Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friend virus is an acutely oncogenic retrovirus that causes erythroblastosis and polycythemia in mice. Previous studies suggested that the Friend virus oncoprotein, gp55, constitutively activates the erythropoietin receptor (EPOR), causing uncontrolled erythroid proliferation. Those studies showed that gp55 confers growth factor independence on an interleukin-3 (IL-3)-dependent cell line (Ba/F3) when the EPOR is coexpressed. Subsequently, we showed that a truncated form of the stem-cell kinase receptor (sf-STK) is required for susceptibility to Friend disease. Given the requirement for sf-STK, we sought to establish the in vivo significance of gp55-mediated activation of the EPOR. We found that the cytoplasmic tyrosine residues of the EPOR, and signal transducer and activator of transcription-5 (STAT5), which acts through these sites, are not required for Friend virus-induced erythroblastosis. The EPOR itself was required for the development of erythroblastosis but not for gp55-mediated erythroid proliferation. Interestingly, the murine EPOR, which is required for gp55-mediated Ba/F3-cell proliferation, was dispensable for erythroblastosis in vivo. Finally, gp55-mediated activation of the EPOR and STAT5 are required for Friend virus-induced polycythemia. These results suggest that Friend virus activates both sf-STK and the EPOR to cause deregulated erythroid proliferation and differentiation.
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PMID:Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia. 1617 61

Myelodysplastic syndromes (MDS) are characterized by refractory cytopenias due to ineffective hematopoiesis in the marrow. Cytokines play an important role in the regulation of hematopoiesis; dysregulation of their levels can lead to hematopoietic failure. Considerable evidence implicates tumor necrosis factor alpha, transforming growth factor beta, interferons, interleukin 1beta, vascular endothelial growth factor (VEGF), and other inhibitory cytokines in the pathogenesis of MDS. These cytokines are produced by the interactions between the MDS clone and the bone marrow microenvironment. Therapeutic strategies therefore may augment the action of stimulatory growth factors or disrupt the effects of myelosuppressive cytokines. Erythropoietin alone and in combination with low-dose granulocyte colony-stimulating factor can lead to erythroid responses in selected patients. Agents targeting inhibitory cytokines include thalidomide, lenalidomide, etanercept, infliximab, VEGF receptor inhibitor PTK-787, antithymocyte globulin, and SCIO-469, a p38 mitogen-activated protein kinase inhibitor. Given the biologic heterogeneity of MDS, no single treatment is effective for all patients with the disease. With more detailed knowledge of cytokine signaling cascades, coupled with technological improvements in genomics and proteomics, the future treatment of this challenging disease may lie in combination therapies customized for relevant biologic effectors.
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PMID:Cytokine targets in the treatment of myelodysplastic syndromes. 1623 78

Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is generally reversible. However, there is evidence that MMC may also cause a late-stage or residual bone marrow injury. The present study in female CD-1 mice investigated the haematological and bone marrow changes induced by MMC in a repeat dose study lasting 50 days. Control and MMC-treated mice were dosed intraperitoneally on eight occasions over 18 days with vehicle, or MMC at 2.5 mg/kg, autopsied (n = 6-12) at 1, 7, 14, 28, 42 and 50 days after the final dose and haematological changes investigated. Femoral nucleated bone marrow cell counts and levels of apoptosis were also evaluated and clonogenic assays carried out; serum levels of FLT3 ligand (FL) were assessed. At day 1 post-dosing, MMC induced significant reductions in RBC, Hb and haematocrit (HCT) values, and there were decreases in reticulocyte, platelet, and femoral nucleated cell counts (FNCC); neutrophil, lymphocyte and monocyte values were also significantly reduced. On days 7 and 14 post-dosing, all haematological parameters showed evidence of a return towards normal values, but at these times, and at day 28, values for RBC and FNCC remained significantly reduced in comparison with controls. At days 42 and 50 post-dosing, many haematological parameters in MMC-treated mice had returned to control levels; however, there remained evidence of late-stage effects on RBC, Hb and HCT values, and FNCC also continued to be significantly decreased. Results for granulocyte-macrophage colony-forming units and erythroid colonies showed a profound decrease immediately post-dosing, but a return to normal values was evident at day 50. Serum FL concentrations demonstrated very significant increases in the immediate post-dosing period, but a return to normal was seen at day 50 post-dosing; a relatively similar pattern was seen in the number of apoptotic femoral marrow nucleated cells. The histopathological examination of kidney tissues from MMC animals at day 42 and 50 post-dosing showed evidence of hydronephrosis with cortical glomerular/tubular atrophy and degeneration. It is therefore concluded that MMC administered on eight occasions over 18 days to female CD-1 mice at 2.5 mg/kg induced profound changes in haematological and bone marrow parameters in the immediate post-dosing period with a return to normal levels at day 50 post-dosing; however, there was evidence of mild but significant late-stage/residual effects on RBC and FNCC, and on cells of the erythroid lineage in the bone marrow.
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PMID:The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse. 1630 46

