UNIPROT:P10721 - FACTA Search

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Query: UNIPROT:P10721 (c-kit)
6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell factor (SCF) binds and activates the receptor tyrosine kinase c-Kit, and this interaction is critical for normal hematopoiesis. SCF also synergizes with a variety of growth factors, including those binding members of the cytokine receptor superfamily. The mechanisms mediating this synergy remain to be defined. The present study investigates both structural and biochemical cross-talk between c-Kit and the receptor for granulocyte macrophage colony-stimulating factor (GM-CSF). We have found that c-Kit forms a complex with the beta-chain of the GM-CSF receptor, and this interaction involves the first part of the c-Kit kinase domain. Although inhibition of c-Kit kinase activity completely blocked SCF-induced proliferation, there was still greater than additive growth induced by SCF in combination with GM-CSF. In contrast, an inhibitory antibody against the extracellular domain of c-Kit (K-27) completely inhibited growth in response to SCF alone or in combination with GM-CSF. These results support a kinase-independent component of the synergistic growth induced by SCF and GM-CSF that may relate to interaction of these receptors. It is also clear that a significant part of the synergistic growth is dependent of c-Kit kinase activity. Although synergistic increases in phosphorylation of c-Kit and the beta-chain of the GM-CSF receptor were not observed, SCF and GM-CSF in combination prolonged the duration of Erk1/2 phosphorylation in a phosphatidylinositol 3-kinase-dependent manner. Consistent with these findings, phosphatidylinositol 3-kinase is synergistically activated by SCF and GM-CSF together. Hence, c-Kit makes both kinase-independent and -dependent contributions to the proliferative synergy induced by SCF in combination with GM-CSF.
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PMID:Synergistic growth of stem cell factor and granulocyte macrophage colony-stimulating factor involves kinase-dependent and -independent contributions from c-Kit. 1530 71

1. The aim of the present study was to examine the effects of mobilization of bone marrow cells by granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) on ventricular function after myocardial infarction (MI). 2. After ligation of the left coronary artery, rats were divided into a vehicle control group (MI group) and a CSF-treated group (MI-CSF group). Rats in the MI-CSF group received a combination of G-CSF (50 microg/kg per day) and M-CSF (10(6) IU/kg per day) for 5 days after MI. Two weeks after MI, hearts were isolated and perfused with a Krebs' buffer and their functional responses to step-wise elevation of left ventricular end-diastolic pressure (LVEDP) were assessed. In histological analysis, proliferating cells and bone marrow-derived cells were identified by antibodies against Ki-67 and c-kit and organization of collagen was examined by picrosirius red staining. The mRNA levels of transforming growth factor (TGF)-beta(1), collagen type I and collagen type III were measured by quantitative reverse transcription-polymerase chain reaction. 3. Numbers of Ki-67- and c-kit-positive cells in the infarct border zone after MI were increased by CSF treatment, but few of those cells were stained by anti-alpha-sarcomeric actin. The levels in mRNA of TGF-beta1 and collagen type I in the infarct border zone were higher in the CSF-treated group compared with the MI group. Although CSF treatment did not reduce ventricular hypertrophy or infarct size at 2 weeks after MI, it did significantly improved the response of left ventricular developed pressure to step-wise elevation of LVEDP. This effect was mimicked by treatment with M-CSF alone. The functional improvement by CSF treatment was correlated with suppression of enlargement of the infarct-non-infarct border associated with infarct expansion. Collagen fibres in the border zone were thicker and orientated more orderly in the CSF-treated group than in the untreated group. 4. The results suggest that G-CSF/M-CSF treatment improves contractile function of the ventricle after infarction, presumably by acceleration of infarct repair and suppression of remodelling in the border zone.
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PMID:Granulocyte colony stimulating factor/macrophage colony stimulating factor improves postinfarct ventricular function by suppression of border zone remodelling in rats. 1565 52

Hematopoietic cell-specific disruption of the STAT3 gene induces hyperproliferation of cells of the myeloid lineage. Osteoclasts (OC), the bone-resorbing cells, are generated from the same precursors as monocyte/macrophages. STAT3 mutant mice exhibit decreased bone density, bone volume, and increased numbers of TRAP-positive OC. In vitro generation of OC showed significantly greater numbers of OC in mutant mice. The increased numbers of Mac1+ cells and c-kit+ cells were detected by FACS analysis, suggesting an increased number of OC precursors. Treatment of splenocytes with CSF-1 and RANKL significantly increased the Mac-1+RANK+ cells, with much higher levels observed in cells from mutant mice compared with littermate controls. Besides enhanced number of Mac1+ OC precursors, we also identified an OC-generating Mac1- c-kit+ population in mutant mice which was absent in littermate controls. The Mac1- c-kit- cells did not generate OC. Finally, we determined that protein expression and mRNA level of c-fos, a transcription factor which is essential for OC differentiation, were enhanced in OC precursors of mutant mice, which may contribute to the osteopenic phenotype.
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PMID:Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice. 1569 17

