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

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
 ...
PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

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.
 ...
PMID:Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. 751 61

Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoiesis, interacts with many growth factor receptors, such as interleukin-3, granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF receptors. Here, we studied the interactions between TNF alpha and the stem cell factor (SCF) receptor, c-kit, in normal CD34+ hematopoietic progenitors and their leukemic counterpart, ie, acute myeloid leukemic (AML) CD34+ cells coexpressing c-kit antigen. The results showed that (1) incubation of normal bone marrow mononuclear cells with 200 U/mL rhTNF alpha for 20 hours induced a diminution of 31.2% +/- 5.2% of CD34+ cells coexpressing c-kit; (2) the same decrease was observed using purified CD34+ cells and, furthermore, their proliferative response to SCF was inhibited by 31.5% +/- 7.3% after exposure to TNF alpha; (3) similar experiments performed on CD34+ c-kit+ AML cells from 11 patients gave comparable results. Further analysis at the mRNA level indicated that TNF alpha decreased c-kit mRNA transcripts. Moreover, using monoclonal antibodies against the two types of TNF alpha receptors, p75 and p55, we showed that the downregulation of c-kit proto-oncogene product by TNF alpha, on normal and leukemic CD34+ cells, was exclusively mediated by the TNF alpha p55 receptor. Therefore, we conclude that TNF alpha acts as a downregulator of the SCF receptor expression.
 ...
PMID:Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto-oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNF alpha receptors. 752 32

TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibitory effects on hematopoiesis. We have previously demonstrated that TNF-alpha directly inhibits CSF-induced proliferation of primitive murine lineage-negative bone marrow progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced inhibition of more committed Lin- progenitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in hematopoiesis. Numerous studies have demonstrated the ability of stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to synergize with other hematopoietic growth factors, but little is known about cytokines capable of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Lin- and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-kit cell surface expression as well as c-kit mRNA levels. Finally, treatment of the FDC-P1 cell line with TNF-alpha resulted in increased levels of the tumor suppressor p53 mRNA, suggesting another mechanism by which hematopoietic effects of TNF-alpha may be mediated.
 ...
PMID:Inhibition of stem cell factor-induced proliferation of primitive murine hematopoietic progenitor cells signaled through the 75-kilodalton tumor necrosis factor receptor. Regulation of c-kit and p53 expression. 753 12

Scatchard binding analysis has been employed to characterize expression of low-affinity receptors for tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by isolated human placental syncytiotrophoblast microvillous plasma membrane (StMPM) vesicles. Trophoblastic receptors for the c-kit ligand (stem cell factor) could not be identified using the same methods. No high-affinity receptors could be detected for GM-CSF or IFN-gamma, but a minority of high-affinity TNF-alpha receptors were identified. Cross-inhibition studies indicated the low-affinity receptors to be specific for each cytokine rather than to be non-specific cytokine-binding factors. Only relatively high-affinity receptors for TNF-alpha and IFN-gamma could be detected on the BeWo human choriocarcinoma cytotrophoblast cell line, whereas receptor affinity for GM-CSF was similar to that on syncytiotrophoblast. Immunohistochemical staining has confirmed expression of IFN-gamma receptor by syncytiotrophoblast: in contrast, staining for the established TNF-R1 and TNF-R2 receptors was associated mainly with placental vascular endothelium. These low-affinity cytokine receptors could reflect unique biological responses of foetal syncytiotrophoblast in the presence of local concentrations of maternal cytokine.
 ...
PMID:Low-affinity receptors for tumour necrosis factor-alpha, interferon-gamma and granulocyte-macrophage colony-stimulating factor are expressed on human placental syncytiotrophoblast. 840 76

The distribution of myeloid lineage-associated cytokine receptors and lysosomal proteins was analyzed in human CD34+ cord blood cell (CB) subsets at different stages of myeloid commitment by reverse-transcriptase polymerase chain reaction (RT-PCR). The highly specific granulomonocyte-associated lysosomal proteins myeloperoxidase (MPO) and lysozyme (LZ), as well as the transcription factor PU.1, were already detectable in the most immature CD34+Thy-1+ subset. Messenger RNA (mRNA) levels for the granulocyte-colony stimulating factor (G-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha subunit and tumor necrosis factor (TNF) receptors I (p55) and II (p75) were also detected in this subset in addition to c-kit and flt-3, receptors known to be expressed on progenitor cells. By contrast, the monocyte-macrophage colony stimulating factor (M-CSF) receptor was largely absent at this stage and in the CD34+Thy-1-CD45RA- subsets. The M-CSF receptor was first detectable in the myeloid-committed CD34+Thy-l-CD45RA+ subset. All other molecules studied were found to be expressed at this stage of differentiation. Different cocktails of the identified ligands were added to sorted CD34+Thy-1+ single cells. Low proliferative capacity was observed after 1 week in culture in the presence of stem cell factor (SCF) + Flt-3 ligand (FL) + G-CSF. Addition of GM-CSF to this basic cocktail consistently increased the clonogenic capacity of single CD34+Thy-1+ cells, and this effect was further enhanced (up to 72.3 +/- 4.3% on day 7) by the inclusion of TNF-alpha. In conclusion, the presence of myeloid-associated growth factor receptor transcripts in CD34+ CB subsets does not discriminate the various stages of differentiation, with the exception of the M-CSF receptor. In addition, we show that TNF-alpha is a potent costimulatory factor of the very immature CD34+Thy-1+ CB subset.
 ...
PMID:Analysis of myeloid-associated genes in human hematopoietic progenitor cells. 932 52

