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)

Erythropoietin (EPO) can rescue erythroid cells from apoptosis during erythroid development, leading to red cell production. However, the detailed mechanism of how EPO protects erythroid cells from apoptosis is still open to question. To address this problem, we used a human EPO-dependent leukemia cell line UT-7/EPO and normal erythroid progenitor cells. After deprivation of EPO, UT-7/EPO cells underwent apoptosis, accompanied by down-regulation of the Bcl-xL protein. In addition, the cleaved products of caspase-3, p11 and p21, and a few cleaved forms of inhibitor of caspase-activated DNase (ICAD) were detected in these cells. When the cells were pre-treated with the pancaspase inhibitor Z-VAD-FMK, the ratio of apoptotic cells was significantly reduced, suggesting that EPO protects the UT-7/EPO cells from apoptosis via inhibition of caspase activities. When an MEK 1/2 inhibitor U0126 inhibited activities of extracellular signal-regulated kinases (ERKs), the expression of Bcl-xL protein was down-regulated and subsequently apoptosis was induced. Interestingly, Z-VAD-FMK blocked U0126-induced down-regulation of Bcl-xL protein and apoptosis, strongly suggesting that Bcl-xL expression is regulated by caspases which lies downstream of ERK activation pathway in EPO signaling. Importantly, these findings were also observed in normal erythroid progenitor cells. In conclusion, the activation of ERKs by EPO up-regulates Bcl-xL expression via inhibition of caspase activities, resulting in the protection of erythroid cells from apoptosis.
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PMID:Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling. 1265 55

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

Increases in fetal hemoglobin have been identified after birth in several clinical settings associated with stressed or malignant erythropoiesis. To better understand the relationship between the expression of this fetal protein and growth, donated human erythroid progenitor cells were cultured in the presence of erythropoietin (EPO) plus the growth-modifying cytokine stem cell factor (SCF), and several growth-related signaling pathways were interrogated. Only the MEK1/2 inhibitor (PD98059) demonstrated significant effects on fetal hemoglobin. In the absence of PD98059, levels of fetal hemoglobin averaged 27.4% +/- 7.9% in EPO+SCF compared with 1.26% +/- 1.7% in EPO alone (P =.02). A linear dose response in levels of fetal hemoglobin to PD98059 was detected (0.16 microM = 27.13%, 0.8 microM = 19.6%, 4 microM = 12.2%, 20 microM = 1.54%). Western blot analyses revealed that SCF was required for phosphorylation of MEK and p44MAPK in this setting, and quantitative polymerase chain reaction demonstrated a significant increase in gamma-globin mRNA. Particular perturbations of growth-related signaling may also function to activate tissue-specific genes normally expressed during fetal development. This concept may be relevant for the development of new treatment rationales for beta hemoglobinopathies.
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PMID:A signaling mechanism for growth-related expression of fetal hemoglobin. 1459 35

Making decisions between self-renewal and differentiation is a central ability of stem cells. Elucidation of molecular networks governing this decision is therefore of prime importance. A model of choice to explore this question is represented by chicken erythroid progenitors, in which self-renewal versus differentiation as well as progenitor maturation are regulated by external factor combinations. We used this system to study whether similar or different signalling pathways were involved in the self-renewal of early, immature or more mature erythroid progenitors. We show that a transforming growth factor (TGF)-alpha-activated Ras/MEK-1/ERK1/2 pathway is strictly required for immature self-renewing cells but becomes fully dispensable when those cells are induced to differentiate. Consequently, pharmacological inhibition of this pathway led to spontaneous differentiation, only dependent on the presence of survival signals. Conversely, ectopic expression of a constitutive form of MEK-1 stimulates renewal and arrests differentiation process. Finally, we demonstrate that the ERK/MAPK signalling pathway is required in early but not in late primary erythroid progenitors, which can be turned into each other by different growth factor combinations specifically driving their renewal. To the best of our knowledge, this is the first description of a central role of ERK/MAPK signalling in regulating progenitor plasticity in the same cell type under different environmental conditions.
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PMID:The MEK-1/ERKs signalling pathway is differentially involved in the self-renewal of early and late avian erythroid progenitor cells. 1468 80

