeloma cell lines to IFNalpha. 1223 75

Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation. STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the DNA binding of the STAT proteins. The mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2 proteins. In these conditions, the expression of cartilage-specific matrix genes, type II collagen, aggrecan core, and link proteins was found to be markedly down-regulated. This negative effect was abolished by addition of parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP kinases with PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These IL-6 effects might contribute to the phenotype loss of chondrocytes in joint diseases and the alteration of articular cartilage associated with this pathology.
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PMID:JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. 1241 23

Human plasmacytoid or CD4(+)CD11c(-) type 2 dendritic cell precursors (PDC) were identified as natural type I interferon (IFN)-producing cells in response to viral and bacterial infection. They represent effector cells of innate immunity and link it to the distinct adaptive immunity by differentiating into mature DC. It has been reported that oligodeoxyribonucleotides containing unmethylated CpG motifs (CpG DNA) stimulate PDC to produce IFN-alpha, but the molecular mechanisms involved remain unknown. We found that CpG-DNA-induced IFN-alpha production in PDC was completely impaired by the inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway. Expression of IFN regulatory factor (IRF)-7 was enhanced by CpG-DNA treatment, which was preceded by the phosphorylation of signal transducer and activator of transcription (STAT)1 on Tyr-701, as well as its enhanced phosphorylation on Ser-727. All of these events were also suppressed by the p38 MAPK inhibitor. STAT1, STAT2, and IRF-9, components of IFN-stimulated gene factor 3 (ISGF3), were recognized in the nuclear fraction of CpG-DNA-treated cells. Neither anti-IFN-alpha/beta antibodies (Ab) nor anti-IFNAR Ab suppressed STAT1 phosphorylation, enhancement of IRF-7 expression, or IFN-alpha production in the early phase of the culture. These results suggest that CpG DNA induces p38 MAPK-dependent phosphorylation of STAT1 in a manner independent of IFN-alpha/beta, which may cause ISGF3 formation to increase the transcription of the IRF-7 gene, thereby leading to IFN-alpha production in human PDC.
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PMID:CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors. 1242 24

Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent challenge with LPS. It has not been known whether previous exposure to CpG DNA induces a similar suppressive response to subsequent stimulation with CpG DNA. In the present study, we demonstrate that pretreatment with CpG DNA induces suppression of cytokine release in a murine macrophage-like cell RAW264.7 in response to subsequent challenge by CpG DNA. Additionally, CpG DNA-mediated activation of mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase, and p38, and activation of transcription factors AP-1, CREB, NF-kappaB, and STAT1 are greatly suppressed in the cells pre-exposed to CpG DNA. Pretreatment with CpG DNA also partially inhibited LPS-mediated production of cytokines and activation of mitogen-activated protein kinases and transcription factors. Neither LPS nor CpG DNA treatment inhibited Toll-like receptor 4, MD2, Toll-like receptor 9, myeloid differentiation factor 88, Toll/IL-1R domain-containing adaptor protein, Tollip, and TNF-alpha receptor-associated factor 6 expression. Interestingly, CpG DNA or LPS stimulation led to the inhibition of IL-1R-associated kinase expression. These results indicate that CpG DNA-induced refractory of RAW264.7 cells may be, at least in part, due to suppressed IL-1R-associated kinase expression.
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PMID:CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptor-associated kinase expression. 1251 73

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-gamma (IFN-gamma) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule-1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-gamma-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-gamma, ICAM-1 was expressed at a lower level than in cells treated with IFN-gamma alone. However, lovastatin does not reduce TNF-alpha induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-gamma activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-gamma-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-gamma-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-alpha does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-gamma action in atherosclerotic process
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PMID:Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. 1252 87

The c-fos gene was one of the earliest vertebrate genes shown to be transcriptionally induced by growth factors. Intensive study of the promoter of c-fos (-325 to -80) by transient or permanent transfections of synthetic DNA constructs has repeatedly shown the importance of several sequence elements and the resident nuclear proteins that bind them (e.g. ternary complex factor/ELK1; serum response factor, cAMP response element-binding protein/amino-terminal fragment/AP-1). However these studies have left unanswered numerous questions about the role of these proteins in the regulation of the native chromosomal gene. In particular, the role of a site in this enhancer that binds STATs has been controversial. We present evidence here that STAT3 and not STAT1 accumulates on the chromosomal c-fos promoter and provides a boost to transcription without the activation of resident nuclear proteins through serine kinases. Also, when resident nuclear proteins such as ELK1 are activated to varying extents by mitogen-activated protein kinase pathways, STAT3 activation provides a 2-fold boost regardless of the final level of activated transcription. Thus the several proteins that interact with the c-fos enhancer apparently can act either in a cooperative or independent manner to achieve very different levels of transcription.
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PMID:Independent and cooperative activation of chromosomal c-fos promoter by STAT3. 1260 Sep 88

