Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to evaluate the effect of stem cell factor (SCF) on the in vitro growth of bone marrow hematopoietic progenitors from patients with acquired severe aplastic anemia (AA) or Fanconi's anemia (FA). For this purpose, we studied 11 patients with acquired AA (5 at diagnosis, 6 after ALG treatment), 12 patients with FA, and nine normal controls. Bone marrow cells were plated in vitro for colony-forming unit granulocyte-macrophage (CFU-GM) (in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF]), and for burst-forming unit-erythroid (BFU-E) and CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM) colonies (in the presence of erythropoietin and interleukin-3 [IL-3]), with or without 20 ng/mL of SCF. In normal controls, SCF enhanced the growth of CFU-GM colonies from 103 to 263 (median), of BFU-E from 168 to 352, and of GEMM colonies from 6 to 38/10(5) cells plated. In patients with acquired AA, SCF induced a significant enhancement of BFU-E growth (8 to 29; P = .01) and allowed the formation of GEMM colonies that were not scored in baseline culture conditions (0 to 8; P = .01). CFU-GM growth was enhanced (4 to 20), but not significantly (P = .3). This was true both for patients at diagnosis and after antilymphocyte globulin treatment. By contrast, 10 of 12 FA patients grew no CFU-GM, BFU-E, or CFU-GEMM colonies, with or without SCF. In two FA patients (one transfusion-dependent and one transfusion-independent), an enhancement of CFU-GM and/or BFU-E was observed. The lack of response of hematopoietic progenitor cells from FA patients to GM-CSF+SCF or IL-3+SCF was not dependent on a defective expression of cytokine receptor messenger RNAs. Northern blot analysis showed in marrow cells from acquired AA and FA patients the presence of normal transcripts for alpha- and beta-chains of GM-CSF/IL-3 receptor and for c-kit protein. In conclusion, SCF promotes the in vitro growth of hematopoietic progenitors in patients with acquired AA, but not in patients with FA, pointing out the intrinsic nature of the defect in the latter disorder.
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PMID:Effect of stem cell factor on colony growth from acquired and constitutional (Fanconi) aplastic anemia. 137 17

Ligand-induced dimerization is a key step in the activation of receptor tyrosine kinases, including the epidermal growth factor receptor, stem cell factor receptor (c-kit), and colony-stimulating factor 1 receptor (c-fms). The erythropoietin receptor (EPOR), a member of the cytokine receptor family, contains no kinase motif and its activation mechanism remains unclear. Here we show that chimeric receptors carrying the extracellular domain of the epidermal growth factor receptor or c-kit linked to the cytoplasmic domain of the EPOR, transmitted epidermal growth factor or stem cell factor-dependent proliferation signals in an interleukin 3-dependent cell line. The chimeric receptors as well as the wild-type EPOR also mediated the ligand-induced tyrosine phosphorylation of a set of similar proteins. Moreover, erythropoietin triggered mitogenic signals of chimeric receptors carrying the extracellular domain of the EPOR linked to the tyrosine kinase of c-fms. These data demonstrate the interchangeability of domains between two distinct receptor families and suggest that ligand-induced dimerization is a key step in activating the EPOR.
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PMID:Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. 750 12