K562 cells contain a Bcr-Abl chimeric gene and differentiate into various lineages in response to different inducers. We studied the role of the mitogen-activated protein kinase (MAPK) kinase 1 (MEK1)/extracellular signal-regulated kinase (ERK) pathway during the erythroid differentiation of K562 cells induced by tyrosine kinase inhibitors (herbimycin A or STI571), using genetically modified cells (constitutively MEK1-activated K562: K562/MEK1, and inducible ERK-inactivated K562: K562/CL100). Basal expression of glycophorin A was markedly reduced in K562/MEK1 cells compared with that in parental cells, while it was augmented in K562/CL100 cells. Herbimycin A and STI571 differentiated K562 cells accompanying with the transient down-regulated ERK. Moreover, the erythroid differentiation was markedly suppressed in K562/MEK1 cells, and early down-regulation of ERK activity was not observed in these cells. In contrast, the induction of ERK-specific phosphatase in K562/CL100 cells potentiated erythroid differentiation. Once the phosphatase was induced, the initial ERK activity became repressed and its early down-regulation by the inhibition of Bcr-Abl was marked and prolonged. These results demonstrate that the erythroid differentiation of K562 cells induced by herbimycin A or STI571 requires the down-regulation of MEK1/ ERK pathway.
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PMID:Inactivation of ERK accelerates erythroid differentiation of K562 cells induced by herbimycin A and STI571 while activation of MEK1 interferes with it. 1503 Jan 67

Oncogenic mutations in ras genes frequently occur in patients with myeloid disorders, and in these patients erythropoiesis is often affected. Previously, we showed that expression of oncogenic H-ras in purified mouse primary fetal liver erythroid progenitors blocks terminal erythroid differentiation and supports erythropoietin (Epo)-independent proliferation. As a first step in understanding the underlying molecular mechanisms we examined the signaling pathways downstream of Ras in primary erythroid cells. We found that 3 major pathways are abnormally activated by oncogenic H-ras: Raf/ERK (extracellular signal-regulated kinase), phosphatidyl inositol 3 (PI3)-kinase/Akt, and RalGEF/RalA. However, only constitutive activation of the MEK (MAPK [mitogen-activated protein kinase]/ERK kinase)/ERK pathway alone could recapitulate all of the effects of oncogenic H-ras expression in blocking erythroid differentiation and inducing Epo-independent proliferation. Although expression of a constitutively active Akt kinase (ca.Akt) in erythroid progenitors does not significantly affect erythroid differentiation in the presence of Epo, coexpression of ca.Akt together with a constitutively active MEK causes prolonged Epo-independent proliferation of erythroid progenitors in addition to a block in differentiation. Moreover, the effects of oncogenic H-ras expression on primary erythroid cells are blocked by the addition of U0126, a specific inhibitor of MEK1 and MEK2, allowing normal terminal erythroid proliferation and differentiation. Our data suggest that the interruption of constitutive MEK/ERK signaling is a potential therapeutic strategy to correct impaired erythroid differentiation in patients with myeloid disorders.
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PMID:Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. 1516 36

K562 cells can be induced to differentiate along the erythroid lineage by a variety of chemical compounds, including hemin, butyrate, cisplatin and ara-C. Differential signaling through MAP kinases has been suggested to be involved in this differentiation process. We have investigated the involvement of ERK activation/inhibition in hemin-, butyrate-, cisplatin- and ara-C-induced erythroid differentiation using the K562 cell line. ERK activity decreased for 2-4h after administration of either inducing agent. ERK was then activated by hemin and cisplatin, while ERK phosphorylation remained decreased during incubation with butyrate and ara-C. There was no activation of JNK or p38. The MEK-1 inhibitors UO126 or PD98059 induced erythroid differentiation in K562 cells and acted additively with butyrate. Inhibition of MEK-1 reduced the hemoglobin accumulation by hemin and cisplatin; erythroid differentiation by ara-C was unchanged. The results suggest that inhibition of signaling through ERK in K562 cells may be needed to enter the erythroid differentiation process, while after initiation both activation and inhibition of signaling through ERK enhance erythroid differentiation, which, however, is dependent on the inducing compound.
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PMID:ERK signaling pathway is differentially involved in erythroid differentiation of K562 cells depending on time and the inducing agent. 1519 84

