Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of signaling pathways shared by interleukin (IL)-11, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (ONC) remain elusive. We report here that treatment of 3T3-L1 cells with IL-11, IL-6, LIF, and ONC induces overlapping but distinct patterns of tyrosine phosphorylation and activates indistinguishable primary response genes. We further demonstrate for the first time that IL-11, IL-6, LIF, and ONC can trigger the activation of mitogen-activated protein kinases and the 85-92-kDa ribosomal S6 protein kinase (pp90rsk). In addition, our data also show that preincubation of cells with a tyrosine kinase inhibitor herbimycin A, but not with a serine/threonine kinase inhibitor H7, blocks activation of mitogen-activated protein kinases and pp90rsk. Interestingly, H7, but not herbimycin A, inhibits pp90rsk activity in the in vitro kinase assays. These results suggest that pp90rsk is one of the potential candidates for the H7-sensitive protein kinase(s), which is critical for the activation of primary response genes by these cytokines.
 ...
PMID:Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells. 750 17

Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), and interleukin-6 (IL6) compose a family of distantly related cytokines that initiate signaling by inducing either homodimerization of the "beta" signal transducing receptor component gp130 (in the case of IL6) or heterodimerization between gp130 and the gp130-related LIFR beta (in the case of CNTF, LIF, and OSM); dimerization of beta receptor components in turn activates members of the Jak/Tyk family of receptor-associated tyrosine kinases. Here we report that CNTF, LIF, OSM, and IL6 induce most of the same protein tyrosine phosphorylations, regardless of the cell type assayed or whether they initiate signaling by inducing homo- or heterodimerization of beta components. Although several of the protein tyrosine phosphorylations induced by the CNTF/LIF/OSM/IL6 family of factors may correspond to novel tyrosine kinase targets, we have been able to demonstrate the involvement of known signaling molecules, such as phospholipase C gamma, phosphoinositol 3-kinase, phosphotyrosine phosphatase (PTP1D), pp120, SHC, GRB2, STAT91, Raf-1, and the mitogen-activated protein kinases ERK1 and ERK2, revealing substantial convergence not only between the pathways activated by this cytokine family and other cytokines, but with pathways previously known to be activated only by factors that utilize receptor tyrosine kinases. Our data suggest the beta receptor components can form complexes with some of the signaling proteins identified and may play some role in their recruitment.
 ...
PMID:Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. 751 71

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.
 ...
PMID:Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts. 758 9

IL-6 is a multifunctional cytokine involved in hemopoiesis, immune regulation, inflammation, neural development, and infection. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor, oncostatin M, IL-11, ciliary neurotropic factor, and cardiotropin-1, all of which initiate signaling through a receptor-associated gp130. IL-6 induces homodimerization of gp130 and activates the Jak/STAT pathway of signal transduction. In addition, IL-6 stimulates the mitogen-activated protein kinases designated ERK (extracellular signal-regulated kinase)-1 and -2. Activation of ERK-1 and -2 may involve the Src homology-2 containing proteins Shc and Grb2. Here we provide evidence that Shc could function as signaling molecules for IL-6 in DeFew-IL-6R/gp130 cells, a human B lymphoma cell line engineered to express high levels of both the IL-6R (p80) and the gp130 subunit. IL-6 was shown to promote the rapid tyrosine phosphorylation of gp130, Jak2, and Shc proteins. Moreover, Shc associated both in vivo and in vitro with phosphorylated gp130 through the Shc-Src homology-2 domain. We also report that Shc bound to activated Jak2 by using the Shc amino terminal phosphotyrosine interaction domain. Following IL-6 stimulation, Shc physically associated with Grb2. Thus, the data point to Shc proteins as a functional link between the Jak2 and Ras pathways of IL-6 signal transduction.
 ...
PMID:Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. 912 68

