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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A primary signaling cascade responsible for the expression of cytokine-stimulated immediate early genes involves the activation of the Jak/Stat pathway. In addition to being tyrosine-phosphorylated, several signal transducers and activators of transcription (Stats), including Stat1alpha, Stat3, and Stat4, are phosphorylated on a conserved serine residue, which is a consensus phosphorylation site for mitogen-activated protein kinases (MAPKs). Serine phosphorylation of Stat1alpha is required for maximal transcriptional activation of early response genes by interferon gamma (IFNgamma) as well as the antiviral and antigrowth actions of this cytokine. Incubation of cells with either IFNgamma or oncostatin M (OSM) activates Raf-1, a serine/threonine kinase responsible for the ultimate activation of p42 MAPK. To examine whether any of the signaling components that are required for activation of the Jak/Stat pathway are also necessary for activation of Raf-1 by IFNs and OSM, we examined activation of Raf-1 in cell lines that are deficient in either Stat1alpha or Stat2. Unexpectedly, incubation of Stat1-deficient, but not Stat2-deficient cells with IFNgamma or OSM for 5 min displayed no increase in Raf-1 activity. In peripheral blood lymphocytes Raf-1 was associated with Stat1, and this interaction was disrupted after incubation of cells with IFNgamma. Stat1-negative cells reconstituted with either Stat1alpha or Stat1alpha with a point mutation in the site where it is serine-phosphorylated displayed normal activation of Raf-1 by IFNgamma and OSM. However, activation of Raf-1 was not observed in lines that expressed Stat1alpha containing a mutation in its tyrosine phosphorylation site or in its SH2 domain. These results provide the first example of a novel role of Stat1alpha not as a transcription factor, but as a protein which may function to scaffold signaling components required for activation of the distinct Raf/MEK/MAPK signaling cascade.
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PMID:Activation of Raf-1 by interferon gamma and oncostatin M requires expression of the Stat1 transcription factor. 966 40

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte-restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-kappaB. Activation of NF-kappaB by OSM did not require IkappaB-alpha degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-kappaB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-kappaB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-kappaB and that activation of NF-kappaB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.
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PMID:Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation. 1115 86

Cytokine oncostatin M (OM) has profound effects on proliferation and differentiation of breast cancer cells. OM treated cells show reduced growth rate and differentiated phenotypes. The mechanisms underlying the OM growth-inhibitory activity in breast cancer cells have not been fully elucidated. In this study, we investigated the OM-elicited signaling pathways in breast cancer cell lines MDA-MB231 and MCF-7. We show that OM rapidly activates the extracellular signal-regulated kinase (ERK) and the signal transducer and activator of transcription (STAT) 1 and 3 in both cell lines. Intriguingly, OM-induced growth inhibition and morphological changes in MDA-MB231 cells are completely abolished by inhibitors to ERK upstream kinase MEK (nitrogen/extracellular-regulated protein kinase kinase), but the MEK inhibitors have little effects on OM growth-inhibitory activity in MCF-7 cells. In addition, expressions of the cyclin kinase inhibitors p21 and p27 are strongly induced by OM in MCF-7 cells, but their expression is only slightly increased by OM in MDA-MB231 cells. These data together demonstrate that the growth-inhibitory activity of OM can be mediated by different signaling pathways in a cell line-specific manner. While the MEK/ERK pathway is the predominant signaling pathway that leads to the growth inhibition of MDA-MB231 cells, activation of additional signaling pathways are necessary for OM to exert its growth-inhibitory activity in MCF-7 cells.
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PMID:Oncostatin M-induced growth inhibition and morphological changes of MDA-MB231 breast cancer cells are abolished by blocking the MEK/ERK signaling pathway. 1143 97

The physiological benefit of the febrile response is poorly understood. Here we show that fever-range thermal stress enhances the function of the L-selectin lymphocyte homing receptor through an interleukin-6 (IL-6)-dependent signaling mechanism. Thermal stimulation of L-selectin adhesion in vitro and in vivo is mediated by engagement of the gp130 signal-transducing chain by IL-6 and a soluble form of the IL-6 receptor-alpha (sIL-6Ralpha) binding subunit. Thermal control of adhesion is maintained in IL-6-deficient mice through a gp130-dependent compensatory mechanism mediated by IL-6-related cytokines (i.e., oncostatin M [OSM], leukemia inhibitory factor [LIF], and IL-11). Combined biochemical and pharmacological inhibitor (PD98059, U0126, SB203580, SP600125) approaches positioned MEK1/ERK1-2, but not p38 MAPK or JNK, in the IL-6/sIL-6Ralpha signaling pathway upstream of activation of L-selectin/cytoskeletal interactions and L-selectin avidity/affinity. These results highlight a role for gp130-linked IL-6/sIL-6Ralpha transsignaling in amplifying lymphocyte trafficking during febrile inflammatory responses.
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PMID:Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. 1473 59

