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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the roles of suppressor of cytokine signaling (SOCS) family members in erythropoietin (EPO) signaling, we explored SOCS gene regulation, mRNA stability, and protein function in two EPO-responsive hematopoietic cell lines. Using two independent approaches, one involving inhibition of specific signaling molecules and the other employing cell lines that express particular EpoR mutants and thereby activate only subsets of signaling cascades, we demonstrate that induction of SOCS1, SOCS2, SOCS3, and cytokine-inducible SH2-containing protein (CIS) in response to EPO stimulation appears to depend on Stat5 but not on mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K). SOCS4 expression, in contrast, does not appear to be EPO inducible. Furthermore, we show differential stabilities of SOCS transcripts, with SOCS2 the longest-lived and SOCS1 and CIS the least stable, and provide evidence in support of EPO-independent expression of SOCS3 and SOCS4. In order to understand the effects of SOCS on EPO-mediated effects, we generated multiple stable cell lines that inducibly express particular SOCS proteins. Overexpression of SOCS1, SOCS3, or CIS negatively regulates EPO-mediated cell proliferation Stat5 phosphorylation, and activation of a Stat-dependent luciferase reporter. In contrast, SOCS2 is less effective, and SOCS4 is ineffective at counteracting EPO-mediated events. Thus, we have demonstrated differential regulation and function of various SOCS family members in EPO-dependent hematopoietic cells.
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PMID:Differential roles of SOCS family members in EpoR signal transduction. 1239 24

We previously reported that erythropoietin (Epo) has a mitogenic effect on rat vascular smooth muscle cells (VSMC) and that activation of the mitogen-activated protein kinase (MAPK) cascade is an important mediator for Epo-induced mitogenesis. An increase in intracellular cAMP has an antiproliferative effect on VSMC. We therefore hypothesized that cAMP effectors inhibit Epo-induced MAPK activation in rat VSMC. When we exposed VSMC to recombinant human Epo (rHuEpo), DNA synthesis was increased. Forskolin (Fsk) or cilostazol (Cil) decreased the DNA synthesis stimulated by rHuEpo. Coincubation with Rp-cAMPS triethylamine canceled the suppression of DNA synthesis and MAPK activity by Fsk. Both rHuEpo and phorbol 12-myristate 13-acetate upregulated phosphorylations of MEK and MAPK. Pretreatment with Fsk inhibited these phosphorylations. Protein kinase C inhibitors also suppressed MEK and MAPK phosphorylations. Moreover, Fsk induced phosphorylation of Raf-1 at serine-259. These results indicated that cAMP inhibited Epo-induced MAPK activation and that this suppression might be regulated upstream or at Raf-1. The results also suggested that these agents, which could accumulate cAMP, might be protective for Epo-stimulated direct action.
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PMID:Modulation of the erythropoietin-induced proliferative pathway by cAMP in vascular smooth muscle cells. 1241 9

Type I interferons (IFNs), pleiotropic cytokines with antiviral, antiproliferative, apoptotic, and immunoregulatory functions, are efficacious in the treatment of malignancies, viral infections, and autoimmune diseases. Binding of these cytokines to their cognate receptor leads to activation of the Jak-signal transducers and activators of transcription (STAT) signaling pathway and altered gene expression. This signal pathway has been intensely studied using human IFN-alpha 2 and IFN-beta. However, there are over 14 human IFN-alpha subtypes and over 10 murine IFN-alpha subtypes, with a single IFN-beta subtype in both species. J2E cells are immortalized at the proerythroblast stage of development and produce a rapid and fatal erythroleukemia in vivo. These cells retain the ability to respond to erythropoietin in vitro by proliferating, differentiating, and remaining viable in the absence of serum. Here, we show that J2E cells are also functionally regulated differentially by IFN subtype treatment in vitro. A novel finding was the selective activation of STAT and mitogen-activated protein kinase (MAPK) molecules by different subtypes binding the IFN receptor. These findings indicate distinct effects for individual type I IFN subtypes, which are able to differentially activate members of the STAT and MAPK family. Finally, we investigated the efficacy of IFN naked DNA therapy in treating J2E-induced erythroleukemia in athymic nude mice. IFN subtypes differentially regulated the onset of erythroleukemia with delayed onset and increased survival, possibly via a reduction in cell viability, and enhanced antiproliferative and apoptotic effects observed for IFNA6 and IFNA9 treatment, respectively. Moreover, these data highlight the necessity to choose the best IFN subtype in disease treatment.
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PMID:Type I interferon differential therapy for erythroleukemia: specificity of STAT activation. 1244 59

