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)

Previous reports have shown a direct effect of erythropoietin (Epo) on vascular smooth muscle cells (VSMCs). Our aim was to assess expression of the Epo receptor (EpoR) on VSMCs and to study the activation of two major signaling cascades activated by Epo, namely JAK2/STAT5 and MAPK pathways. All experiments were performed in parallel using the Epo-responsive UT7 cell line. From semiquantitative RT-PCR experiments, VSMCs were estimated to express approximately 30-fold less EpoR mRNA than UT7 cells. Epo-induced phosphorylation of proteins involved in the EpoR/JAK2/STAT5 cascade could not be detected in VSMCs, even using pharmacological doses of Epo (250 IU/ml). In contrast, a strong activation of MAP kinase pathway was detected with as low as 10 IU/ml Epo. We suggest that MAPK activation reflects a physiologically relevant effect of Epo on VSMCs that may be correlated to cell proliferation.
 ...
PMID:Low doses of EPO activate MAP kinases but not JAK2-STAT5 in rat vascular smooth muscle cells. 1140 98

Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded GR and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STAT5-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.
 ...
PMID:Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1. 1143 8

Previous studies have indicated a redundancy in the effects of the cytokines, IL-3, IL-5, and nerve growth factor (NGF) on acute priming of human basophils. In the current study, we have examined the effects of these three cytokines on 18-h priming for leukotriene C4 generation, their ability to induce Fc(epsilon)RIbeta mRNA expression, or their ability to sustain basophil viability in culture. We also examine a variety of the signaling steps that accompany activation with these cytokines. In contrast with the ability of IL-3 to alter secretagogue-mediated cytosolic calcium responses following 18-h cultures, 18-h treatment with IL-5 or NGF did not affect C5a-induced leukotriene C4 generation or alter C5a-induced intracellular Ca2+ concentration elevations. IL-3 and IL-5, but not NGF, induced Fc(epsilon)RIbeta mRNA expression and all three improved basophil viability in culture with a ranking of IL-3 > IL-5 > or = NGF. All three cytokines acutely activated the extracellular signal-regulated kinase pathway and the signaling elements that preceded extracellular signal-regulated kinase and cytosolic phospholipase A2 phosphorylation, consistent with their redundant ability to acutely prime basophils. However, only IL-3 and IL-5 induced Janus kinase 2 and STAT5 phosphorylation. This pattern of signal element activation among the three cytokines most closely matched their ability to induce expression of Fc(epsilon)RIbeta mRNA. Induction of the sustained calcium signaling that follows overnight priming with IL-3 appeared to be related to the strength of the early signals activated by these cytokines but the relevant pathway required was not identified. None of the signaling patterns matched the ability of the cytokines to promote basophil survival.
 ...
PMID:Differences in functional consequences and signal transduction induced by IL-3, IL-5, and nerve growth factor in human basophils. 1149 16

The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules (MICs) that were identified based on their ability to bind to the human cytomegalovirus (HCMV) glycoprotein UL16. UL16 also binds to a member of another family of MHC class I-like molecules, MICB. The ULBPs and MICs are ligands for NKG2D/DAP10, an activating receptor expressed by natural killer (NK) cells and other immune effector cells, and this interaction can be blocked by UL16. Engagement of NKG2D/DAP10 by ULBPs or MICs expressed on a target cell can overcome an inhibitory signal generated by NK-cell recognition of MHC class I molecules and trigger NK cytotoxicity. ULBPs elicit their effects on NK cells by activating the janus kinase 2, signal transducer and activator of transcription 5, extracellular-signal-regulated kinase mitogen-activated protein kinase and Akt/protein kinase B signal transduction pathways. Although ULBPs alone activate multiple signaling pathways and induce modest cytokine production, ULBPs synergize strongly with interleukin-12 for production of interferon-gamma by NK cells. This finding is consistent with reports in T cells that NKG2D/DAP10 can act as a co-stimulatory receptor in a similar manner as CD28. The possible roles of ULBPs in mediating immune responses to viruses and tumors and the potential mechanisms by which UL16 may allow HCMV to evade immune detection are areas of active investigation.
 ...
PMID:The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions. 1151 39

SOCS proteins take part in a classical negative feedback loop to attenuate cytokine signaling. Although STAT family members positively modulate Socs gene expression, little else is known about Socs gene regulation. Here, we identify functional binding sites for GFI-1B, a proto-oncogenic transcriptional repressor, in the promoters of murine Socs1 and Socs3. Thus, mutating these sites relieved transcriptional repression, as determined by luciferase reporter assays of transiently transfected erythropoietin-responsive 32D-EpoR and HCD57 cells. Furthermore, cotransfection of Gfi-1B expression plasmid repressed reporter activity of wild-type (but not mutagenized) Socs1 and Socs3 promoters, strongly suggestive of direct GFI-1B binding to these promoters. In addition, overexpression of Gfi-1B resulted in reduced transcript levels of Socs1 and Socs3, but not Socs2 or Cis. Upon stimulation with erythropoietin, Socs transcripts were rapidly induced, whereas Gfi-1B mRNA was down-regulated. Interestingly, the latter effect appears to rely on STAT5 activity, but not on phosphoinositide 3-kinase or MAPK pathways. Thus, cytokine-mediated STAT5 activation allows relief of direct repression by GFI-1B of the Socs1 and Socs3 promoters, but apparently not of the Socs2 and Cis promoters. This constitutes a previously undescribed mode of controlling cytokine responsiveness, through the direct repression of a tumor suppressor (SOCS1) by a proto-oncoprotein (GFI-1B).
 ...
PMID:Regulation of Socs gene expression by the proto-oncoprotein GFI-1B: two routes for STAT5 target gene induction by erythropoietin. 1169 36

