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)

KIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias.
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PMID:KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. 1561 74

Intercellular adhesion molecule-1 (ICAM-1) has been shown to play crucial roles in mast cell interaction with other inflammatory cells and recruitment into the inflamed tissue. In the present study, human mast cell line-1 (HMC-1) was stimulated with different cytokines including stem cell factor (SCF), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-13, IL-18, and IL-25. Cell-surface expression of ICAM-1 was assessed by flow cytometry. To elucidate the intracellular signal transduction regulating the ICAM-1 expression, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-kappaB translocation were assessed by enzyme-linked immunosorbent assay. Results showed that SCF, TNF-alpha, and IL-13 but not IL-18 and IL-25 could up-regulate the surface expression of ICAM-1 on HMC-1 cells. A synergistic effect of SCF and TNF-alpha on ICAM-1 expression was demonstrated. This synergistic effect was shown to be dose-dependently enhanced by SCF but not TNF-alpha. Results indicated that SCF activated ERK, and TNF-alpha activated the p38 MAPK and NF-kappaB pathway. Selective inhibitor of ERK, PD098059, and c-kit inhibitors, STI571 and PP1, suppressed the combined SCF and TNF-alpha-induced ICAM-1 expression. BAY117082 but not SB203580, which are the inhibitors of NF-kappaB and p38 MAPK, respectively, suppressed the TNF-alpha-induced ICAM-1 expression. Therefore, SCF and TNF-alpha acted through ERK and the NF-kappaB pathway to regulate the ICAM-1 expression and elicited the synergistic effect. In conclusion, our results provide insight for cross-talk between different signaling pathways that can help in understanding the fine control of adhesion molecule expression under the concerted effects of cytokines.
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PMID:Synergistic effect of SCF and TNF-alpha on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells. 1580 27

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim-/- mast cells. Because apoptosis is abnormally reduced in bim-/- mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.
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PMID:Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim. 1585 72

In synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines such as IL-3, IL-5, and IL-13 and a decreased IL-6 expression. In this study we analyzed the kinetics and the mechanisms of these IL-4 effects on mast cells purified from intestinal tissue. If the cells were first cultured with IL-4 for 14 days and then without IL-4 for another 14 days, mast cells lost the capacity of producing higher amounts of Th2 cytokines and regained the capacity of producing IL-6. The IL-4-induced up-regulation of mast cell proliferation and FcepsilonRI expression was also reversible if IL-4 was withdrawn for 14 days. Interestingly, in contrast to IL-4, proliferation and phenotype of human intestinal mast cells were not affected by IL-13 although both cytokines were capable of inducing STAT6 activation. Instead, IL-4 treatment (but not IL-13 treatment) was associated with an increased activity of ERK1/2 and c-Fos, the downstream target of ERK1/2 and component of the transcription factor AP-1. Consistently, mast cell proliferation and cytokine expression in response to IL-4 was blocked by the MEK inhibitor PD98059. In summary, our data show that the IL-4 effects on human intestinal mast cell functions are reversible and accompanied by an increased activity of ERK1/2 and c-Fos.
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PMID:IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos. 1590 15

Stem cell factor (SCF) is a major mast cell growth factor, which could be involved in the local increase of mast cell number in the asthmatic airways. In vivo, SCF expression increases in asthmatic patients and this is reversed after treatment with glucocorticoids. In vitro in human lung fibroblasts in culture, IL-1beta, a pro-inflammatory cytokine, confirms this increased SCF mRNA and protein expression implying the MAP kinases p38 and ERK1/2 very early post-treatment, and glucocorticoids confirm this decrease. Surprisingly, glucocorticoids potentiate the IL-1beta-enhanced SCF expression at short term treatment, implying increased SCF mRNA stability and SCF gene transcription rate. This potentiation involves p38 and ERK1/2. Transfection experiments with the SCF promoter including intron1 also confirm this increase and decrease of SCF expression by IL-1beta and glucocorticoids, and the potentiation by glucocorticoids of the IL-1beta-induced SCF expression. Deletion of the GRE or kappaB sites abolishes this potentiation, and the effect of IL-1beta or glucocorticoids alone. DNA binding of GR and NF-kappaB are also demonstrated for these effects. In conclusion, this review concerns new mechanisms of regulation of SCF expression in inflammation that could lead to potential therapeutic strategy allowing to control mast cell number in the asthmatic airways.
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PMID:Regulation of stem cell factor expression in inflammation and asthma. 1596 14

