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

Humanized M195 (HuM195) is a genetically engineered, human IgG1 version of the parent M195, a mouse immunoglobulin G2a, anti-CD33 monoclonal antibody which reacts with early myeloid progenitor cells and myelogenous leukemia cells. In Phase I studies in patients with relapsed and refractory myelogenous leukemia, HuM195 safely targeted to sites of disease and was nonimmunogenic. HuM195 shows only modest capability of antibody-dependent cellular cytotoxicity (ADCC) against target HL60 cells and minimal cytolytic activity mediated by human complement. Therefore, efforts were made to enhance ADCC using cytokines. gamma-Interferon, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor did not promote neutrophil-mediated ADCC with HuM195. However, interleukin-2 (IL-2) showed a range of 2-6-fold increases in ADCC against fresh myelogenous leukemia cells and HL60 cells over that seen with HuM195 or low-dose IL-2 alone. ADCC potency was not improved further by the use of homodimeric HuM195. Flow cytometry and Fc receptor-blocking experiments showed that CD16(+) cells were essential for IL-2-enhanced ADCC. As compared to HL60 cells, a multidrug-resistant line of HL60 cells was at least as susceptible to killing by IL-2 or HuM195 or in combination, suggesting that the mechanism of killing may be active against cells surviving and resistant to chemotherapy. Since these in vitro levels of IL-2 and HuM195 can be safely achieved in patients, the enhancement of HuM195 ADCC with low-dose IL-2 is a possible strategy that may be used in vivo to eliminate minimal disease in future trials of patients with myeloid leukemias.
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PMID:Interleukin-2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti-CD33) in myelogenous leukemia. 981 88

Myeloid leukemia cells, the human promyelocytic cell line HL-60, and a subpopulation of normal marrow cells produce a leukemia-associated inhibitor (LAI) that reversibly downmodulates DNA synthesis of normal granulopoietic progenitor cells colony-forming unit granulocyte-macrophage (CFU-GM). We isolated an active 125-kD component of LAI from HL-60 conditioned medium (CM), subjected it to cyanogen bromide cleavage and show by amino acid sequencing of the resulting peptides that it consists of a complex of the serine proteinase inhibitor alpha1-antitrypsin and a 31-kD fragment that retained the S-phase inhibitory activity, but resisted sequencing. This finding suggested that the 31-kD fragment originated from one of the neutrophil serine proteases (ie, elastase, proteinase 3, or cathepsin G) produced by normal promyelocytes, as well as HL-60 cells, for storage in primary granules and partly secreted during synthesis as enzymatically inactive proforms. Immunoblot analysis showed that the 125-kD complex contained proteinase 3 (PR3), and immunoprecipitation of PR3 from HL-60 CM abrogated the S-phase inhibitory activity, whereas immunoprecipitation of cathepsin G or elastase did not. Immunoprecipitation of PR3 from CM of a subpopulation of normal marrow cells also abrogated the S-phase inhibitory effect. Furthermore, CM from rat RBL and murine 32D cell lines transfected with human PR3 both reduced the fraction of CFU-GM in S-phase with 30% to 80% at 1 to 35 ng/mL PR3, whereas CM of the same cells transfected with cathepsin G or elastase did not. Also, an enzymatically silent mutant of PR3 exerted full activity, showing that the S-phase modulatory effect is not dependent on proteolytic activity. Amino acid sequencing of biosynthetically radiolabeled PR3 showed that PR3 from transfected cells is secreted after synthesis as proforms retaining amino terminal propeptides. In contrast, mature PR3 extracted from mature neutrophils has only minor activity. The inhibitory effect of secreted PR3 is reversible and abrogated by granulocyte (G)- or granulocyte-macrophage colony-stimulating factor (GM-CSF). Experiments with highly purified CD34(+) bone marrow cells suggested that PR3 acts directly on the granulopoietic progenitor cells. These observations suggest a role for PR3 in regulation of granulopoiesis, and possibly in suppression of normal granulopoiesis in leukemia.
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PMID:A secreted proform of neutrophil proteinase 3 regulates the proliferation of granulopoietic progenitor cells. 992 Aug 33

Myeloperoxidase (MPO) is present in azurophilic granules which appear in the promyelocyte stage of differentiation, and is the most common functional protein of myeloid cells. With progress in molecular biology, the expression and regulation of MPO have been clarified in normal myeloid and leukemic cells, not only by enzymatical activity but at the gene level MPO expression is affected by the differentiation of myeloid cells, and has been suggested to be regulated by myeloid cell growth factors, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and interleukin-3. In the past decade the signal transduction from their receptors has been clarified. This review describes the expression and regulation of the MPO gene in myeloid cells including myeloid disorders, such as myeloid leukemia or myelodysplastic syndromes, The effects on MPO by myeloid growth factors and signal transduction from their receptors are also presented.
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PMID:Myeloperoxidase gene expression and regulation by myeloid cell growth factors in normal and leukemic cells. 1003 23

Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.
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PMID:In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. 1049 20

By virtue of its high expression in both developing hematopoietic tissues and many myeloid leukemia cells lines, the embryonic tyrosine kinase receptor ETK2 (also known as Tyro3, Sky, and Rse) has been postulated to play a role in early hematopoiesis. To investigate this role, we expressed murine ETK2 in the interleukin 3 (IL-3) dependent myeloid progenitor cell line FDC-P1 and examined its effect on growth factor dependence.ETK2 cDNAs encoding full-length or kinase domain-deleted receptor were retrovirally transduced into murine FDC-P1 cells. Survival, cell cycle status, and proliferative responses of ETK2 expressing clones were studied at normal and reduced growth factor concentrations. ETK2 was expressed as a functional tyrosine kinase of 110 and 150 kDa. This proto-oncogene altered the growth of FDC-P1 cells, allowing survival at reduced growth factor concentrations and delaying apoptosis after IL-3 withdrawal. ETK2-expressing clones contained a higher fraction of cells in the S/G2/M phases of the cell cycle, both after cytokine withdrawal and in the presence of IL-3. Furthermore, these cells had a modestly enhanced proliferative response to IL-3 and granulocyte-macrophage colony-stimulating factor, suggesting that ETK2 intracellular signaling may converge with that of hematopoietic growth factors. The effects of ETK2 expression on viability and proliferation were largely dependent on a functional intracellular tyrosine kinase domain. These results support a role for ETK2 in the survival and/or expansion of primitive hematopoietic cells and suggest that this tyrosine kinase may be implicated in myeloid leukemogenesis as well.
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PMID:ETK2 receptor tyrosine kinase promotes survival of factor-dependent FDC-P1 progenitor cells. 1088 Jul 58

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
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PMID:Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. 1091 Sep 6

The c-fes locus encodes a 93-kDa non-receptor protein tyrosine kinase (Fes) that regulates the growth and differentiation of hematopoietic and vascular endothelial cells. Unique to Fes is a long N-terminal sequence with two regions of strong homology to coiled-coil oligomerization domains. We introduced leucine-to-proline substitutions into the coiled coils that were predicted to disrupt the coiled-coil structure. The resulting mutant proteins, together with wild-type Fes, were fused to green fluorescent protein and expressed in Rat-2 fibroblasts. We observed that a point mutation in the first coiled-coil domain (L145P) dramatically increased Fes tyrosine kinase and transforming activities in this cell type. In contrast, a similar point mutation in the second coiled-coil motif (L334P) was without effect. However, combining the L334P and L145P mutations reduced transforming and kinase activities by approximately 50% relative to the levels of activity produced with the L145P mutation alone. To study the effects of the coiled-coil mutations in a biologically relevant context, we expressed the mutant proteins in the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid leukemia cell line TF-1. In this cellular context, the L145P mutation induced GM-CSF independence, cell attachment, and spreading. These effects correlated with a marked increase in L145P protein autophosphorylation relative to that of wild-type Fes. In contrast, the double coiled-coil mutant protein showed greatly reduced kinase and biological activities in TF-1 cells. These data are consistent with a role for the first coiled coil in the negative regulation of kinase activity and a requirement for the second coiled coil in either oligomerization or recruitment of signaling partners. Gel filtration experiments showed that the unique N-terminal region interconverts between monomeric and oligomeric forms. Single point mutations favored oligomerization, while the double point mutant protein eluted essentially as the monomer. These data provide new evidence for coiled-coil-mediated regulation of c-Fes tyrosine kinase activity and signaling, a mechanism unique among tyrosine kinases.
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PMID:A point mutation in the N-terminal coiled-coil domain releases c-Fes tyrosine kinase activity and survival signaling in myeloid leukemia cells. 1150 60