K562 cells can be used as a model of erythroid differentiation on being induced by hemin. We found that the level of annexin1 gene expression was notably increased during this indicated process. To test the hypothesis that annexin1 can regulate erythropoiesis, K562 cell clones in which annexin1 was stably increased and was knocked down by RNAi were established, respectively. With analysis by hemoglobin quantification, benzidine staining, and marker gene expression profile determination, we confirmed that hemin-induced erythroid differentiation of K562 cells was modestly stimulated by overexpression of annexin1 while it was significantly blocked by knock down of annexin1. Further studies revealed that the mechanisms of annexin1 regulation of the erythroid differentiation was partially related to the increased ERK phosphorylation and expression of p21(cip/waf), since specific inhibitor of MEK blocked the function of annexin1 in erythroid differentiation. We concluded that annexin1 exerted its erythropoiesis regulating effect by ERK pathway.
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PMID:Annexin1 regulates the erythroid differentiation through ERK signaling pathway. 1588 23

Fetal hemoglobin (HbF) induction is an effective approach to improve clinical symptoms in sickle cell disease. Understanding molecular mechanisms for gamma-gene re-activation will aid efforts to design lead compounds. A potential inhibitory role for the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway in gamma-gene expression has been suggested recently. Therefore, we determined the ability of U0126, a selective inhibitor of MEK1/2 the upstream activators of ERK, to re-activate gamma-globin expression. K562 stable lines over-expressing constitutively active MEK1 were established. A significant increase in ERK phosphorylation was observed and gamma-gene expression was silenced concomitantly, however U0126 attenuated this effect. Studies in human erythroid progenitors confirmed the ability of U0126 to induce HbF. Cellular mechanisms for the inhibitory role of ERK signaling in drug-mediated HbF induction will be discussed.
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PMID:Erk pathway inhibitor U0126 induces gamma-globin expression in erythroid cells. 1617 57

Members of the mitogen-activated protein kinase (MAPK) family, including Jun amino-terminal kinase (JNK) and extracellular signal-related kinase (ERK), play an important role in the proliferation of erythroid cells in response to erythropoietin (Epo). Erythroid cells infected with the Friend spleen focus-forming virus (SFFV) proliferate in the absence of Epo and show constitutive activation of Epo signal transduction pathways. We previously demonstrated that the ERK pathway was constitutively activated in Friend SFFV-infected erythroid cells, and in this study JNK is also shown to be constitutively activated. Pharmacological inhibitors of both the ERK and JNK pathways stopped the proliferation of primary erythroleukemic cells from Friend SFFV-infected mice, with little induction of apoptosis, and furthermore blocked their ability to form Epo-independent colonies. However, only the JNK inhibitor blocked the proliferation of erythroleukemia cell lines derived from these mice. The JNK inhibitor caused significant apoptosis in these cell lines as well as an increase in the fraction of cells in G(2)/M and undergoing endoreduplication. In contrast, the growth of erythroleukemia cell lines derived from Friend murine leukemia virus (MuLV)-infected mice was inhibited by both the MEK and JNK inhibitors. JNK is important for AP1 activity, and we found that JNK inhibitor treatment reduced AP1 DNA-binding activity in primary erythroleukemic splenocytes from Friend SFFV-infected mice and in erythroleukemia cell lines from Friend MuLV-infected mice but did not alter AP1 DNA binding in erythroleukemia cell lines from Friend SFFV-infected mice. These data suggest that JNK plays an important role in cell proliferation and/or the survival of erythroleukemia cells.
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PMID:Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells. 1618 78


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