Interleukin-6 (IL-6) subfamily of cytokines, including oncostatin M (OSM), leukemia inhibitory factor (LIF), and IL-6, has been implicated in a variety of physiological responses, such as cell growth, differentiation, and inflammation. In the present study, we demonstrated that both OSM and LIF stimulated the proliferation of human adipose tissue-derived mesenchymal stem cells (hATSCs), however, IL-6 had no effect on cell proliferation. OSM treatment induced phosphorylation of ERK, and pretreatment with U0126, a MEK inhibitor, prevented the OSM-stimulated proliferation of hATSCs, suggesting that the MEK/ERK pathway is involved in the OSM-induced proliferation. Treatment with OSM also induced phosphorylation of JAK2 and JAK3, and pretreatment of the cells with WHI-P131, a JAK3 inhibitor, but not with AG490, a JAK2 inhibitor, attenuated the OSM-induced proliferation of hATSCs. Furthermore, OSM treatment elicited phosphorylation of STAT1 and STAT3, and pretreatment with WHI-P131 specifically prevented the OSM-induced phosphorylation of STAT1, without affecting the OSM-induced phosphorylation of ERK and STAT3. These results suggest that two separate signaling pathways, such as MEK/ERK and JAK3/STAT1, are independently involved in the OSM-stimulated proliferation of hATSCs.
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PMID:Oncostatin M induces proliferation of human adipose tissue-derived mesenchymal stem cells. 1597 22

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) induce DNA synthesis in Swiss 3T3 cells through common signaling mechanism(s), whereas other related cytokines such as interleukin-6 and ciliary neurotrophic factor do not cause this response. Induction of DNA replication by LIF or prostaglandin F2alpha (PGF2alpha) occurs, in part, through different signaling events. LIF and OSM specifically trigger STAT1 cytoplasmic to nuclear translocation, whereas PGF2alpha fails to do so. However, LIF and PGF2alpha can trigger increases in ERK1/2 activity, which are required for their mitogenic responses because U0126, a MEK1/2 inhibitor, prevents both ERK1/2 activation and induction of DNA synthesis by LIF or PGF2alpha treatment. PGF2alpha induces cyclin D expression and full phosphorylation of retinoblastoma protein. In contrast, LIF fails to promote increases in cyclin D mRNA/protein levels; consequently, LIF induces DNA synthesis without promoting full phosphorylation of retinoblastoma protein (Rb). However, both LIF and PGF2alpha increase cyclin E expression. Furthermore, LIF mitogenic action does not involve protein kinase C (PKC) activation, because a PKC inhibitor does not block this effect. In contrast, PKC activity is required for PGF2alpha mitogenic action. More importantly, the synergistic effect between LIF and PGF2alpha to promote S phase entry is independent of PKC activation. These results show fundamental differences between LIF- and PGF2alpha-dependent mechanism(s) that induce cellular entry into S phase. These findings are critical in understanding how LIF and other related cytokine-regulated events participate in normal cell cycle control and may also provide clues to unravel crucial processes underlying cancerous cell division.
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PMID:Leukemia inhibitory factor induces DNA synthesis in Swiss mouse 3T3 cells independently of cyclin D1 expression through a mechanism involving MEK/ERK1/2 activation. 1629 39