The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34(+) cells. In serum-free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one-log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non-receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1-2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3-kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co-operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose-dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo- and Scf-mediated co-operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak-Stat, PI3K and MAPK pathways.
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PMID:Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor. 1598 54

CD34+ hematopoietic stem/progenitor cells (HSCs) reside in the bone marrow in close proximity to the endosteal bone surface, surrounded by osteoblasts, stromal cells, and various extracellular matrix molecules. We used a bioartificial matrix of fibrillar collagen I, the major matrix component of bone, as a scaffold for ex vivo expansion of HSCs. CD34+ HSCs were isolated from umbilical cord blood and cultivated within reconstituted collagen I fibrils in the presence of fms-like tyrosine kinase-3 ligand, stem cell factor, and interleukin (IL)-3. After 7 days of culture, the cell number, number of colony-forming units (CFU-C), and gene-expression profile of the cultured cells were assessed. Although the total expansion factor of CD34+ cells was slightly lower when cells were cultivated in the collagen I gel, the frequency of CFU-C was greater than in control suspension cultures. Gene-expression analysis with microarray chip technology revealed the upregulation of more than 50 genes in the presence of collagen I. Among these, genes for several growth factors, cytokines, and chemokines (e.g., IL-8 and macrophage inhibitory protein 1alpha) could be confirmed using quantitative polymerase chain reaction. Furthermore, greater expression levels of the negative cell-cycle regulator BTG2/TIS21 and an inhibitor of the mitogen-activated protein kinase pathway, DUSP2, underline the regulatory role of the extracellular matrix. Together, these data show that the expansion of CD34+ cord blood cells in a culture system containing a three-dimensional collagen I matrix induces a qualitative change in the gene-expression profile of cultivated HSCs.
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PMID:Gene-expression profiling of CD34+ hematopoietic cells expanded in a collagen I matrix. 1616 51

The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factor-stimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H- or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.
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PMID:Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling. 1617 Mar 39

Despite intensive investigation, controversial results have been obtained concerning the precise signaling pathway(s) regulated by K-ras in different cell types. We show that in primary fetal liver erythroid progenitors, erythropoietin activates all three Ras isoforms, but preferentially N- and K-ras. In K-ras(-/-) fetal liver cells (FLC), erythropoietin- or stem cell factor-dependent Akt activation is greatly reduced, whereas other pathways including Stat5 and p44/p42 MAP kinase are activated normally. We further studied the effects of reduced cytokine-dependent Akt activation in erythroid differentiation. We find that freshly isolated K-ras(-/-) FLC show an approximately 7-fold increase of apoptosis and delayed erythroid differentiation, but only at the stage of erythroid progenitors and very early erythroblasts. When K-ras(-/-) erythroid progenitors are cultured in vitro, there is a significant delay in erythroid differentiation but little increase in apoptosis. Furthermore, we show that partial pharmacologic inhibition of the phosphatidylinositol 3-kinase/Akt pathway in wild-type erythroid progenitors leads to a delay in erythroid differentiation similar to that observed in K-ras(-/-) FLC. Taken together, our data identify K-ras as the major regulator for cytokine-dependent Akt activation, which is important for erythroid differentiation in vivo.
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PMID:Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythroid progenitors in vivo. 1620 68

Mouse mast cell development and survival are largely controlled by the cytokines IL-3 and stem cell factor (SCF). We have found that IL-3 stimulation of bone marrow cells induces the production of TNF via a PI3K- and MAPK kinase/ERK-dependent pathway. Specifically, Mac-1-positive cells were responsible for TNF production, which peaked on days 7-10 of culture and decreased rapidly thereafter. The importance of IL-3-induced TNF secretion was demonstrated by the failure of TNF-deficient bone marrow cells to survive for >3 wk when cultured in IL-3 and SCF, a defect that was reversed by the addition of soluble TNF. The development of human mast cells from bone marrow progenitors was similarly hampered by the addition of TNF-blocking Abs. Cell death was due to apoptosis, which occurred with changes in mitochondrial membrane potential and caspase activation. Apoptosis appeared to be due to loss of IL-3 signaling, because TNF-deficient cells were less responsive than their wild-type counterparts to IL-3-mediated survival. In vitro cultured mast cells from TNF-deficient mice also demonstrated reduced expression of the high affinity IgE receptor, which was restored to normal levels by the addition of soluble TNF. Finally, TNF-deficient mice demonstrated a 50% reduction in peritoneal mast cell numbers, indicating that TNF is an important mast cell survival factor both in vitro and in vivo.
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PMID:IL-3-mediated TNF production is necessary for mast cell development. 1645 67


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