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)

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are a group of kinases that play an important role in proliferation and differentiation. In megakaryocyte-like human erythroleukemia (HEL) cells, ERK2 was found to be predominantly expressed and strongly activated by prostaglandin (PG) E(2), thrombin, and epinephrine. On the other hand, adenosine, ADP, ATP, and UTP did not significantly increase ERK1/2 phosphorylation. However, of the agonists tested, only ADP was able to stimulate thymidine uptake. Pretreatment with pertussis toxin abolished the PGE(2) response but had less of an effect on thrombin. PGE(2)- and thrombin-induced ERK1/2 activation was mimicked by 4-beta-phorbol-12-myristate-13-acetate and ionomycin and blocked by mitogen-activated protein kinase kinase inhibitor 1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene but displayed differential sensitivity to protein kinase C inhibitor bisindolylmaleimide I and Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Analogs of cAMP or agents that stimulate cAMP production were either weak or ineffective activators. Further studies indicate that the effect of thrombin was blocked by the phosphoinositide 3-kinase inhibitor wortmannin but not by agents inhibiting tyrosine kinase activity. On the contrary, herbimycin, but not wortmannin, attenuated the effect of PGE(2). Collectively, these results indicate that ERK1/2 are selectively activated by G protein-coupled receptors and not functionally associated with proliferation in HEL cells. ERK1/2 activation in response to PGE(2) and thrombin is mediated by distinctive types of G proteins and is differentially regulated by multiple pathways, including calcium mobilization, protein kinase C, phosphoinositide 3-kinase, and tyrosine kinases.
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PMID:Extracellular signal-regulated kinases and g protein-coupled receptors in megakaryocytic human erythroleukemia cells: selective activation, differential regulation, and dissociation from mitogenesis. 1175 34

The proto-oncogene c-Jun has been implicated in the control of cell proliferation and differentiation and more recently in the regulation of apoptosis. We have previously reported the involvement of c-Jun in the erythroid differentiation block in murine erythroleukemia (MEL) cells. As reported here, we investigated the role of c-Jun in the regulation of terminal differentiation and apoptosis of MEL cells by studying different stable transfectant clones containing c-jun constructs in sense or antisense orientation. c-Jun did not prevent cell growth arrest in G0/G1 and p21 induction that are normally associated with terminal differentiation induced by DMSO treatment, suggesting that c-Jun may uncouple phenotypic differentiation and terminal cell division in the MEL cell system. Spontaneous apoptosis was accelerated in c-jun expressing MEL cells before and after DMSO treatment. Moreover, c-Jun sensitized apoptosis induced by various drugs. Drug-induced apoptosis was associated with c-Jun N-terminal kinase (JNK) activation and c-Jun N-terminal phosphorylation (JNP). In contrast, overexpression of c-jun delayed apoptosis in serum-starved cells, indicating that c-Jun may reduce or accelerate apoptosis in MEL cells depending on the nature of the apoptotic stimulus. These results suggest that the proto-oncogene c-Jun may modulate differentiation and apoptosis of leukemic cells.
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PMID:C-Jun modulates apoptosis but not terminal cell differentiation in murine erythroleukemia cells. 1184 Feb 90

During the initial stage of Friend virus-induced erythroleukemia in mice, interaction of the viral protein gp55 with the erythropoietin receptor, and other host factors, drives the expansion of erythroid precursor cells. Recently, we demonstrated that the Friend virus susceptibility locus, Fv2, which is required for the expansion of infected cells, encodes a naturally occurring, N-terminally truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Here we show that in vitro expression of Sf-Stk confers Friend virus sensitivity to erythroid progenitor cells from Fv2(rr) mice. Furthermore, our data reveal that Sf-Stk kinase activity and Y436, but not Y429, are required for Epo-independent colony formation following Friend virus infection. Introduction of a mutation that results in failure to bind Grb2 abrogates the ability of Sf-Stk to induce colonies in response to Friend virus, while the Grb2 binding site from EGFR restores this response. Consistent with the ability of Grb2 to recruit SOS and Gab1, the Ras/MAPK and PI3K pathways are activated by Sf-Stk, and both of these pathways are required for gp55-mediated erythroblast proliferation. These data clearly demonstrate a requirement for signaling through Sf-Stk in the Epo-independent expansion of Friend virus-infected cells, and suggest a pivotal role for Grb2 in this response.
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PMID:Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus. 1203 58

The aim of this study was to identify key genes whose expression is altered by heme and heme deficiency in the human erythroleukemia K562 cells and in the NGF-induced rat pheochromocytoma neuronal PC12 cells, respectively. By quantitative RT-PCR, Northern blotting, and Western blotting analyses, we found that the expression of the CDK inhibitors p18 and p21 was upregulated at the early and late stages of heme-induced erythroid differentiation of K562 cells, respectively, while the expression of cyclin D1 was downregulated. Data from succinyl acetone and desferrioxamine treatments suggest that these effects of heme in K562 cells were specific. Further, by microarray expression analysis, we found that inhibition of heme synthesis by succinyl acetone in NGF-induced PC12 cells drastically altered the expression of several groups of important neuronal genes, including the structural genes encoding neurofilament proteins and synaptic vesicle proteins, regulatory genes encoding signaling components beta-arrestin and p38 MAPK, and stress-response genes encoding hsp70. These results show that heme and heme deficiency affect the expression of diverse genes in a cell-type specific manner in mammalian cells, and that heme, although needed at different levels, is critical for both erythropoiesis and neurogenesis. These studies provide insights into how heme may act to control diverse regulatory processes in mammals.
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PMID:An examination of heme action in gene expression: heme and heme deficiency affect the expression of diverse genes in erythroid k562 and neuronal PC12 cells. 1204 72

