UNIPROT:P04141 - FACTA Search

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We show in this report that the human myeloid leukemia cell line GFD8 is a useful model to compare the biological function of the structurally related c-Myb and B-Myb proto-oncogenes and to investigate the c-myb domains required for this function. GFD8 cells are dependent for growth on granulocyte-macrophage colony-stimulating factor and differentiate in response to phorbol myristate acetate (PMA). We have stably transfected this cell line with constructs constitutively expressing c-Myb or B-Myb. Deregulated expression of both c-Myb and B-Myb inhibited the differentiation observed in response to PMA and, in particular, the induction of the CD11b and CD11c antigens on the cell surface, and the induction of adherence. Furthermore, c-Myb and B-Myb enhanced expression of CD13 upon PMA treatment. Although deregulated Myb expression did not alter the growth factor dependence of the cells, it led to an increase in G2 relative to G1 arrest in cells induced to differentiate in response to PMA, whereas control vector-transfected cells were blocked mostly in G1. This decrease in G1 block took place despite normal induction of the cyclin-dependent kinase inhibitor protein p21 (CIP1/WAF1). Thus, GFD8 cells stably expressing the human B-Myb protein behaved in a manner indistinguishable from those stably expressing C-Myb for both differentiation and cell cycle parameters. In agreement with these findings and differently from most previous reports, transactivation assays show that B-myb can indeed act as a strong activator of transcription. Finally, we demonstrated that although the DNA-binding domain of c-myb is required for both the differentiation block and the shift in cell cycle after PMA treatment, phosphorylation by casein kinase II and mitogen-activated protein kinase at positions 11 and 12 or 532 of c-myb, respectively, are not. We conclude that c-Myb and B-Myb may activate a common cellular program in the GFD8 cell line involved in both differentiation and cell cycle control.
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PMID:Redundant functions of B-Myb and c-Myb in differentiating myeloid cells. 941 19

Cytokine-mediated inhibition of eosinophil apoptosis is a mechanism causing tissue eosinophilia. Previously published work suggested that activation of the Lyn-Ras-Raf-1-MAP kinase pathway is obligatory for prevention of eosinophil apoptosis by eosinophil hematopoietins. We demonstrate herein that activation of freshly isolated human blood eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased tyrosine phosphorylation of Jak2. The tyrosine kinase blocker, tyrphostin B42, prevented activation of Jak2 but not Lyn, suggesting that Jak2 is the specific target for tyrphostin B42 in eosinophils. In addition, since Lyn remained unaffected by tyrphostin B42, it is unlikely that Jak2 is required for Lyn activation in this model. To test whether tyrosine phosphorylation of Jak2 is linked to GM-CSF-mediated prolonged eosinophil survival, we determined the effect of tyrphostin B42 on eosinophil viability and apoptosis. Prevention of Jak2 activation by tyrphostin B42 was associated with the inability of GM-CSF to prevent eosinophil apoptosis. These data suggest that disruption of not only the Lyn-Ras-Raf-1-MAP kinase but also the Jak-STAT pathway blocks the ability of eosinophil survival factors to prevent apoptosis in eosinophils.
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PMID:Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. 946 45

RAFTK, a novel nonreceptor protein kinase, has been shown to be involved in focal adhesion signal transduction pathways in neuronal PC12 cells, megakaryocytes, platelets, and T cells. Because focal adhesions may modulate cytoskeletal functions and thereby alter phagocytosis, cell migration, and adhesion in monocyte-macrophages, we investigated the role of RAFTK signaling in these cells. RAFTK was abundantly expressed in THP1 monocytic cells as well as in primary alveolar and peripheral blood-derived macrophages. Colony-stimulating factor-1 (CSF-1)/macrophage colony-stimulating factor (M-CSF) stimulation of THP1 cells increased the tyrosine phosphorylation of RAFTK; similar increases in phosphorylation were also detected after lipopolysaccharide stimulation. RAFTK was phosphorylated with similar kinetics in THP1 cells and peripheral blood-derived macrophages. Immunoprecipitation analysis showed associations between RAFTK and the signaling molecule phosphatidylinositol-3 (PI-3) kinase. PI-3 kinase enzyme activity also coprecipitated with the RAFTK antibody, further confirming this association. The CSF-1/M-CSF receptor c-fms and RAFTK appeared to associate in response to CSF-1/M-CSF treatment of THP1 cells. Inhibition of RAFTK by a dominant-negative kinase mutant reduced CSF-1/M-CSF-induced MAPK activity. These data indicate that RAFTK participates in signal transduction pathways mediated by CSF-1/M-CSF, a cytokine that regulates monocyte-macrophage growth and function.
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PMID:The related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated and participates in colony-stimulating factor-1/macrophage colony-stimulating factor signaling in monocyte-macrophages. 957 36