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production. Most patients with PV harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. With the use of an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from patients with PV harboring the JAK2 V617F mutation were able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts on CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIP(short), a potent cellular inhibitor of death receptor-induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with the inhibition of death receptor signaling, possibly contributing to a deregulation of erythropoiesis.
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PMID:Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. 1638 30

Nuclear factor erythroid 2-related factor (Nrf2) confers protection against cell death induced by hyperoxia and other proapoptotic stimuli. Because phosphoinositide-3-kinase (PI3K)/Akt signaling promotes cell survival, the significance of this pathway in mediating reactive oxygen species (ROS)-dependent hyperoxia-induced Nrf2 activation was investigated in the murine pulmonary epithelial cell line, C10. Inhibition of the PI3K pathway markedly attenuated hyperoxia-induced Nrf2 translocation and ARE (antioxidant response element)-mediated transcription. Consistent with this, hyperoxia markedly stimulated the activation of PI3K pathway, while an NADPH oxidase inhibitor and an antioxidant prevented such activation. The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression. Moreover, overexpression of a dominant-negative Akt mutant attenuated the transcription, whereas a constitutively active mutant stimulated it. These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia. Inhibition of the PI3K pathway prevented hyperoxia-stimulated Akt and ERK1/2 kinase activation, which is critical for Nrf2-mediated transcription. Likewise, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, blocked hyperoxia-stimulated Akt and ERK1/2 phosphorylation, Nrf2 nuclear accumulation, and ARE-driven transcription. Consistent with this result, an NADPH oxidase inhibitor blocked hyperoxia- stimulated EGFR phosphorylation, which was correlated with the attenuation of Akt and ERK activation. Collectively, our data suggest that EGFR-PI3K signaling through Akt and ERK kinases regulates ROS-dependent, hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.
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PMID:Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. 1648 36

Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
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PMID:Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. 1649 68

Normal erythropoiesis critically depends on the balance between the renewal of precursor cells and their differentiation. If the renewal phase is shortened, the decrease in the precursor pool results in anemia; conversely, impaired differentiation increases the number of proliferating progenitors and the potential risk of leukemic transformation. Using gene ablation, we have discovered 2 self-sustaining signal transduction loops that antagonize each other and regulate erythroid progenitor proliferation and differentiation, respectively. We identify Raf-1 as the main activator of the MEK/ERK cascade and as the key molecule in maintaining progenitor proliferation. Differentiation, in contrast, is mediated by Fas via the activation of both the ASK1/JNK/p38 module and the caspase cascade. The point of convergence between the 2 cascades is activated ERK, which positively feeds back on the proliferation pathway by maintaining the expression of Raf-1, while inhibiting the expression of Fas and therefore differentiation. In turn, Fas, once expressed, antagonizes proliferation by exerting a negative feedback on ERK activation and Raf-1 expression. Simultaneously, Fas-mediated caspase activation precipitates differentiation. These results identify Raf-1 and Fas as the key molecules whose expression finely tunes erythropoiesis and the extent of ERK activation as the switch that tips the balance between them.
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PMID:A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation. 1652 94