To elucidate which cytokine receptors may be expressed by human glioblastoma and normal astrocytic cells, the presence of messenger ribonucleic acid (RNA) for a number of cytokine receptors was examined in 16 glioblastoma cell lines and adult and fetal astrocytes. A complementary deoxyribonucleic acid copy of total RNA was synthesized and amplified with specific primers using the polymerase chain reaction method. The receptors studied were interleukin (IL)-1 receptor type I (IL-1RI) and type II (IL-1RII), p75 and p55 tumor necrosis factor (TNF) receptors (p75TNFR and p55TNFR), interferon (IFN)-alpha/beta and -gamma receptors (IFN-alpha/beta R and IFN-gamma R), granulocyte-macrophage (GM) colony-stimulating factors receptor alpha subunit (GM-CSFR), G-CSF receptor (G-CSFR), M-CSF receptor (c-fms, M-CSFR), stem cell factor receptor (c-kit, SCFR), IL-6 receptor (IL-6R), and IL-8 receptor (IL-8R). Transcripts for IL-1RI, p55TNFR, IFN-alpha/beta R, and IFN-gamma R were present in all cell lines. The presence of IL-1RII, p75TNFR, GM-CSFR, M-CSFR, SCFR, IL-6R, and IL-8R was identified in 13, eight, seven, eight, 14, three, and one cell lines, respectively. Normal astrocytes were positive for IL-1RI, p75TNFR, p55TNFR, IFN-alpha/beta R, IFN-gamma R, M-CSFR, and SCFR, showing a similarity to glioblastoma cells. Expression of IL-1RII was observed in adult astrocytes but not in fetal astrocytes. Furthermore, gene expression was assessed in normal brain tissue and 11 glioblastoma tissue specimens. The normal brain tissue expressed IL-1RI, IL-1RII, IFN-alpha/beta R, M-CSFR, and SCFR. Of the 11 glioblastoma tissue specimens, IL-1RI was positive in 11, IL-1RII in 10, p75TNFR in nine, p55TNFR in nine, IFN-alpha/beta R in 10, IFN-gamma R in 10, GM-CSFR in two, G-CSFR in three, IL-8R in eight, and M-CSFR and SCFR in 11. These expressions were consistent with those in the cell lines, except for IL-8R. It is concluded that glioblastoma cells and normal astrocytes express a similar set of cytokine receptor genes in vitro and in vivo. Possible autocrine loops are suggested for IL-1 alpha/IL-1RI, TNF-alpha/p55TNFR, IFN-beta/IFN-alpha/beta R, M-CSF/M-CSFR, and SCF/SCFR in glioblastomas.
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PMID:Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. 751 61

To find out which cytokines are involved in the pathogenesis of multiple myeloma, we investigated cytokine receptor expression on myeloma cells using a panel of monoclonal antibodies (MoAbs). Flow cytometric analysis of five myeloma cell lines (RPMI8226, ARH77, KMM-1, U266, and Hs) and myeloma cells freshly isolated from eight patients showed that interleukin-1 receptor (IL-1R) type I and type II, IL-2R alpha and beta chains, IL-4R, IL-6R, IL-7R, IL-8R, granulocyte macrophage colony-stimulating factor receptor (GM-CSFR), c-kit (stem cell factor receptor [SCFR]), membrane bound stem cell factor (MBSCF), and tumor necrosis factor (TNF) receptors type I and type II were not always detected on the myeloma cells. However, interferon-gamma receptor, gp130, and Fas antigen were constitutively expressed, except one sample. To determine the role of Fas antigen on myeloma cells, these cells were cultured with anti-Fas MoAb. Apoptotic changes characterized by loss of cell volume, membrane blebbing, fragmentation of nuclei, and condensed chromatin were observed in three of five myeloma cell lines. When bcl-2 expression was examined, it was seen in all the cell lines regardless of the sensitivity to anti-Fas MoAb. Furthermore, anti-Fas MoAb not only induced apoptosis of freshly isolated myeloma cells but also inhibited the DNA synthesis, although such effects varied from patient to patient. The data indicate that only some myeloma cells undergo apoptosis in response to the signal mediated by the Fas antigen.
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PMID:Myeloma cells express Fas antigen/APO-1 (CD95) but only some are sensitive to anti-Fas antibody resulting in apoptosis. 753 May 6

CD34, a stem cell marker, has been shown to be expressed on human CD3-CD4-CD8- (triple-negative; TN) thymocytes. Phenotypic and functional analyses suggest the following differentiation sequence: CD34+1-3-4-8(-)--> CD34+1+3-4 +/- 8(-)-->CD34-1+3-4+8(+/-)-->CD34-1++3-4+8+. In this report, we examined cytokine receptor gene expression on these subsets by reverse transcription-polymerase chain reaction analysis (RT-PCR). We were able to detect interleukin-7 receptor (IL-7R), c-kit and IL-2R gamma in all CD34+ thymocyte subsets, consistent with previous functional studies. We found IL-1R, granulocyte/macrophage colony-stimulating factor receptor-alpha and IL-4R transcripts in CD3- and CD34+ subsets. Secondly, we investigated T cell receptor (TCR)-delta and -beta gene rearrangement and transcription in CD34+ thymocytes. Our results show that a full-length TCR-delta transcript and the recombination activating genes RAG-1 and RAG-2 mRNA were already expressed in the CD34+1- subset. Mature V beta-containing TCR transcripts were also detected in the CD34+1+ subset, but not in the CD1- fraction. Furthermore, PCR analysis of D-J beta gene rearrangements showed that > or = 70% of CD34+1- cells are in a TCR beta germ-line configuration, although D-J beta recombination had already started in this population.
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PMID:CD34-positive early human thymocytes: T cell receptor and cytokine receptor gene expression. 758 13