Growth hormone (GH) is a major growth-promoting and metabolic regulatory hormone. Interaction of GH with its cell surface GH receptor (GHR), by virtue of receptor dimerization, causes activation of the GHR-associated cytoplasmic tyrosine kinase, JAK2. Several signalling pathways, including the STAT5, PI3 kinase and MAP kinase pathways, are thereby accessed, resulting in various biochemical and biological cellular signalling outcomes which are rapidly becoming deciphered. Various mechanisms probably exist to terminate, modulate and prevent GH signalling. Some of these mechanisms regulate receptor abundance and/or availability while others may alter the responsiveness of downstream signalling molecules to receptor engagement. In this review, recent insights into modulation of GH signalling are discussed. Special emphasis is placed on mechanisms of homologous and heterologous desensitization and on the likelihood that inducible GHR proteolysis, in addition to causing GH binding protein generation, may also serve as an important mechanism of heterologous GHR downregulation.
 ...
PMID:Growth hormone signalling and its regulation: preventing too much of a good thing. 1173 35

The cytokine receptor common beta subunit (beta(c)) transmits intracellular signals upon binding ligand such as granulocyte-macrophage colony-stimulating factor or interleukin-3 (IL-3); however, transcriptional regulation under the control of signaling events downstream of the beta(c) is not fully understood. Using murine Ba/F3 cells, here we demonstrate that the beta(c)-mediated signals stimulate NF-kappa B-driven gene expression of not only the reporter construct but also endogenous target genes such as IL-6. Analyzing the effects of several inhibitors or mutant receptors revealed that this NF-kappa B activation is mediated neither by MEK/ERK/MAPK nor by the phosphatidylinositol 3-kinase pathway but by STAT5. Overexpression experiments of the wild-type or constitutive active form of STAT5 further confirmed this notion. In addition, STAT5-dependent NF-kappa B activation is mediated not through an inducible nuclear translocation but via up-regulation of both DNA binding activity and transactivation potential of NF-kappa B. Furthermore, we also show that as yet undefined humoral factor(s) may be involved in this NF-kappa B activation process. Taken together, we may propose that cytokine receptor-mediated STAT5 activation and expression of its target genes culminates in a unique mode of NF-kappa B activation and gene expression.
 ...
PMID:Cytokine receptor common beta subunit-mediated STAT5 activation confers NF-kappa B activation in murine proB cell line Ba/F3 cells. 1174 13

The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-gamma production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors.
 ...
PMID:UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. 1177 60

CD11b(+)Gr-1(+) myeloid suppressor cells (MSC) accumulate in lymphoid organs under conditions of intense immune stress where they inhibit T and B cell function. We recently described the generation of immortalized MSC lines that provide a homogeneous source of suppressor cells for dissecting the mechanism of suppression. In this study we show that the MSC lines potently block in vitro proliferation of T cells stimulated with either mitogen or antigenic peptide, with as few as 3% of MSC cells causing complete suppression. Inhibition of mitogenic and peptide-specific responses is not associated with a loss in IL-2 production or inability to up-modulate the early activation markers, CD69 and CD25, but results in direct impairment of the three IL-2R signaling pathways, as demonstrated by the lack of Janus kinase 3, STAT5, extracellular signal-regulated kinase, and Akt phosphorylation in response to IL-2. Suppression is mediated by and requires NO, which is secreted by MSC in response to signals from activated T cells, including IFN-gamma and a contact-dependent stimulus. Experiments with inducible NO synthase knockout mice demonstrated that the inhibition of T cell proliferation by CD11b(+)Gr-1(+) cells in the spleens of immunosuppressed mice is also dependent upon NO, indicating that the MSC lines accurately represent their normal counterparts. The distinctive capacity of MSC to generate suppressive signals when encountering activated T cells defines a specialized subset of myeloid cells that most likely serve a regulatory function during times of heightened immune activity.
 ...
PMID:Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. 1177 62

Vitamin C is present in the cytosol as ascorbic acid, functioning primarily as a cofactor for enzymatic reactions and as an antioxidant to scavenge free radicals. Human granulocyte macrophage-colony-stimulating factor (GM-CSF) induces an increase in reactive oxygen species (ROS) and uses ROS for some signaling functions. We therefore investigated the effect of vitamin C on GM-CSF-mediated responses. Loading U937 cells with vitamin C decreased intracellular levels of ROS and inhibited the production of ROS induced by GM-CSF. Vitamin C suppressed GM-CSF-dependent phosphorylation of the signal transducer and activator of transcription 5 (Stat-5) and mitogen-activated protein (MAP) kinase (Erk1 and Erk2) in a dose-dependent manner as was phosphorylation of MAP kinase induced by both interleukin 3 (IL-3) and GM-CSF in HL-60 cells. In 293T cells transfected with alpha and beta GM-CSF receptor subunits (alphaGMR and betaGMR), GM-CSF-induced phosphorylation of betaGMR and Jak-2 activation was suppressed by vitamin C loading. GM-CSF-mediated transcriptional activation of a luciferase reporter construct containing STAT-binding sites was also inhibited by vitamin C. These results substantiate the importance of ROS in GM-CSF signaling and indicate a role for vitamin C in downmodulating GM-CSF signaling responses. Our findings point to vitamin C as a regulator of cytokine redox-signal transduction in host defense cells and a possible role in controlling inflammatory responses.
 ...
PMID:Vitamin C inhibits granulocyte macrophage-colony-stimulating factor-induced signaling pathways. 1196 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>