A novel family of proteins, the Mep/AMT/Rh glycoprotein family may mediate important roles in transmembrane ammonia transport in a wide variety of single-celled and multicellular organisms. Results from our laboratory have examined the expression of the non-erythroid proteins, Rh B Glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg), in a wide variety of mammalian tissues. In the kidney, Rhbg and Rhcg are present in distal nephron sites responsible for ammonia secretion. In the mouse kidney, Rhbg immunoreactivity is exclusively basolateral and Rhcg immunoreactivity is exclusively apical, whereas in the rat kidney Rhcg exhibits both apical and basolateral expression. Chronic metabolic acidosis increases Rhcg expression in the outer and inner medulla of the rat kidney; these changes, at least in the outer medullary collecting duct, involve changes in total cellular protein expression in both principal and intercalated cell and changes in its subcellular localization. In the liver, Rhbg is present in the basolateral plasma membrane of the perivenous hepatocyte and Rhcg is present in bile duct epithelia. In the gastrointestinal tract, Rhbg and Rhcg exhibit cell-specific, axially heterogeneous, and polarized expression. These patterns of expression are consistent with Rhbg and Rhcg mediating important roles in mammalian ammonia biology. The lack of the effect of chronic metabolic acidosis on Rhbg expression raises the possibility that Rhbg may function either as ammonia sensing-protein or that it may mediate roles other than ammonia transport.
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PMID:Expression of the non-erythroid Rh glycoproteins in mammalian tissues. 1656 23

Rh (Rhesus) is a major blood group system in man, which is clinically significant in transfusion medicine. Rh antigens are carried by an oligomer of two major erythroid specific polypeptides, the Rh (D and CcEe) proteins and the RhAG glycoprotein, that shared a common predicted structure with 12 transmembrane a-helices (M0 to M11). Non erythroid homologues of these proteins have been identified (RhBG and RhCG), notably in diverse organs specialized in ammonia production and excretion, such as kidney, liver and intestine. Phylogenetic studies and experimental evidence have shown that these proteins belong to the Amt/Mep/Rh protein superfamily of ammonium/methylammonium permease, but another view suggests that Rh proteins might function as CO2 gas channels. Until recently no information on the structure of these proteins were available. However, in the last two years, new insight has been gained into the structural features of Rh proteins (through the determination of the crystal structures of bacterial AmtB and archeaebacterial Amt-1. Here, models of the subunit and oligomeric architecture of human Rh proteins are proposed, based on a refined alignment with and crystal structure of the bacterial ammonia transporter AmtB, a member of the Amt/Mep/Rh superfamily. This alignment was performed considering invariant structural features, which were revealed through Hydrophobic Cluster Analysis, and led to propose alternative predictions for the less conserved regions, particularly in the N-terminal sequences. The Rh models, on which an additional Rh-specific, N-terminal helix M0 was tentatively positioned, were further assessed through the consideration of biochemical and immunochemical data, as well as of stereochemical and topological constraints. These models highlighted some Rh specific features that have not yet been reported. Among these, are the prediction of some critical residues, which may play a role in the channel function, but also in the stability of the subunit structure and oligomeric assembly. These results provide a basis to further understand the structure/function relationships of Rh proteins, and the alterations occurring in variant phenotypes.
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PMID:Hydrophobic cluster analysis and modeling of the human Rh protein three-dimensional structures. 1658 6

The Rhesus (Rh) blood group system is expressed by a pair of 12-transmembrane-domain-containing proteins, the RhCcEe and RhD proteins. RhCcEe and RhD associate as a Rh core complex that comprises one RhD/CcEe protein and most likely two Rh-associated glycoproteins (RhAG) as a trimer. All these Rh proteins are homologous and share this homology with two human non-erythroid proteins, RhBG and RhCG. All Rh protein superfamily members share homology and function in a similar manner to the Mep/Amt ammonium transporters, which are highly conserved in bacteria, plants and invertebrates. Significant advances have been made in our understanding of the structure and function of Rh proteins, as well as in the clinical management of Rh haemolytic disease. This review summarises our current knowledge concerning the molecular biology of Rh proteins and their role in transfusion and pregnancy incompatibility.
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PMID:Molecular biology of Rh proteins and relevance to molecular medicine. 1676 38


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