We described recently the activation of the Janus kinasesignal transducer and activator of transcription (JakSTAT) and mitogen-activated protein (MAP) kinase pathways by leukemia inhibitory factor (LIF) through gp130, a signal transducer of IL-6-related cytokines, that transduces hypertrophic signals in cardiac myocytes. In addition, stimulation of gp130 by IL-6-related cytokines is known to exert a cytoprotective effect. In the present study, we investigated the possibility that activation of gp130 initiates activation of the cytoprotective genes in cardiac myocytes. Incubation of cardiac myocytes with LIF induced the expression of bcl-x, and the isoform that was induced by LIF was identified as bcl-xL. Induction of bcl-xL protein was also identified by Western blotting. Antisense oligonucleotide against bcl-x mRNA inhibited protective effect of LIF accompanied with the reduction in bclxL protein. We constructed bcl-x promoter-luciferase reporter gene plasmids (-639/+10- or -161/+10-luciferase), and transfected them to cardiac myocytes. LIF stimulation increased the luciferase activity of -639/+10-luciferase plasmids. Although -161/+10-luciferase plasmids presented comparable responsiveness to LIF, the basal transcription level was impaired. The LIF-responsive cis-element was localized to a DNA fragment (positions -161 to +10) that contains an interferon-gamma activation site (GAS) motif (GGA) at position -41 of the bcl-x gene promoter. This motif bound to STAT1, not to STAT3, and site-directed mutagenesis revealed that this motif was essential for LIF-responsive promoter activity. These data suggest that LIF induces bcl-x mRNA via STAT1 binding cis-element in cardiac myocytes, presenting cytoprotective effect.
 ...
PMID:Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. 918 13

Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through glycoprotein (gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
 ...
PMID:Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes. 954 5

c-Jun N-terminal protein kinase (JNK) and p38, two distinct members of the mitogen-activated protein (MAP) kinase family, regulate gene expression in response to various extracellular stimuli, yet their physiological functions are not completely understood. In this report we show that JNK and p38 exerted opposing effects on the development of myocyte hypertrophy, which is an adaptive physiological process characterized by expression of embryonic genes and unique morphological changes. In rat neonatal ventricular myocytes, both JNK and p38 were stimulated by hypertrophic agonists like endothelin-1, phenylephrine, and leukemia inhibitory factor. Expression of MAP kinase kinase 6b (EE), a constitutive activator of p38, stimulated the expression of atrial natriuretic factor (ANF), which is a genetic marker of in vivo cardiac hypertrophy. Activation of p38 was required for ANF expression induced by the hypertrophic agonists. Furthermore, a specific p38 inhibitor, SB202190, significantly changed hypertrophic morphology induced by the agonists. Surprisingly, activation of JNK led to inhibition of ANF expression induced by MEK kinase 1 (MEKK1) and the hypertrophic agonists. MEKK1-induced ANF expression was also negatively regulated by expression of c-Jun. Our results demonstrate that p38 mediates, but JNK suppresses, the development of myocyte hypertrophy.
 ...
PMID:Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. 958 92

Propagation of mouse embryonic stem (ES) cells in vitro requires exogenous leukemia inhibitory factor (LIF) or related cytokines. Potential downstream effectors of the LIF signal in ES cells include kinases of the Src, Jak, and mitogen-activated protein families and the signal transducer and transcriptional activator STAT3. Activation of nuclear STAT3 and the ability of ES cells to grow as undifferentiated clones were monitored during LIF withdrawal. A correlation was found between levels of STAT3 activity and maintenance of an undifferentiated phenotype at clonal density. In contrast, variation in STAT3 activity did not affect cell proliferation. The requirement for STAT3 was analyzed by targeted mutagenesis in ES cell lines exhibiting different degrees of LIF dependency. An insertional mutation was devised that abrogated Stat3 gene expression but could be reversed by Cre recombination-mediated excision. ES cells heterozygous for the Stat3 mutation could be isolated only from E14 cells, the line least dependent on LIF for self-renewal. Targeted clones isolated from other ES cell lines were invariably trisomic for chromosome 11, which carries the Stat3 locus, and retained normal levels of activated STAT3. Cre-regulated reduction of Stat3 gene copy number in targeted, euploid E14 clones resulted in dose-dependent losses of STAT3 activity and the efficiency of self-renewal without commensurate changes in cell cycle progression. These results demonstrate an essential role for a critical amount of STAT3 in the maintenance of an undifferentiated ES cell phenotype.
 ...
PMID:Essential role of STAT3 for embryonic stem cell pluripotency. 1007 99