We have characterized the transduction pathways induced by leptin in the placenta, using human BeWo cells that express endogenous leptin receptors and synthesize leptin in a regulated manner. We first examined if the JAK-STAT phosphorylation cascade was functional in these cells. Phosphorylated JAK2 was primarily bound to a short 106kDa leptin receptor isoform and to a lesser extent to a 210kDa molecule. Leptin neither enhanced JAK2 phosphorylation nor activated STAT3 and STAT1 proteins indicating that JAK2 is constitutively activated and that the JAK-STAT transduction pathway is not recruited by leptin in BeWo cells. By contrast, leptin stimulated the transcription of the c-fos gene (3-fold) and cell proliferation (2-fold) as measured by DNA synthesis. Both effects were dependent on the rapid phosphorylation of p42-44 MAPK but not p38 MAPK. We conclude that a functional JAK-STAT pathway is not required for leptin to transduce proliferative signals in human placental cells. These findings extend the physiological action of leptin beyond its central effects, to the control of placental gene transcription and cell proliferation.
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PMID:Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation. 1265 12

A431 epidermoid carcinoma cells have an increased expression of EGF receptor. In contrast to many other cell lines and primary cells, these respond to EGF in high (more than 1 ng/ml) concentrations by cell cycle arrest, apoptosis and detachment. Clonal variants of A431 (1a and 8a), able to grow in the presence of EGF in high concentration, were previously developed in our laboratory (Gudkova, Sorokin, 1989). Here we tested upper pathways of signal transduction from EGF receptor in the clonal variants, as compared to A431. We found no reasonable difference in the expression of EGF receptor, as well as in its EGF-induced phosphorylation in A431 and clonal variants. There were also no changes in the amount and activation of ERK MAP kinase in different cell lines. In contrast, the amount of STAT1 transcription factor, known to play pro-apoptotic and antiproliferative roles, was strictly diminished in both the clonal variants tested (1a and 8a), as compared to the parental line A431. However, EGF-induced tyrosine phosphorylation of STAT1 decreased only in 8a. Increased phosphorylation of Akt protein kinase, the key component of PI-3 kinase of the anti-apoptotic and proliferative signaling pathway, was also observed in clonal variants. The data obtained demonstrate that resistance to EGF can be acquired in cells having similar levels of EGF receptor expression and phosphorylation, but different in STAT1 or PI-3 kinase signal transduction pathways. These pathways may presumably represent two antagonistic key elements regulating A431 proliferation and apoptosis.
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PMID:[EGF-induced signal transduction in clonal cells of epidermoid carcinoma A431]. 1272 80

Members of the interleukin-6 (IL-6) family of cytokines exert their biological effects via binding to their cognate ligand-binding receptor subunit on a target cell. The subsequent recruitment of the common signal transducer glycoprotein 130 and activation of the JAK/STAT and SHP-2/Ras/mitogen-activated protein kinase (MAPK) pathways are responsible for the majority of cellular responses elicited by IL-6 cytokines. Several types of experiments suggest that the Src family of kinases (SFK) also participates in IL-6 family cytokine-mediated signaling events. SYF cells, which lack expression of SFKs Src, Yes, and Fyn, were used to determine the role of SFKs in IL-6 family cytokine signaling and gene induction. SYF and wild type (WT) control fibroblasts displayed similar activation of signaling intermediates following stimulation with leukemia inhibitory factor (LIF). LIF-stimulated tyrosine phosphorylation of SHP-2 and subsequent activation of MAPK in SYF cells were identical to that seen in LIF-stimulated WT cells. Both LIF-stimulated tyrosine phosphorylation of STAT1 and STAT3, as well as LIF-stimulated DNA binding activity of STAT-containing nuclear complexes were indistinguishable when compared in SYF and WT cells. In addition, the phosphatidylinositol 3-kinase-sensitive Akt kinase and p38 MAPK were activated by LIF in both SYF and WT cells. Furthermore, LIF-stimulated expression of c-fos, egr-1, and suppressor of cytokine signaling-3 was retained in SYF cells. The IL-6 family cytokine oncostatin M was also capable of activating MAPK, STAT3, STAT1, Akt, and p38 in both WT and SYF cells. These results demonstrate that IL-6 family cytokines can activate a full repertoire of signaling pathways and induce gene expression independent of SFKs.
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PMID:Src family kinase-independent signal transduction and gene induction by leukemia inhibitory factor. 1276 51

We report the case of a man with chronic lymphocytic leukemia (CLL) who, in the absence of cytotoxic chemotherapy, began taking a Chinese herbal extract. Shortly thereafter, he experienced a steady decline of his lymphocytosis and adenopathy, and he remains in remission now over 10 years later. The herbal extract inhibited the survival of primary CLL cells under in vitro culture conditions. However, it did not inhibit the activation of Akt or MAP kinase, nor did it inhibit the serine phosphorylation of STAT1. Thus, through an as yet unknown mechanism, this extract appears to exert pro-apoptotic effects in CLL.
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PMID:Sustained complete remission of CLL associated with the use of a Chinese herbal extract: case report and mechanistic analysis. 1280 45


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