We studied the effects of cyclosporin A (CsA) on the erythroid differentiation of human erythroid leukemia cell line K562. After K562 was treated with CsA for 4 days, the percentage of hemoglobinized cells was increased by 3.3 times. Because it was reported p38 MAPK (p38) and ERK are involved in erythropoietin-induced erythroid differentiation, we studied their roles using specific inhibitors. p38 inhibitor (SB203580) prevented CsA-induced hemoglobin synthesis in K562 cells, although MEK/ERK inhibitor (U0126) enhanced it by 3.3 times in K562 cells. These results indicate activation of p38 and inactivation of ERK are involved in CsA-induced erythroid differentiation of K562 cells.
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PMID:Cyclosporin A induces erythroid differentiation of K562 cells through p38 MAPK and ERK pathways. 1250 71

We have recently shown that a heterotrimeric G(i) protein is coupled to the erythropoietin (Epo) receptor. The G(i) protein constitutively associates in its heterotrimeric form with the intracellular domain of Epo receptor (EpoR). After Epo stimulation G(i) is released from the receptor and activated. In the present study we have investigated the functional role of the heterotrimeric G(i) protein bound to EpoR. In Chinese hamster ovary cells expressing EpoR, the G(i) inhibitor pertussis toxin blocked mitogen-activated protein kinase (MAPK) Erk1/2 activation induced by Epo. Epo-dependent MAPK activation was also sensitive to the G beta gamma competitive inhibitor beta ARK1-ct (C-terminal fragment of the beta-adrenergic receptor kinase), to the Ras dominant negative mutant RasN17, and to the phosphoinositide 3-kinase (PI3K) inhibitor LY 294002. A region of 7 amino acids (469-475) in the C-terminal end of EpoR was shown to be required for G(i) binding to EpoR in vivo. Deletion of this region in EpoR abolished both MAPK and PI3K activation in response to Epo. We conclude that in Chinese hamster ovary cells, Epo activates MAPK via a novel pathway dependent on G(i) association to EpoR, G beta gamma subunit, Ras, and PI3K. The tyrosine kinase Jak2 also contributes to this new pathway, more likely downstream of beta gamma and upstream of Ras and PI3K. This pathway is similar to the best characterized pathway used by seven transmembrane receptors coupled to G(i) to activate MAPK and may cooperate with other described Epo-dependent MAPK activation pathways in hematopoietic cells.
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PMID:Activation of the mitogen-activated protein kinases Erk1/2 by erythropoietin receptor via a G(i )protein beta gamma-subunit-initiated pathway. 1253 95

There have been conflicting reports regarding the role of p38 mitogen-activated protein kinase (MAPK) in the regulation of differentiation, proliferation and apoptosis in erythroid cell lines. We have, therefore, examined the functions of this kinase in primary human erythroid progenitors. Cells in steady-state culture showed low-level p38 MAPK activity, which decreased further within 1 h of growth factor withdrawal and increased over a limited range within minutes of re-exposure of cells to erythropoietin or stem cell factor, demonstrating the link between low-level p38 MAPK activity and the prevailing growth factor milieu. Use of the p38 MAPK-specific inhibitor SB203580 demonstrated that this level of activity was necessary for (1) optimal proliferation, (2) erythroid burst-forming unit migration and (3) full upregulation of E-cadherin and CD36 expression, but not haemoglobin A or glycophorin A expression, during human erythroid differentiation. In contrast, cells deprived of growth factors for an 8-h period, following a transient decrease in p38 MAPK activity, demonstrated sustained, substantial and caspase-independent increases in p38 MAPK activity, and its blockade using SB203580 reduced the proportion of erythroblasts undergoing apoptosis by 40 +/- 7%, demonstrating a role for p38 MAPK in apoptosis induction in human erythroblasts. Thus, in primary human erythroblasts, different environmental conditions induce different levels of p38 MAPK activity, which have distinct functions.
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PMID:Different levels of p38 MAP kinase activity mediate distinct biological effects in primary human erythroid progenitors. 1261 25