Several lines of evidence indicate that estrogen inhibits parathyroid hormone (PTH)-induced bone resorption in vivo and in vitro. However, its precise mechanism remains unknown. The present study was performed to investigate whether osteoclast precursor cells possess the receptors for PTH/PTH-related protein (PTHrP) and/or estrogen and to clarify the mechanism by which estrogen affects PTH-induced osteoclast-like cell (Ocl) formation. The polymerase chain reaction (PCR) product corresponding in size to the mouse PTH/PTHrP receptor cDNA was detected in mouse hemopoietic blast cells supported by granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as in osteoblastic MC3T3-E1 cells. The nucleotide sequence of the PTH/PTHrP receptor PCR product of hemopoietic blast cells was found to be 95.4% identical to that of PTH/PTHrP receptor cDNA of rat osteoblastic ROS cells. The PCR product corresponding in size to the mouse estrogen receptor cDNA was detected in mouse hemopoietic blast cells supported by GM-CSF as well as in MC3T3-E1 cells. The nucleotide sequence of the estrogen receptor PCR product of hemopoietic blast cells was completely identical to that of mouse estrogen receptor cDNA. 17Beta-estradiol (17beta-E2) but not 17alpha-E2 dose dependently antagonized Ocl formation stimulated by human (h) PTH(1-34) at a minimal effective concentration of 10(-10) M in the hemopoietic blast cell culture. 17Beta-E2 also significantly inhibited Ocl formation stimulated by 10(-8) M hPTHrP(1-34), while it did not affect 1,25-dihydroxyvitamin D3-induced Ocl formation. However, 10(-8) M 17beta-E2 significantly inhibited Ocl formation stimulated by dibutyryladenosine cAMP (10(-4) M) and Sp-cAMPS (10(-4) M), an activator of cAMP-dependent protein kinase (PKA) as well as forskolin (10(-5) M). In contrast, 17beta-E2 did not affect Ocl formation by either phorbol myristate acetate (10(-7) M), an activator of protein kinase C (PKC), or A23187 (10(-7) M), a calcium ionophore. The pretreatment with 17beta-E2 significantly inhibited Ocl formation induced by the combined treatment with PTH and PKC inhibitors (H7 or staurosporine), while it did not affect Ocl formation stimulated by the combined treatment with PTH and Rp-cAMPS, a PKA inhibitor. The present data indicate that estrogen inhibits PTH-stimulated Ocl formation by directly acting on hemopoietic blast cells, possibly through blocking a PKA pathway but not a calcium/PKC pathway.
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PMID:Estrogen via the estrogen receptor blocks cAMP-mediated parathyroid hormone (PTH)-stimulated osteoclast formation. 961 Jul 50

The signal transduction pathways activated by tumor necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) that lead to priming of polymorphonuclear leukocytes (PMNs) are unknown. The hypotheses that these cytokines stimulate multiple mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), and p38 MAPK, and that these MAPKs participate in priming of human PMNs were examined. TNF-alpha stimulated a dose-dependent increase in ERK and p38 MAPK activities that was maximal at 10 min. JNKs were not stimulated by TNF-alpha or GM-CSF. GM-CSF stimulated ERK activity comparable to that of TNF-alpha, but GM-CSF was a less potent stimulus of p38 MAPK activity. The tyrosine kinase inhibitor, genistein, inhibited ERK and p38 MAPK stimulation by both cytokines. The phosphatidylinositol 3-kinase inhibitor, wortmannin, attenuated stimulation of ERKs and p38 MAPK by GM-CSF, but not TNF-alpha. GM-CSF, but not TNF-alpha, stimulated wortmannin-sensitive activation of Raf-1. TNF-alpha and GM-CSF priming of superoxide release stimulated by N-formyl-methionyl-leucyl-phenylalanine was significantly attenuated by the MEK inhibitor, PD098059, and the p38 MAPK inhibitor, SB203580. Incubation with both MAPK inhibitors produced an additive effect. Our data suggest that TNF-alpha and GM-CSF activate ERKs and p38 MAPK by different signal transduction pathways. Both ERK and p38 MAPK cascades contribute to the ability of TNF-alpha and GM-CSF to prime the respiratory burst response in human PMNs.
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PMID:Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-alpha and GM-CSF. 976 35

