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)

Thrombopoietin (Tpo) is a cytokine which stimulates megakaryocyte maturation. We found that Tpo is constitutively and ubiquitously expressed in all tissues examined, including bone marrow stromal cells, even in thrombocytopenia, thrombosis and steady-state condition in mice. Thus, platelet level in circulation is not regulated by Tpo gene expression. Furthermore, when the purified megakaryocytes were cocultured with the stromal cells, most of the megakaryocytes adhered to the stromal cells and remained unchanged, while free megakaryocytes induced proplatelet formation. Thus the stromal cells in bone marrow secrete Tpo and stimulate megakaryocytopoiesis, but the interaction of megakaryocytes with the stromal cells may suppress platelet formation. Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2, which in turn activate STAT1, STAT3 and STAT5. Further, Tpo stimulates transcription factors GATA-1 and NF-E2, which induce differentiation markers, GPIIb/IIIa and Pm-1. In addition, Shc, Vav, Ras, Raf-1, MAPKK, MAPK and Pim-1 are also activated. Thus, Tpo activates a lineage-specific cascade as well as a specific JAK-STAT cascade and a common signaling cascade.
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PMID:Regulation of megakaryocytopoiesis by thrombopoietin and stromal cells. 920 16

The erythroid transcription factor NF-E2 is an obligate heterodimer composed of two different subunits (p45 and p18), each containing a basic region-leucine zipper DNA binding domain, and it plays a critical role in erythroid differentiation as an enhancer-binding protein for expression of the beta-globin gene. We show here that dimethyl sulfoxide treatment of wild-type murine erythroleukemia cells, but not a mutant clone of dimethyl sulfoxide-resistant cells, increases NF-E2 activity significantly, which involves both up-regulation of DNA binding and transactivation activities. Both activities were reduced markedly by treatment of cells with 2-aminopurine but not by genistein. Activation of the Ras-Raf-MAP kinase signaling cascade increased NF-E2 activity significantly, but this was suppressed when MafK was overexpressed. Domain analysis revealed an activation domain in the NH2-terminal region of p45 and a suppression domain in the basic region-leucine zipper of MafK. These findings indicate that induction of NF-E2 activity is essential for erythroid differentiation of murine erythroleukemia cells, and serine/threonine phosphorylation may be involved in this process. In addition, they also suggest that a MafK homodimer can suppress transcription, not only by competition for the DNA binding site, but also by direct inhibition of transcription. Hence, MafK may function as an active transcription repressor.
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PMID:Regulation of NF-E2 activity in erythroleukemia cell differentiation. 947 96

Activation of the mitogen-activated protein kinase (MAPK) pathway enhances long-range transactivation by the beta-globin locus control region (LCR) (W. K. Versaw, V. Blank, N. M. Andrews, and E. H. Bresnick, Proc. Natl. Acad. Sci. USA 95:8756-8760, 1998). The enhancement requires tandem recognition sites for the hematopoietic transcription factor NF-E2 within the hypersensitive site 2 (HS2) subregion of the LCR. To distinguish between mechanisms of induction involving the activation of silent promoters or the increased efficacy of active promoters, we analyzed basal and MAPK-stimulated HS2 enhancer activity in single, living cells. K562 erythroleukemia cells stably transfected with constructs containing the human Agamma-globin promoter linked to an enhanced green fluorescent protein (EGFP) reporter, with or without HS2, were analyzed for EGFP expression by flow cytometry. When most cells in a population expressed EGFP, MAPK augmented the activity of active promoters. However, under conditions of silencing, in which cells reverted to a state with no measurable EGFP expression, MAPK activated silent promoters. Furthermore, studies of populations of EGFP-expressing and non-EGFP-expressing cells isolated by flow cytometry showed that MAPK activation converted nonexpressing cells into expressing cells and increased expression in expressing cells. These results support a model in which MAPK elicits both graded and stochastic responses to increase HS2-mediated transactivation from single chromatin templates.
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PMID:Enhancement of beta-globin locus control region-mediated transactivation by mitogen-activated protein kinases through stochastic and graded mechanisms. 1040 46

Commitment of hematopoietic cells to the erythroid lineage involves the actions of several transcription factors, including TAL1, LMO2, and GATA-2. The differentiation of committed erythroid progenitor cells involves other transcription factors, including NF-E2 and EKLF. Upon binding erythropoietin, the principal regulator of erythropoiesis, cell surface erythropoietin receptors dimerize and activate specific intracellular kinases, including Janus family tyrosine protein kinase 2, phosphoinositol-3 kinase, and mitogen-activated protein kinase. Important substrates of these kinases are tyrosines in the erythropoietin receptors themselves and the signal transducer and transcription activator proteins. Erythropoietin prevents erythroid cell apoptosis. Some of the apoptotic tendency of erythroid cells can be attributed to proapoptotic molecules produced by hematopoietic cells, macrophages, and stromal cells. Cell divisions accompanying terminal erythroid differentiation are finely controlled by cell cycle regulators, and disruption of these terminal divisions causes erythroid cell apoptosis. In reticulocyte maturation, regulated degradation of internal organelles involves a lipoxygenase, whereas survival requires the antiapoptotic protein Bcl-x.
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PMID:New insights into erythropoiesis. 1184 90