Over 100 years after the first description of macrophages by Metchnikoff, there are still questions as to the mechanisms leading to the heterogeneity of their lineage. Current views are based on the mononuclear phagocyte system (MPS) theory, where all mammalian macrophages are derived from circulating blood monocytes and ultimately from hematopoietic stem cells in the bone marrow. Our studies on the regulation of fish macrophage development, suggested that teleosts have alternate pathways of monopoiesis, which undoubtedly contribute to macrophage heterogeneity in the goldfish. Macrophage heterogeneity has been attributed to a network of positive and negative regulators of macrophage development, including soluble mediators known as colony-stimulating factors of which two (M-CSF and GM-CSF) promote formation and growth of mature macrophages. In contrast to our knowledge of CSFs and their receptors in mammals, there is no published information about fish macrophage CSFs. Since fish macrophages generate their own growth factors, it is reasonable to assume that pathways of fish macrophage development and hematopoiesis may be distinct from those of mammalian macrophages. More importantly, the presence of fish progenitor/stem cells and developing macrophages in long-term cultures, allowed us to address pathways of macrophage differentiation, which could not be addressed in mammalian macrophage culture systems. Characterization of primary kidney macrophage (PKM) cultures from goldfish hematopoietic tissues (kidney) indicated that three distinct subpopulations developed in response to endogenous macrophage growth factors. These macrophage subpopulations expressed several differentiation markers, including the hematopoietic stem cell antigen AC133, c-kit, granulin, CD63, macrosialin, c/EBPbeta, legumain, and the colony-stimulating factor receptor-1 (CSF-1R). In the goldfish, there appeared to be a stringent control between those early progenitors that self-renewed, and those that were recruited into the maturation pathways. We report that upon commitment, goldfish macrophages developed through two distinct differentiation pathways: one consistent with the "classical" pathway (MPS) of macrophage development (progenitors-->monocytes-->mature macrophages), and an "alternate" pathway (AP-macrophages) where mature macrophages appeared to rapidly develop from early progenitors in the absence of an intermediate monocyte stage. AP-macrophages represent a unique subset of spontaneously growing cells. Their self-renewal was promoted by endogenous macrophage growth factors (MGF), and effectively controlled by a novel soluble form of the CSF-1R (sCSF-1R). The discovery of sCSF-1R in the goldfish highlights the inherent complexity in the hematopoietic regulatory machinery of teleosts.
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PMID:Development of goldfish macrophages in vitro. 1593 14

Acute myeloid leukaemia (AML) is a heterogenous malignant disease with diverse biological features in which disease progression at the level of CD34+ cells has a major impact on the resistance to chemotherapy and relapse. The AML blast cells in these elderly patients are often characterised by several unfavourable covariates that predict the poor treatment outcome, including high stem cell marker CD34 expression, minimally or undifferentiated features, high P-glycoprotein expression, high bcl-2/bax ratio, unfavourable karyotype and more frequent internal tandem duplications (ITDs) and mutations of class III receptor-type tyrosine kinase for key haematopoietic cytokines: Flt-3 (receptor for Flt-ligand), c-kit (receptor for stem cell factor) and fms (receptor for M-CSF). Testing the new and more specific molecular-targeted therapeutic approaches in CD34+ AML cells can provide the basis for a more effective combined molecular/chemotherapy regimen and may consequently improve the treatment outcome in elderly AML patients. Therefore, the present study was performed to evaluate whether stem cell factor-antibody (anti-SCF) can enhance the efficacy of the two main chemotherapeutic drugs used in AML therapy: cytarabine and daunorubicin at low doses in human-resistant CD34+ AML cells, in an attempt to identify a novel effective regimen with tolerable side-effects for elderly AML patients. The effect of anti-SCF on each of the two chemotherapeutic drugs-induced apoptosis and necrosis was investigated in KG1a human-resistant CD34+ AML cells expressing P-glycoprotein to determine its enhancing activity. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells from 12.0+/-1.7 to 40.9+/-5.9% and from 16.3+/-0.9 to 48.9+/-1.0%, respectively, p<0.01. It has also exerted its significant enhancement activity on the low dose cytarabine- and daunorubicin-induced apoptosis+necrosis in KG1a CD34+ AML cells in the presence of SCF, p<0.05. Anti-SCF has significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells from 26.7+/-0.6 to 64.6+/-1.0% and from 59.8+/-3.1 to 80.1+/-7.9%, respectively, p<0.01. The addition of SCF has not altered the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells (Table 4). Anti-SCF has also significantly enhanced the low dose cytarabine- and daunorubicin-induced bcl-2 reduction in KG1a CD34+ AML cells in the presence of SCF, p<0.05. The unique potent enhancing activity of anti-SCF on low dose chemotherapy-induced apoptosis and necrosis in extremely resistant AML cells suggest a novel promising role for the treatment of elderly AML patients. Further studies are warranted to evaluate a similar enhancing effect for anti-SCF in blast cells from elderly AML patients in primary cultures before its introduction in a pilot clinical study. In conclusion, the combination of anti-SCF and the low dose cytarabine provides a promising solution for the dilemma of therapy in elderly AML patients.
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PMID:Human stem cell factor-antibody [anti-SCF] enhances chemotherapy cytotoxicity in human CD34+ resistant myeloid leukaemia cells. 1611 92