Incubation of human neutrophils with a chemotactic peptide [N-formylmethionyl-leucylphenylalanine (fMLP)] gave rise to an increase in the phosphoinositide 3-kinase (PI3K) activity, phosphorylation of p47phox and superoxide-anion (O2(-)) generation in the same fMLP-concentration-dependent manner. These responses to fMLP were markedly enhanced when the cells had been incubated for 10 min before the addition of fMLP with increasing concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) that were only slightly effective themselves. Wortmannin, an inhibitor of PI3K, suppressed all of these fMLP actions in the same concentration-dependent manner in either GM-CSF-primed or non-primed cells. Sustained activation of protein kinase C by the addition of PMA caused marked phosphorylation of p47phox and respiratory burst itself without activation of PI3K. This strong action of PMA was not primed by GM-CSF. The chemotactic peptide was without effect in pertussis-toxin-treated cells, indicating that its actions are mediated by betagamma-subunits liberated from toxin-susceptible heterotrimeric Gi proteins (Gbetagamma). Thus one of the mechanisms of GM-CSF-mediated priming of fMLP-induced respiratory burst is synergistic activation of wortmannin-sensitive PI3K by Gbetagamma in the presence of tyrosine-phosphorylated proteins in GM-CSF-treated cells, as recently indicated in a cell-free system [Kurosu, Maehama, Okada, Yamamoto, Hoshino, Fukui, Ui, Hazeki and Katada (1997) J. Biol. Chem. 272, 24252-24256]. GM-CSF primed fMLP-induced MAP (mitogen-activated protein) kinase activation enormously as well. The MAP kinase activation was primed even in the presence of wortmannin, indicating that PI3K was not the sole site where tyrosine kinase-related and Gbetagamma-mediated intracellular signals converge to elicit the priming. The GM-CSF priming of fMLP-induced PI3K activation and O2(-) generation was much smaller in magnitude in neutrophils in which cAMP accumulated upon incubation with prostaglandin E1 than in the cells without the nucleotide accumulation. Thus the GM-CSF priming site, in addition to PI3K, might be just the target of cAMP-dependent protein kinase A in fMLP-initiated signalling cascades or could be localized immediately downstream thereof.
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PMID:Enhancement of chemotactic peptide-induced activation of phosphoinositide 3-kinase by granulocyte-macrophage colony-stimulating factor and its relation to the cytokine-mediated priming of neutrophil superoxide-anion production. 988 16

The factor-independent Dami/HEL and Meg-01 and factor-dependent Mo7e leukemic cell lines were used as models to investigate JAK/STAT signal transduction pathways in leukemic cell proliferation. Although Dami/HEL and Meg-01 cell proliferation in vitro was independent of and unresponsive to exogenous cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), IL-6, thrombopoietin (TPO), and tumor necrosis factor-alpha (TNF-alpha), the growth of Mo7e cells was dependent on hematopoietic growth factors. When these cell lines were cultured in medium without cytokines, a constitutively activated STAT-like DNA-binding factor was detected in nuclear extracts from both Dami/HEL and Meg-01 cells. However, the STAT-like factor was not detectable in untreated Mo7e cells, but was activated transiently in Mo7e cells in response to cytokine treatments. The constitutively activated and cytokine-induced STAT-like DNA-binding factor in these three cell lines was identified as STAT5 by oligonucleotide competition gel mobility assays and by specific anti-STAT antibody gel supershift assays. Constitutive activation of JAK2 also was detected in the factor-independent cell lines, but not in Mo7e cells without cytokine exposure. Meg-01 cells express a p185 BCR/ABL oncogene, which may be responsible for the constitutive activation of STAT5. Dami/HEL cells do not express the BCR/ABL oncogene, but increased constitutive phosphorylation of Raf-1 oncoprotein was detected. In cytokine bioassays using growth factor-dependent Mo7e and TF-1 cells as targets, conditioned media from Dami/HEL and Meg-01 cells did not show stimulatory effects on cell proliferation. Our results indicate that the constitutive activation of JAK2/STAT5 correlates with the factor-independent growth of Dami/HEL and Meg-01 cells. The constitutive activation of JAK2/STAT5 in Dami/HEL cells is triggered by a mechanism other than autocrine cytokines or the BCR/ABL oncoprotein.
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PMID:Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. 1009 Sep 48