The regulation of erythroid cells is complex and occurs at multiple levels. Erythroid precursors, once committed to this lineage, develop in association with specific macrophages within erythroblastic islands. While erythropoietin (Epo) is the principal regulator of erythroid progenitors, other cytokines and nuclear hormones also play an important role in the maturation of these cells. Signalling from the Epo-receptor activates several pathways, including the JAK/STAT, ras/raf/MAP kinase and PI3 kinase/Akt cascades to promote cell survival, proliferation and differentiation. Transcription factors such as GATA-1, EKLF and NF-E2 are crucial for progression along the erythroid maturation pathway; these, and a myriad of other transcription factors, must be expressed at the correct developmental stage for normal red blood cells to be formed.
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PMID:New insights into the regulation of erythroid cells. 1523 Mar 44

Chlorogenic acid, the ester of caffeic acid with quinic acid, is one of the most abundant polyphenols in the human diet. The antioxidant and anticarcinogenic properties of chlorogenic acid have been established in animal studies. However, little is known about the molecular mechanisms through which chlorogenic acid inhibits carcinogenesis. In this study, we found that chlorogenic acid inhibited the proliferation of A549 human cancer cells in vitro. The results of the soft agar assay indicated that chlorogenic acid suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells in a dose-dependent manner. Pretreatment of JB6 cells with chlorogenic acid blocked UVB- or TPA-induced transactivation of AP-1 and NF-kappaB over the same dose range. At low concentrations, chlorogenic acid decreased the phosphorylation of c-Jun NH2-terminal kinases, p38 kinase, and MAPK kinase 4 induced by UVB/12-O-tetradecanoylphorbol-13-acetate, yet higher doses were required to inhibit extracellular signal-regulated kinases. Chlorogenic acid also increased the enzymatic activities of glutathione S-transferases (GST) and NAD(P)H: quinone oxidoreductase. Further studies indicated that chlorogenic acid could stimulate the nuclear translocation of Nrf2 (NF-E2-related factor) as well as subsequent induction of GSTA1 antioxidant response element (ARE)-mediated GST activity. The phosphatidylinositol 3-kinase pathway might be involved in the activation of Nrf2 translocation. These results provide the first evidence that chlorogenic acid could protect against environmental carcinogen-induced carcinogenesis and suggest that the chemopreventive effects of chlorogenic acid may be through its up-regulation of cellular antioxidant enzymes and suppression of ROS-mediated NF-kappaB, AP-1, and MAPK activation.
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PMID:Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. 1594 51

The stress-inducible protein heme oxygenase-1 exerts potent antiinflammatory, antiapoptotic and cytoprotective effects in vitro and in vivo. Another important mediator of cytoprotection, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activates many proteins involved in the maintenance of cellular homeostasis. Since activation of heme oxygenase-1 and PI3K/Akt both protect the cellular environment, we postulated that PI3K/Akt can regulate the induction of heme oxygenase-1 by proinflammatory stress. The treatment of primary murine macrophage cells (RAW 264.7) with lipopolysaccharide induced heme oxygenase-1 protein and mRNA expression, and increased the phosphorylation of Akt and p38 mitogen activated protein kinase (p38 MAPK). These cellular effects of lipopolysaccharide were markedly diminished by pre-treatment with wortmannin, a specific inhibitor of PI3K. Furthermore, lipopolysaccharide-inducible heme oxygenase expression was blocked by SB203580, a specific inhibitor of p38 MAPK. Both wortmannin and SB203580 decreased lipopolysaccharide-inducible NF-E2-related factor (Nrf2) DNA binding activity. Transfection of macrophages with dominant negative mutants of PI3K, Akt and Nrf2, as well as wortmannin treatment, significantly reduced the transcriptional activity of a minimal heme oxygenase-1 promoter luciferase construct (D33HO-1luc). We demonstrate, to our knowledge for the first time, that upon proinflammatory stimulation heme oxygenase-1 gene expression in macrophages depends on PI3K/Akt and p38 MAPK acting upstream of Nrf2-dependent promoter activation.
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PMID:Phosphatidylinositol 3-kinase/Akt pathway mediates heme oxygenase-1 regulation by lipopolysaccharide. 1630 68