DT(388)-GM-CSF, a targeted fusion toxin constructed by conjugation of human granulocyte-macrophage colony-stimulating factor (GM-CSF) with the catalytic and translocation domains of diphtheria toxin, is presently in phase I trials for patients with resistant acute myeloid leukemia. HL-60/VCR, a multidrug-resistant human myeloid leukemia cell line, and wild-type HL-60 cells were used to study the impact of DT(388)-GM-CSF on metabolism of ceramide, a modulator of apoptosis. After 48 hours with DT(388)-GM-CSF (10 nM), ceramide levels in HL-60/VCR cells rose 6-fold and viability fell to 10%, whereas GM-CSF alone was without influence. Similar results were obtained in HL-60 cells. Examination of the time course revealed that protein synthesis decreased by about 50% and cellular ceramide levels increased by about 80% between 4 and 6 hours after addition of DT(388)-GM-CSF. By 6 hours this was accompanied by activation of caspase-9, followed by activation of caspase-3, cleavage of caspase substrates, and chromatin fragmentation. Hygromycin B and emetine failed to elevate ceramide levels or induce apoptosis at concentrations that inhibited protein synthesis by 50%. Exposure to C(6)-ceramide inhibited protein synthesis (EC(50) approximately 5 microM) and decreased viability (EC(50) approximately 6 microM). Sphingomyelinase treatment depleted sphingomyelin by about 10%, while increasing ceramide levels and inhibiting protein synthesis. Diphtheria toxin increased ceramide and decreased sphingomyelin in U-937 cells, a cell line extremely sensitive to diphtheria toxin; exposure to DT(388)-GM-CSF showed sensitivity at less than 1.0 pM. Diphtheria toxin and conjugate trigger ceramide formation that contributes to apoptosis in human leukemia cells through caspase activation and inhibition of protein synthesis.
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PMID:Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT(388)-granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF. 1153 31

We report here that Janus kinase 3 (Jak3) is a primary response gene for interleukin-6 (IL-6) in macrophage differentiation, and ectopic overexpression of Jak3 accelerates monocytic differentiation of normal mouse bone marrow cells stimulated with cytokines. Furthermore, we show that incubation of normal mouse bone marrow cells with a JAK3-specific inhibitor results in profound inhibition of myeloid colony formation in response to granulocyte-macrophage colony-stimulating factor or the combination of stem cell factor, IL-3, and IL-6. In addition, mutagenesis of the Jak3 promoter has revealed that Sp1 binding sites within a -67 to -85 element and a signal transducer and activator of transcription (Stat) binding site at position -44 to -53 are critical for activation of Jak3 transcription in murine M1 myeloid leukemia cells stimulated with IL-6. Electrophoretic mobility shift assay (EMSA) analysis has demonstrated that Sp1 can bind to the -67 to -85 element and Stat3 can bind to the -44 to -53 STAT site in IL-6-stimulated M1 cells. Additionally, ectopic overexpression of Stat3 enhanced Jak3 promoter activity in M1 cells. This mechanism of activation of the murine Jak3 promoter in myeloid cells is distinct from a recently reported mechanism of activation of the human JAK3 promoter in activated T cells.
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PMID:Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation. 1497 41

To investigate the tumoricidal activity of dendritic cell (DC) stimulated by interferon-gamma (IFN-gamma) against freshly isolated myeloid leukemia cells and its mechanism, the peripheral blood monocytes collected from healthy donors were cocultured with interleukin-4 and granulocyte-macrophage colony-stimulating factor in medium to induce DC for 7 days. After 12 hour culture in the absence or presence of IFN-gamma, the changes of costimulatory molecules were analyzed with flow cytometry. To assay the cytotoxicity of DC against freshly isolated acute myeloid cells, they were cocultured at various effector-to-target ratio for 18 hours, then the percentage of tumoricidal activity was measured with (51)Cr release assay. To explore the mechanism of DC-mediated cytotoxicity, the change of DC surface or intracellular protein expression of Fas ligand (Fas L), TNF-alpha and TNF related apoptosis-inducing ligand (TRAIL) were analyzed with flow cytometry. The results showed that IFN-gamma enhanced cytotoxicity of DC against AML cells was (33.8 +/- 1.6)% at E:T as 20:1, compared with unstimulated DC (P < 0.05); IFN-gamma up-regulated expression of costimulatory molecules of DC surface such as CD86 and CD83; after stimulation with IFN-gamma, expression of intracellular TRAIL of DC was significantly enhanced, but expression of TRAIL on cell surface of DC was low; while the significant changes of Fas L and TNF-alpha expression neither on cell surface or in cells were not observed before or after stimulation with IFN-gamma. It is concluded that DC stimulated by IFN-gamma exhibit tumoricidal activity against AML cells. The cytotoxicity is partially related to maturation of DC and TRAIL inducing apoptosis, but not associated with death domain-independent mechanism of Fas L and TNF-alpha.
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PMID:[Cytotoxicity of IFN-gamma-activated dendritic cells to freshly isolated acute myeloid leukemia cells]. 1640 83


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