Colony-stimulating factor 1 (CSF-1) is required for the development of monocytes/macrophages from progenitor cells and for the survival and activation of mature macrophages. The receptor for CSF-1 is the product of the c-fms proto-oncogene, which, on binding ligand, can stimulate a mitogenic response in the appropriate cells. To investigate which genes are regulated in response to CSF-1-stimulation in murine bone-marrow-derived macrophages (BMM), we employed mRNA differential display reverse transcriptase-mediated PCR to identify cDNA species induced by CSF-1. Both Northern and Western blot analyses confirmed the increased expression of one of the cDNA species identified as coding for the catalytic subunit of protein phosphatase 2A (PP2A), an observation not previously reported during the response to a growth factor. To determine the significance of the increased expression of PP2A in response to CSF-1, the PP2A inhibitor okadaic acid (OA) was added to CSF-1-treated BMM and found to inhibit DNA synthesis in a dose-dependent manner. Further analysis with flow cytometry in the presence of OA led to the novel conclusion that PP2A activity is critical for CSF-1-driven BMM cell cycle progression in both early G1 and S phases. Surprisingly, in the light of previous studies with other cells, the PP2A-dependent proliferation could be dissociated from activation by extracellular signal-regulated protein kinase (ERK) in macrophages because OA did not affect either the basal or CSF-1-induced ERK activity in BMM. Two-dimensional SDS/PAGE analysis of lysates of 32P-labelled BMM, which had been treated with CSF-1 in the presence or absence of OA, identified candidate substrates for PP2A.
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PMID:Protein phosphatase 2A is expressed in response to colony-stimulating factor 1 in macrophages and is required for cell cycle progression independently of extracellular signal-regulated protein kinase activity. 1021 88

The common beta chain (beta(c)) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors is the major signaling subunit of these receptors coupling ligand binding to multiple biological activities. It is thought that these multiple functions arise as a consequence of the recruitment of specific signaling molecules to tyrosine-phosphorylated residues in the cytoplasmic domain of beta(c). However, the contribution of serine phosphorylation in beta(c) to the recruitment of signaling molecules is not known. We show here the identification of a phosphoserine motif in the cytoplasmic domain of beta(c) that interacts with the adaptor protein 14-3-3zeta. Coimmunoprecipitation and pull-down experiments with a glutathione S-transferase (GST):14-3-3zeta fusion protein showed that 14-3-3 directly associates with beta(c) but not the GM-CSF receptor alpha chain. C-terminal truncation mutants of beta(c) further showed that a region between amino acids 544 and 626 in beta(c) was required for its association with 14-3-3zeta. This region contains the sequence (582)HSRSLP(587), which closely resembles the RSXSXP (where S is phosphorylated) consensus 14-3-3 binding site identified in a number of signaling molecules, including Raf-1. Significantly, substitution of (582)HSRSLP(587) for EFAAAA completely abolished interaction of beta(c) with GST-14-3-3zeta. Furthermore, the interaction of beta(c) with GST-14-3-3 was greatly reduced in the presence of a peptide containing the 14-3-3 binding site, but only when (585)Ser was phosphorylated. Direct binding experiments showed that the peptide containing phosphorylated (585)Ser bound 14-3-3zeta with an affinity of 150 nmol/L. To study the regulation of (585)S phosphorylation in vivo, we raised antibodies that specifically recognized (585)Ser-phosphorylated beta(c). Using these antibodies, we showed that GM-CSF stimulation strongly upregulated (585)Ser phosphorylation in M1 myeloid leukemic cells. The proximity of the SHC-binding site ((577)Tyr) to the 14-3-3-binding site ((582)HSRSLP(587)) and their conservation between mouse, rat, and human beta(c) but not in other cytokine receptors suggest that they form a distinct motif that may subserve specialized functions associated with the GM-CSF, IL-3, and IL-5 receptors.
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PMID:Identification of a 14-3-3 binding sequence in the common beta chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors that is serine-phosphorylated by GM-CSF. 1047 22

Active cyclin-dependent kinases (CDKs) are required for progression through the G1 phase of the cell cycle and entry into S phase. Activity of G1 CDKs is controlled by mechanisms including phosphorylation of Thr14 and Tyr15 residues. Removal of inhibitory phosphates on these amino acid residues is required for G1 CDK activation, and is mediated by the Cdc25A phosphatase. Regulation of active Cdc25A phosphatase levels may be important for the proliferation of hematopoietic progenitor cells, effects assessed in the human growth-factor-dependent cell line Mo7e. Constitutive Cdc25A protein levels were enhanced with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus steel factor (SF). Cdc25A is thought to exert its activity in the nucleus, and nuclear protein levels of Cdc25A were also enhanced with GM-CSF and SF. GM-CSF plus SF promote synergistic growth of Mo7e cells. Pretreatment with macrophage inflammatory protein (MIP-1alpha) inhibited GM-CSF- plus SF-induced growth and upregulation of Cdc25A protein levels. Stimulation with GM-CSF and SF also rapidly increased Cdc25A phosphatase activity, an effect suppressed by MIP-1alpha. A concomitant inhibition of increased CDK4 kinase activity correlated with increased phosphotyrosine levels on CDK4 when cells were pretreated with MIP-1alpha prior to GM-CSF and SF. These data suggest that Cdc25A expression and activity are regulated during proliferation of Mo7e cells.
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PMID:The effects of GM-CSF, steel factor and MIP-1alpha on the expression and activation of Cdc25A phosphatase in Mo7e cells. 1064 70

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