Large ex vivo expansion of hematopoietic stem cells (HSCs) sufficient for use in clinical applications has not been achieved, although the influence of some cytokines including SCF, IL-11, Flt3-L, and TPO for this purpose has been reported. We present evidence for an indirect effect of macrophage colony-stimulating factor (M-CSF) on expansion of murine HSCs. Fresh Lin(-/low) cells were isolated from Ly5.1 mouse bone marrow and cultured with or without M-CSF in the presence of SCF + IL-11 + Flt3-L or SCF + IL-11 + TPO for 6 days. The expanded cells were harvested and transplanted into lethally irradiated Ly5.2 recipients with competitor cells. Culture of Lin(-/low) cells with M-CSF significantly enhanced long-term engraftment. When the more enriched HSC populations of Lin(-/low) c-Kit(+) Sca-1(+) cells were used as a source of HSCs, such a promotive effect was not observed, in agreement with negative expression of the M-CSF receptor (c-Fms). However, co-culture with Lin(-/low) c-Fms(+) resulted in a significant increase of long-term engraftment. These results suggested that M-CSF is an indirect stimulator for ex vivo expansion of HSCs in the presence of SCF, IL-11, Flt3-L, and TPO. These observations provide new directions for ex vivo expansion and insight into new engraftment regulation through M-CSF signaling.
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PMID:Promotive effect of macrophage colony-stimulating factor on long-term engraftment of murine hematopoietic stem cells. 1611 68

OP-9 cells are stromal cells derived from macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice. To evaluate the OP-9 capability to sustain long-term hematopoiesis, we reported the expansion of granulocyte colony-stimulating factor (G-CSF)-mobilized human peripheral blood (PB) CD34(+) cells in co-culture with murine OP-9 and MS-5 stromal cells, either transfected with various combinations of adenovectors (Ad) expressing c-kit ligand (KL) (either soluble or transmembrane form), thrombopoietin (TPO), flt-3/flk2 ligand (FL), and granulocyte-macrophage (GM)-CSF or with weekly addition of these cytokines. Expression of TPO as well as association of TPO, FL, and KL increased progenitor cell and week-6 cobblestone area forming cell (CAFC) production in all stromal co-cultures. Similar progenitor expansion was obtained by weekly addition of soluble cytokine. Five weeks of co-culture with OP9 and TPO, FL + KL resulted in the greatest expansion of progenitor cells and week-6 CAFC as measured by secondary assay on MS-5. In contrast to MS-5 and TPO or TPO + FL + KL cultures where hematopoiesis declined by week 4, progenitor as well as week-6 CAFC expansion continued for over 3 months in TPO + FL + KL OP9 cocultures. This was associated with decrease of CD14(+) macrophage production. The addition of human macrophage (M)-CSF or CD14(+) cells to the co-culture decrease progenitor and stem cell expansion; however, murine M-CSF to OP-9 co-cultures did not decrease progenitor expansion. High levels of stromal-derived factor-1 (SDF-1) production by MS-5 and low or absent production by OP-9 may account for stem cell adhesion and CAFC formation in the former cultures and the predominance of stem and progenitor cells in the nonadherent fraction in the latter cultures.
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PMID:Osteopetrotic mouse stroma with thrombopoietin, c-kit ligand, and flk-2 ligand supports long-term mobilized CD34+ hematopoiesis in vitro. 1630 36

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC(50)s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases.
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PMID:A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. 1712 10

c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase.
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PMID:The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain. 1729 18

c-Kit encodes for the receptor tyrosine kinase (RTK) and belongs to type III receptor family. This includes platelet derived growth factor (PDGF) alpha and beta and macrophage colony stimulating factor (mCSF) apart from others. Their characteristic features are the presence of five immunologlobulin like domains in the extracellular region and 70-100 residues long kinase insert domain in the cytoplasmic region. The RTKs activate several signaling pathways within the cells leading to cell proliferation, differentiation, migration or metabolic changes. The Kit ligand-stem cell factor (SCF) induces a rapid and complete receptor dimerization resulting in activation by autophosphorylation of the catalytic tyrosine kinase and generation of signal transduction leading to regulation of cell growth. Various mutations in c-kit such as insertions and deletions (without affecting reading frame) and point mutations in the inhibitory juxtamembrane (JM) domain encoded by exon 11 have been reported in gastrointestinal stromal tumors (GISTs). Thus, c-kit signaling is believed to play a role in tumorigenesis. Efforts are being made to control and treat these tumors by blocking kit signaling using Imatinib with varying degrees of success. This review deals with the features of c-kit, its ligand and roles in gastrointestinal stromal tumors.
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PMID:Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). 1765 49

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