Heme oxygenase-1 catalyzes the breakdown of heme and is protective in models of kidney transplantation. In this study we describe the induction of heme oxygenase-1 mRNA and protein by insulin. Following treatment with insulin, a five-fold increase in heme oxygenase-1 mRNA and a four-fold increase in protein expression were observed in renal adenocarcinoma cells; insulin-induced heme oxygenase-1 expression was also demonstrated in mouse primary tubular epithelial cells. The induction of heme oxygenase-1 in renal adenocarcinoma cells was blocked by actinomycin D and cycloheximide and was abolished by the phosphatidylinositol 3-kinase inhibitor, LY294002, but not by the inactive analog LY303511. Overexpressing a dominant-negative form of Akt abrogated the heme oxygenase-1-inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase-1 promoter activity and protein expression. The transcription factor NF-E2-related factor-2 was found to translocate to the nucleus following insulin treatment in a phosphatidylinositol 3-kinase-dependent manner. Pretreatment with NF-E2-related factor-2 small-interfering RNA abolished insulin-induced heme oxygenase-1 induction. Insulin was also found to activate the mitogen-activated protein kinase cascades p38 and extracellular signal-related kinase; however, inhibition of these pathways with SB202190 and PD98059 did not alter insulin-induced heme oxygenase-1 expression. Thus, insulin induces heme oxygenase-1 mRNA and protein expression in renal cells in a phosphatidylinositol 3-kinase/Akt and NF-E2-related factor-2-dependent manner.
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PMID:Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells. 1670 10

The induction of NF-E2-related factor-2 (Nrf2)-mediated detoxifying/antioxidant enzymes is recognized as an effective strategy for cancer chemoprevention. Here, we report that 3-morpholinopropyl isothiocyanate (3MP-ITC) is an exceptionally strong chemical inducer of these enzymes. Exposure of 3MP-ITC in HepG2C8 cells not only induced endogenous Nrf2 protein but also suppressed endogenous Kelch-like ECH-associated protein 1, resulting in an increased nuclear accumulation of Nrf2. Using chemical inhibitors of protein synthesis (cycloheximide) and 26S proteosomal degradation (MG-132), we observed that the induction of Nrf2 protein by 3MP-ITC appeared to be post-translationally regulated. 3MP-ITC activated ERK1/2 and JNK1/2 and the activation of antioxidant response element (ARE) by 3MP-ITC was significantly attenuated by chemical inhibition of PKC and PI3K signaling pathways in HepG2C8 cells. Treatment with 3MP-ITC significantly depleted the intracellular level of glutathione (GSH) in HepG2C8 cells and oral administration of 3MP-ITC increased the protein expression of hepatic NAD[P]H:quinone oxidoreductase-1 and Nrf2 in Nrf2 (+/+) but not in Nrf2 (-/-) mice, whereas UDP-glucuronosyl transferase 1A1 was induced in both genotypes. Our results indicate that 3MP-ITC is a novel ITC that strongly induces Nrf2-dependent ARE-mediated detoxifying/antioxidant enzymes in vitro and in vivo via the Nrf2 signaling pathway coupled with GSH depletion and activation of multiple signaling kinase pathways, which could be potentially useful agent for cancer chemoprevention.
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PMID:3-Morpholinopropyl isothiocyanate is a novel synthetic isothiocyanate that strongly induces the antioxidant response element-dependent Nrf2-mediated detoxifying/antioxidant enzymes in vitro and in vivo. 1791 1

Hystidyl-proline [cyclo(His-Pro)] is an endogenous cyclic dipeptide produced by the cleavage of thyrotropin releasing hormone. Previous studies have shown that cyclo(His-Pro) protects against oxidative stress, although the underlying mechanism has remained elusive. Here, we addressed this issue and found that cyclo(His-Pro) triggered nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that up-regulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes, in PC12 cells. Cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion caused by glutamate, rotenone, paraquat and beta-amyloid treatment. Moreover, real-time PCR analyses revealed that cyclo(His-Pro) induced the expression of a number of ARE-related genes and protected cells against hydrogen peroxide-mediated apoptotic death. Furthermore, these effects were abolished by RNA interference-mediated Nrf2 knockdown. Finally, pharmacological inhibition of p-38 MAPK partially prevented both cyclo(His-Pro)-mediated Nrf2 activation and cellular protection. These results suggest that the signalling mechanism responsible for the cytoprotective actions of cyclo(His-Pro) would involve p-38 MAPK activation leading to Nrf2-mediated up-regulation of antioxidant cellular defence.
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PMID:Cyclo(His-Pro) promotes cytoprotection by activating Nrf2-mediated up-regulation of antioxidant defence. 1837 31


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