We have shown that Fv2, the Friend virus susceptibility 2 locus, encodes a naturally occurring amino-terminally truncated form of the STK receptor tyrosine kinase (Sf-Stk). Sf-Stk appears to interact with the viral glycoprotein gp55 and drive erythropoietin (Epo)-independent expansion of Friend virus-infected erythroblasts. Presumably, Sf-Stk provides signals that cooperate with EpoR signaling to induce the polyclonal expansion of infected cells. In this report, we show that macrophage-stimulating protein (MSP), the ligand for full-length STK, can also cooperate with Epo to enhance burst-forming units-erythroid (BFU-E) formation. To evaluate the signals induced by MSP/STK in primary erythroid progenitor cells, we adapted a method for the expansion of murine bone marrow mononuclear cells. The expanded progenitor cells express STK and respond to MSP in a colony assay. Furthermore, we demonstrate that low doses of MSP and Epo stimulation of the expanded cells cooperate to induce the phosphorylation of MAP kinase. Using the MEK inhibitor PD98059, we show that the activation of ERK is required for the enhanced BFU-E formation in response to MSP. These findings suggest that MSP has the ability to enhance erythroid colony formation in response to Epo, and that this response is dependent on the ability of MSP to induce the MAP kinase pathway.
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PMID:Macrophage-stimulating protein cooperates with erythropoietin to induce colony formation and MAP kinase activation in primary erythroid progenitor cells. 1280 76

Improving the ability of the kidney to tolerate ischemic injury has important implications. We investigated the effect of recombinant human erythropoietin (rHuEPO) treatment on subsequent ischemia/reperfusion (I/R) injury and evaluated the role of heat shock protein (HSP) 70 in rHuEPO-induced renal protection. rHuEPO (3000 U/kg) was administered 24 h before I/R injury, and rats were killed at 24, 48, and 72 h after I/R injury. Pretreatment of rHuEPO resulted in the following: i) decreased serum creatinine level; ii) decreased tubular cell apoptosis and necrosis, measured by DNA fragmentation analysis and TUNEL staining and histomorphological criteria; iii) decreased tubular cell proliferation as determined by proliferating cell nuclear antigen expression; iv) increased bcl-2 protein and decreased caspase 3 activity; and v) decreased JNK expression. rHuEPO treatment increased HSP70 expression in a dose-dependent manner in normal rat kidneys, and inhibition of HSP70 expression by quercetin eliminated the renoprotective effect of rHuEPO in ischemic kidneys. Our study demonstrates that rHuEPO has a protective effect on subsequent I/R injury and that this effect is associated with induction of HSP70. Our study provides a new avenue for therapy to prevent renal damage after I/R injury.
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PMID:Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. 1295 99

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation of bone marrow granulocytic progenitor cells and promotes their differentiation into granulocytes. G-CSF is therefore an important component of immune defense against pathogenic microorganisms: recombinant human G-CSF (rhG-CSF) is used to treat patients with a variety of neutropenias. In the present study, we screened approximately 10 000 small nonpeptidyl compounds and found 3 small compounds that mimic G-CSF in several in vitro and in vivo assays. These compounds induced G-CSF-dependent proliferation, but had no effect on interleukin-3-dependent, interleukin-2-dependent, interleukin-10-dependent, thrombopoietin (TPO)-dependent, or erythropoietin (EPO)-dependent proliferation. Each compound induced the phosphorylation of signal transducers and activators of transcription-3 (STAT3) and mitogen-activated protein kinase (MAPK) in a G-CSF-dependent cell line and in human neutrophils. In addition, these compounds induced hematopoietic colony formation from primary rat bone marrow cells in vitro. When subcutaneously injected into normal rats, they caused an increase in peripheral blood neutrophil counts. Furthermore, when they were administered to cyclophosphamide-induced neutropenic rats, blood neutrophil levels increased and remained elevated up to day 8. We therefore suggest that these small nonpeptidyl compounds mimic the activity of G-CSF and may be useful in the treatment of neutropenic patients.
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PMID:A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor. 1451 4

Binding of erythropoietin to the erythropoietin receptor (EpoR) extracellular domain orients the transmembrane (TM) and cytosolic regions of the receptor dimer into an unknown activated conformation. By replacing the EpoR extracellular domain with a dimeric coiled coil, we engineered TM EpoR fusion proteins where the helical TM domains were constrained into seven possible relative orientations. We identify one dimeric TM conformation that imparts full activity to the cytosolic domain of the receptor and signals via JAK2, STAT proteins, and MAP kinase, one partially active orientation that preferentially activates MAP kinase, and one conformation corresponding to the inactive receptor. The active and inactive conformations were independently identified by computational searches for low-energy TM dimeric structures. We propose a specific EpoR-activated interface and suggest its use for structural and signaling studies.
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PMID:Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. 1463 81


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