While investigating the ability of p38 MAPK to regulate cytarabine (Ara C)-dependent differentiation of erythroleukemia K562 cells, we observed effects that indicated that the imidazoline class of p38 MAPK inhibitors prevented nucleoside transport. Incubation of K562 cells with SB203580, SB203580-iodo, or SB202474, an analogue of SB203580 that does not inhibit p38 MAPK activity, inhibited the uptake of [3H]Ara C or [3H]uridine and the differentiation of K562 cells. Consistent with the effects of these compounds on the nitrobenzylthioinosine (NBMPR)-sensitive equilibrative nucleoside transporter (ENT1), incubation with SB203580 or SB203580-iodo eliminated the binding of [3H]NBMPR to K562 cells or membranes isolated from human erythrocytes. Furthermore, using a uridine-dependent cell type (G9c), we observed that SB203580 or SB203580-iodo efficiently inhibited the salvage synthesis of pyrimidine nucleotides in vivo. Thus these studies demonstrate that the NBMPR-sensitive equilibrative nucleoside transporters are novel and unexpected targets for the p38 MAPK inhibitors at concentrations typically used to inhibit protein kinases.
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PMID:Inhibition of nucleoside transport by p38 MAPK inhibitors. 1207 12

Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-alpha). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-alpha, and exogenously added TNF-alpha induced proliferation of HCD57 cells. EPO also could induce TNF-alpha expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-alpha activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-alpha neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-alpha in either an EPO-dependent or constitutive manner. However, TNF-alpha had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-alpha may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-alpha expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-alpha in normal erythropoiesis.
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PMID:Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia. 1239 29

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

RON (Receptuer d'Origine Nantaise) is a member of the MET receptor tyrosine kinase family. RON is expressed in various cell types including macrophages, epithelial and hematopoietic cells. Its ligand, macrophage stimulating protein (MSP, also known as hepatocyte growth factor-like protein), is a multifunctional factor regulating cell growth and survival, adhesion and motility, cytokine production and phagocytosis. Accumulated data indicate that in addition to the regulation of normal cell functions, RON can be involved in cancer development and progression: (i). RON is overexpressed and constitutively active in some primary tumors and tumor cell lines; (ii). experimental mutations of RON cause oncogenic cell transformation, and (iii). RON mediates susceptibility to Friend-virus-induced erythroleukemia in mice. Constitutive activation of intracellular signaling pathways such as the PI-3 kinase/AKT, beta-catenin, MAPK and JNK pathways may underlie the molecular mechanism of RON-mediated oncogenic cell transformation. The present review describes RON-activated signaling pathways, which may play an important role in tumor formation and metastasis.
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PMID:Oncogenic signaling pathways activated by RON receptor tyrosine kinase. 1257 Jun 59

A mouse IgG(1)-producing hybridoma, CSC-31, was isolated and characterized. The monoclonal antibody (MAb) was originally raised against monkey kidney cell-surface molecules. FACS analysis further showed that CSC-31 exhibited broad tissue and species reactivity. Although most human T- and B-cell lines failed to react with CSC-31, myeloid, and erythroleukemia cells lines such as THP-1 and K562 expressed the CSC-31 cell surface marker. Furthermore, in vitro differentiation of HL-60, U-937, and K562 showed that expression of the CSC-31 marker is associated with monocytic or megakaryocytic differentiation. However, up-regulation of the CSC-31 marker expression was not detected during granulocytic or erythroid differentiation. Through the in vitro differentiation of K562, it was demonstrated that up-regulation of the CSC-31 marker required novel PKCs and might be regulated by the MAPK signaling pathway. Last, limited biochemical analysis demonstrated that the CSC-31-specific epitope is sensitive to digestion by papain yet highly resistant to other proteases.
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PMID:Characterization of a pan-species reactive monoclonal antibody specific for a cell surface epitope which could serve as a marker for human monocytic and megakaryocytic differentiation. 1257 8

A novel protein kinase, polyploidy-associated protein kinase (PAPK), was isolated using a subtraction cDNA library approach from a mouse erythroleukemia cell line that had been induced to polyploidy after serum withdrawal. PAPK shares homology with members of the Ste20/germinal center kinase family of protein kinases and is ubiquitously expressed as two spliced forms, PAPK-A and PAPK-B, that encode for proteins of 418 and 189 amino acids, respectively. The expression of endogenous PAPK-A protein increased after growth factor withdrawal in murine hematopoietic and fibroblast cells. When tested in an in vitro kinase assay, PAPK-A was activated in response to the stress-inducing agent hydrogen peroxide and slightly by fetal calf serum. Biochemical characterization of the PAPK-A-initiated pathway revealed that this novel kinase does not affect MAP kinase activity but can stimulate both c-Jun N-terminal kinase 1 (JNK1) and ERK6/p38 gamma. The kinase activity of PAPK appears to be required for the activation of ERK6/p38 gamma but not JNK1. When an inducible construct of PAPK-A was expressed in stably transfected NIH3T3 cells, the cells exhibited distinct cytoskeletal changes and became resistant to apoptotic cell death induced by serum withdrawal, effects of PAPK that require its kinase activity. These data suggest that PAPK is a new member of the Ste20/germinal center kinase family that modulates cytoskeletal organization and cell survival.
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PMID:Identification and characterization of a novel Ste20/germinal center kinase-related kinase, polyploidy-associated protein kinase. 1257 63


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