Sterile tissue injury or infection initiates a local inflammatory response that mobilizes a systemic acute phase reaction resulting in, among other things, the induction of genes encoding the acute phase plasma proteins (APPs). In all vertebrates, a common set of APPs is increased and exerts essential protective functions. Haptoglobin (HP), one of the major APPs, acts as a high-affinity hemoglobin-binding protein and antioxidant. Liver is the major site of HP synthesis; however, regulated, low level expression is also detected in other organs. Induction of the Hp gene is mediated by interleukin-6-type cytokines and is synergistically enhanced by glucocorticoids. Growth stimulation of hepatic cells in vivo or in vitro suppresses the Hp gene-inducing effects of inflammatory cytokines. Receptors for IL-6 cytokines mediate induction of the Hp gene by the transcription factors signal transducer and activator of transcription-3 (STAT3) and CAAT/enhancer binding protein beta (C/EBPbeta), but attenuate the stimulation through co-activated STAT5 and mitogen-activated protein kinases, ERK-1 and ERK-2. The specificity by which the related cytokines, IL-6, oncostatin M, and leukemia inhibitory factor, regulate Hp gene transcription is determined by the profile of the cytokine receptor subunits expressed on the target cells and the relative extents by which these receptors activate the intracellular signaling pathways. The current hypothesis is that HP exerts an anti-inflammatory activity and that by the degree with which HP attenuates the inflammatory process, including the production of IL-6 cytokines, it determines the level and duration of acute phase expression of the Hp gene.
 ...
PMID:Haptoglobin, an inflammation-inducible plasma protein. 1186 81

Cholinergic differentiation factors (CDFs) suppress noradrenergic properties and induce cholinergic properties in sympathetic neurons. The CDFs leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) bind to a LIFR.gp130 receptor complex to activate Jak/signal transducers and activators of transcription and Ras/mitogen-activated protein kinases signaling pathways. Little is known about how these differentiation factors suppress noradrenergic properties. We used sympathetic neurons and SK-N-BE(2)M17 neuroblastoma cells to investigate CDF down-regulation of the norepinephrine synthetic enzyme dopamine-beta-hydroxylase (DBH). LIF and CNTF activated extracellular signal-regulated kinases (ERKs) 1 and 2 but not p38 or Jun N-terminal kinases in both cell types. Preventing ERK activation with PD98059 blocked CNTF suppression of DBH protein in sympathetic neurons but did not prevent the loss of DBH mRNA. CNTF decreased transcription of a DBH promoter-luciferase reporter construct in SK-N-BE(2)M17 cells, and this was also ERK-independent. Cytokine inhibition of DBH promoter activity did not require a silencer element but was prevented by overexpression of the transcriptional activator Phox2a. Inhibiting ERK activation increased basal DBH transcription in SK-N-BE(2)M17 cells, and DBH mRNA in sympathetic neurons. Transfection of Phox2a into PD98059-treated M17 cells resulted in a synergistic increase in DBH promoter activity compared with Phox2a or PD98059 alone. These data suggest that CDFs down-regulate DBH protein via an ERK-dependent pathway but inhibit DBH gene expression through an ERK-independent pathway. They further suggest that ERK activity inhibits basal DBH gene expression.
 ...
PMID:Cytokine suppression of dopamine-beta-hydroxylase by extracellular signal-regulated kinase-dependent and -independent pathways. 1260 84


1 2 Next >>