The development of blood cells requires the interplay of hematopoietic stem and progenitor cells, marrow stroma and polypeptide growth factors. Although many proteins are thought to support the expansion of megakaryocytic precursor cells (e.g., interleukin [IL]-3, c-kit ligand [KL]), identification of the late-acting, lineage-specific growth factor for platelet production, termed Thrombopoietin (Tpo), has remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor family. Based on the cell of origin of its cDNA, we hypothesized that the ligand for c-mpl might be identical with Tpo. Using BaF3 cells engineered to express c-mpl, we employed a functional expression strategy to clone its cDNA. At low concentrations, the recombinant protein supports the growth of megakaryocytic colonies, alone and together with either IL-3 or KL. For IL-3 this appears to be additive, for KL, true synergy was detected. At higher concentrations, the mpl ligand (ML) alone supported a near maximal number of very large megakaryocytic colonies. Using suspension cultures and human megakaryocytic cell lines, we have also shown that ML induces the terminal differentiation of megakaryocytes by enhancing polyploidization and surface membrane expression of GPIb and IIb/IIIa. Moreover, the development of megakaryocytes in vitro appears to be absolutely dependent on the presence of ML. Following receptor engagement, ML induces tyrosine phosphorylation of a number of membrane associated kinases and adaptor molecules, including SHC, JAK2, PLC-gamma and the mpl receptor itself.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The mpl ligand: molecular and cellular biology of the critical regulator of megakaryocyte development. 769 72

Similar to two other hematopoietic growth factor receptors, the c-fms (macrophage colony-stimulating factor receptor) and the c-kit genes, c-mpl has been discovered through the study of oncogenic retroviruses. Unlike c-fms and c-kit, which both belong to a subgroup of tyrosine kinase receptors, the c-mpl proto-oncogene encodes a new member of the cytokine receptor superfamily. We have studied the expression of c-mpl in a series of 105 patients with hematologic malignancies using Northern blot analysis. The levels of c-mpl transcripts in lymphoid malignancies and in chronic myeloproliferative disorders were not significantly different from those found in normal bone marrow cells, in which c-mpl was barely detectable. In contrast, c-mpl expression was increased in 26 of 51 patients with acute myeloblastic leukemia (AML) and in 5 of 16 patients with myelodysplastic syndromes. Amplification of the c-mpl gene was detected in genomic DNA of one M4 AML patient. There was no significant correlation between c-mpl expression and the French-American-British classification of AML. Patients with high c-mpl expression appeared to belong to a subgroup of AML with a low rate of complete remission and a poor prognosis, including secondary leukemia and AML with unfavorable cytogenetic abnormalities.
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PMID:Expression of the c-mpl proto-oncogene in human hematologic malignancies. 839 55

We present a detailed analysis of cytokine expression patterns of the two permanent human bone marrow stromal cell lines, L87/4 and L88/5. These cell lines, previously established in our laboratory, are highly radiotolerant without cell detachment and support long-term cultures of CD(34+)-enriched human cord blood cells. RT-PCR analysis of 22 different cytokines or cytokine receptor mRNAs showed an almost identical expression pattern in the two stromal cell lines compared to primary human Dexter-type stroma. Since stromal feeder lines employed in long-term cultures usually are irradiated and grown in media containing corticosteroids, we analyzed the impact of irradiation and dexamethasone on cytokine production in the two cell lines by RT-PCR, Northern blot analysis, bioassays, and RIAs. By RT-PCR analysis, constitutive mRNA expression of c-kit, G-CSF, GM-CSF, IL-1 beta, IL-6, IL-7, IL-8, IL-11, Kit ligand (KL), LIF, M-CSF, MIP-1 alpha, TGF-beta, and TNF-alpha was demonstrated in both cell lines, with L87/4 a more potent cytokine producer than L88/5. Northern blot data showed an increase in mRNA levels for GM-CSF, IL-1 beta, and LIF by irradiation and IL-1 alpha treatment in both cell lines. IL-1 alpha-induced GM-CSF, IL-1 beta, IL-6, IL-11, and LIF mRNA levels were reduced by the addition of dexamethasone, whereas dexamethasone had no influence on the amounts of IL-1 alpha-induced G-CSF mRNA. L87/4 and, to a lower extent, L88/5 cells showed dexamethasone-dependent increases in KL mRNA, while KL mRNA levels were not stimulated by IL-1 alpha.
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PMID:Constitutive and modulated cytokine expression in two permanent human bone marrow stromal cell lines. 853 85