Nerve growth factor-beta (NGF) is known as a growth factor for human basophils and murine mast cells and has recently been shown to also up-regulate mast cell characteristics in human leukaemic mast cells. We have examined here the effect of NGF on the differentiation of normal human mast cells from cord blood progenitors during culture with stem cell factor (SCF), NGF alone or in combination, or fibroblast supernatants. All these supplements induced mast cell immunoreactivity against tryptase, c-Kit and FcepsilonRIalpha, but none of the cells reacted against the basophil specific antibody 2D7 before or during culture. Intracellular tryptase activity increased as well, with maximal levels on combined culture with SCF and NGF. On reverse transcription-polymerase chain reaction (RT-PCR), cells lacked tryptase and chymase and expressed low levels of FcepsilonRI and c-Kit mRNA prior to culture, with marked up-regulation of FcepsilonRI and c-Kit, and with de novo expression of mast-cell specific alpha- and beta-tryptase by week 3, and of chymase by week 5. Only the TrkA and not the p75 NGF receptor was detected at m-RNA and protein level, and only the TrkA NGF receptor was up-regulated during NGF-driven culture. These findings show therefore that, like SCF, NGF is another growth factor that can induce and regulate human mast-cell development and differentiation.
 ...
PMID:Nerve growth factor-beta induces mast-cell marker expression during in vitro culture of human umbilical cord blood cells. 1071 72

Spindle cell melanoma is a rare and distinctive variant of malignant melanoma that is composed of spindled neoplastic cells and includes desmoplastic and neurotropic melanoma. The lack of expression of several melanoma markers may result in a delayed or wrong diagnosis. In this study, we have analyzed in detail the phenotype of the tumor cells in 9 spindle cell melanomas on both paraffin-embedded and frozen material, using melanocytic, neural, and mesenchymal markers. The neoplastic cells expressed the melanocytic markers S-100, Mel-CAM, and NKIC3, but lacked gp100 and Melan-A; tyrosinase and c-Kit were expressed in 2 of 7 cases. Most cases expressed the neural markers p75-nerve growth factor receptor, neural cell adhesion molecule, and NSE. All cases expressed vimentin but lacked the mesenchymal markers CD34 and alpha-smooth muscle actin. Remarkably, all spindle cell melanomas strongly and diffusely expressed the fibroblastic markers Thy1 (CD90) and aminopeptidase N (CD13) and variably expressed the enzyme prolyl-4-hydroxylase, involved in procollagen formation. The coexpression of melanocytic, neural, and fibroblastic markers suggests bidirectional differentiation of neoplastic melanocytes toward (myo)fibroblasts and Schwann cells, a feature that was confirmed by electron microscopy. Furthermore, the lack of CD90 and CD13 staining in a wide range of melanocytic lesions suggests specificity of these markers for spindle cell melanoma.
 ...
PMID:New phenotypical and ultrastructural findings in spindle cell (desmoplastic/neurotropic) melanoma. 1466 57

Neural crest (NC) cells arise in the dorsal neural tube (NT) and migrate into the embryo to develop into many different cell types. A major unresolved question is when and how the fate of NC cells is decided. There is widespread evidence for multipotential NC cells, whose fates are decided during or after migration. There is also some evidence that the NC is already divided into subpopulations of discrete precursors within the NT. We have investigated this question in the mouse embryo. We find that a subpopulation of cells on the most dorsomedial aspect of the NT express the receptor tyrosine kinase Kit (previously known as c-kit), emigrate exclusively into the developing dermis, and then express definitive markers of the melanocyte lineage. These are thus melanocyte progenitor cells. They are generated predominantly at the midbrain-hindbrain junction and cervical trunk, with significant numbers also in lower trunk. Other cells within the dorsal NT are Kit-, migrate ventrally, and, from embryonic day 9.5, express the neurotrophin receptor p75. These cells most likely only give rise to ventral NC derivatives such as neurons and glia. The p75+ cells are located ventrolateral to the Kit+ cells in areas of the NT where these two cell types are found. These data provide direct in vivo evidence for NC lineage segregation within the mouse neural tube.
 ...
PMID:Neural crest cell lineage segregation in the mouse neural tube. 1554 76

Using an embryoid body (EB) culture system, we developed a functional organ-like cluster--a "gut"--from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited spontaneous contractions but did not exhibit distinct peristalsis-like movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (c-kit [a transmembrane receptor that has tyrosine kinase activity]-positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified; however, enteric neural ganglia were absent in the spontaneously differentiated ES gut. By adding brain-derived neurotrophic factor (BDNF) only during EB formation, we for the first time succeeded in in vitro formation of enteric neural ganglia with connecting nerve fiber tracts (enteric nervous system [ENS]) in the ES gut. The ES gut with ENS exhibited strong peristalsis-like movements. During EB culture in BDNF(+) medium, we detected each immunoreactivity associated with the trk proto-oncogenes (trkB; BDNF receptors) and neural crest marker, proto-oncogene tyrosine-protein kinase receptor ret precursor (c-ret), p75, or sox9. These results indicated that the present ENS is differentiated from enteric neural crest-derived cells. Moreover, focal stimulation of ES guts with ENS elicited propagated increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) at single or multiple sites that were attenuated by atropine or abolished by tetrodotoxin. These results suggest in vitro formation of physiologically functioning enteric cholinergic excitatory neurons. We for the first time succeeded in the differentiation of functional neurons in ENS by exogenously adding BDNF in the ES gut, resulting in generation of distinct peristalsis-like movements.
 ...
PMID:In vitro formation of enteric neural network structure in a gut-like organ differentiated from mouse embryonic stem cells. 1652 1


1 2 Next >>