Stromal-derived factor-1 (SDF-1) is a CXC chemokine that attracts leukocytes and endothelial progenitor cells. In the present study, we demonstrated that oncostatin M (OSM) stimulates expression and secretion of SDF-1 in both human adipose tissue-derived mesenchymal stem cells (hATSCs) and bone marrow-derived mesenchymal stem cells. The OSM-stimulated expression of SDF-1 in hATSCs was completely abrogated by pretreatment of the cells with U0126, an MEK-specific inhibitor, but not with AG490, a JAK2 inhibitor, or WHI-P131, a JAK3 inhibitor, suggesting that ERK, but not JAK2 and JAK3, is involved in the OSM-induced expression of SDF-1. Pretreatment of hATSCs with anti-VEGF neutralizing antibody or VEGF receptor inhibitors, SU5416 and KRN633, had no significant impact on the OSM induction of SDF-1. Furthermore, treatment of hATSCs with recombinant human VEGF165 or adenoviral overexpression of VEGF did not increase the expression of SDF-1. These results suggest that OSM induces secretion of SDF-1 through ERK-, but not VEGF-, dependent signaling pathways in mesenchymal stem cells.
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PMID:Oncostatin M stimulates expression of stromal-derived factor-1 in human mesenchymal stem cells. 1716 99

Growing evidence suggests that a proportion of interstitial myofibroblasts detected during renal tubulointerstitial fibrosis originates from tubular epithelial cells by a process called epithelial-mesenchymal transition (EMT). The IL-6-type cytokine oncostatin M (OSM) has been recently implicated in the induction of EMT. We investigated OSM effects on the expression of both cell-cell contact proteins and mesenchymal markers and studied OSM-induced intracellular signaling mechanisms associated with these events in human proximal tubular cells. Human recombinant OSM attenuated the expression of N-cadherin, E-cadherin, and claudin-2 in human kidney-2 (HK-2) cells associated with the induction of HK-2 cell scattering in 3D collagen matrices. Conversely, expression of collagen type I, vimentin, and S100A4 was induced by OSM. OSM-stimulated cell scattering was inhibited by antibodies against gp130. Besides inducing phosphorylation of Stat1 and Stat3, OSM led to a strong concentration- and time-dependent phosphorylation of the mitogen-activated protein kinases ERK1, ERK2, and ERK5. MEK1/2 inhibitor U0126 (10 muM) blocked basal and OSM-induced ERK1/2 phosphorylation but not phosphorylation of either ERK5 or Stat1/3. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at concentrations which inhibit ERK1/2 phosphorylation but not ERK5 phosphorylation, restored N-cadherin expression in the presence of OSM, inhibited basal claudin-2 expression, but did not affect either basal or OSM-inhibited E-cadherin expression or OSM-induced expression of collagen type I and vimentin. These results suggest that in human proximal tubular cells ERK1/2 signaling represents an important component of OSM's inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.
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PMID:Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. 1788 58

We investigated whether KIT signaling was sufficient to maintain human hematopoietic stem cells in culture or whether, as with murine stem cells, signaling through glycoprotein 130 (gp130) is additionally required. Sorted CD34(+)CD133(+)(CD33/CD38/CD71)(-) cells from human umbilical cord blood (UCB) were cultured in the presence of combinations of KIT-ligand (KL) and the gp130 stimulating molecule oncostatin M (OSM). We found that OSM increased KL-induced proliferation, which was accompanied by an expansion in numbers of mature progenitors colony-forming cells (CFC, CAFCw2). More primitive progenitors, CAFCw6 and long-term culture-CFC, were not maintained by KL as a single factor. Although addition of OSM did not improve survival, the KL/OSM combination showed improved maintenance of immature progenitors as well as higher CD34 expression. Similarly, both KL and OSM were required to maintain NOD/SCID-repopulating activity. In experiments to investigate the underlying mechanism, we found that extracellular signal-regulated kinase (ERK) and its downstream target p90 ribosomal S6 kinase were activated by KL and downregulated by the inclusion of OSM during stimulation. The p38 mitogen-activated protein kinase (p38 MAPK) was not modulated by either KL or OSM. Indeed, many of the effects of OSM (increased cell division, maintenance of CFC, and maintenance of high CD34 expression) could be mimicked by using the mitogen-activated protein kinase kinase inhibitor U0126. More importantly, NOD/SCID-repopulating activity was preserved in the KL/U0126-stimulated cells, but not in cells stimulated with a combination of KL and the p38 MAPK inhibitor SB203580. Our results show that the loss of repopulating activity during KL stimulation is counteracted by OSM through the downregulation of ERK pathway signaling. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Oncostatin M-mediated regulation of KIT-ligand-induced extracellular signal-regulated kinase signaling maintains hematopoietic repopulating activity of Lin-CD34+CD133+ cord blood cells. 1849 91


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