Eighty six of 430 acute myeloblastic leukemia (AML) patients (20.0%) and forty of 173 acute lymphoblastic leukemia (ALL) patients (23.1%) had CD7 on their leukemia cells. CD7(+) AML occurred at a younger age than CD7(-) AML, and is more frequent in males. Hepatomegaly and central nervous system involvement were also more frequent in CD7(+) AML than in CD7(-) AML. The age of onset of CD7(+) ALL is also younger than that of CD7(-) ALL. Phenotypically, CD(+) AML expressed CD34, HLA-DR, and TdT more frequently than CD7(-) AML while CD7(+) ALL expressed CD13/33 more often than CD7(-) ALL cells responded most significantly to interleukin 3 (IL-3), whereas most CD7(-) AML cells responded more significantly to granulocyte macrophage-colony stimulating factor (GM-CSF) and/or granulocyte (G)-CSF than to IL-3. CD7(+)sCD3(-)CD4(-)CD8(-) ALL expressed G-CSF receptor and c-kit mRNA more frequently, which is not usual in other types of ALL. P-glycoprotein (P-gp)/multi-drug resistance gene (MDR1), thought to be expressed in hematopoietic stem cells, is expressed in CD7(+) AML and CD7(+)sCD3(-) CD4(-)CD8(-) ALL significantly more often than in CD7(-) acute leukemias and the CR rate and overall survival of CD7(+)AML was worse than CD7(-) AML. These data, collectively, suggest the close association of CD7(+) AML and CD7(+)sCD3(-)CD4(-)CD8(-) ALL, not only the common expression of CD7 itself but also because their phenotypical immaturity, cytokine receptor expression, P-gp/MDR1 expression and clinical manifestations including the frequent occurrence in males and the poor prognosis. We propose that CD7(+) acute leukemia is an hematopoietic stem cell leukemia which may be separate entity.
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PMID:Biological characteristics of CD7(+) acute leukemia. 872 5

Stem cell factor receptor (SCFR, c-kit), normally expressed on haematopoietic and mast cells, plays a regulatory role in cellular growth and differentiation. Dysregulated expression of SCFR may contribute to neoplastic transformation. We investigated expression of SCFR on malignant canine mast cells obtained directly from spontaneous canine mast cell neoplasms, in an attempt to determine whether these undifferentiated cells maintained expression of this growth-promoting cytokine receptor. Malignant mast cells (histological grade 2) from skin tumours or lymph node metastases were collected from canine patients, and SCFRs were detected by flow cytometric analysis of these cells. All of the tumours bound mouse and canine recombinant stem cell factor (SCF), indicating that the cells not only expressed SCFRs, but that the receptors possessed the functional property of ligand binding. Immunoglobulin Fc receptors for canine IgE were identified on these cells by flow cytometry, a further indication that the cells analysed were mast cells and retained some differentiated features. Immunohistochemical analysis of formalin-fixed, paraffin wax-embedded mast cell tumour biopsies confirmed expression of SCFRs by malignant cells from each tumour. The relative binding of SCF to suspensions of tumour cells, as assessed by flow cytometry, correlated with the intensity of immunolabelling for SCFR in sections of the same tumours, suggesting variability in SCFR expression between tumours. Agarose gel electrophoresis of the products of SCFR reverse transcription-polymerase chain reaction derived from each tumour had the molecular weight predicted for canine SCFR cDNA on the basis of the mouse and human counterparts. This further confirmed SCFR expression by malignant canine mast cells. Taken together, these results show that a membrane receptor capable of triggering cell growth is expressed by malignant canine mast cells, suggesting a role for this receptor in the aetiology of canine mast cell cancer. This relatively common malignancy of the dog would seem to present an opportunity for the investigation of the potential role of the SCF/SCFR pathway in the development of spontaneous malignancies of mast cells.
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PMID:Expression of stem cell factor receptor (c-kit) by the malignant mast cells from spontaneous canine mast cell tumours. 900 81


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