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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-kit protooncogene encodes a type III transmembrane receptor kinase, the stem cell factor receptor, or KIT. The ligand of the KIT. stem cell factor, is a cytokine that stimulates mast cell growth and differentiation. We have studied immunohistochemically KIT expression in 23 canine mast cell tumors (MCTs), 10 histiocytomas, 5 malignant melanomas, and in 2 cell lines derived from mast cells (HMC-1, human and C2, canine). As expected, KIT was detected both in the human mast cell leukemia cell line (HMC- ) and in the canine mastocytoma cell line C2. In normal canine skin, KIT expression was confined to mast cells. All canine MCTs expressed KIT, although the intensity of the staining reaction varied considerably among the 23 neoplasms. Grade III tumors showed the highest expression of KIT, whereas grade I tumors showed the lowest expression of KIT. Two patterns of KIT expression were detected in mast cells. In normal canine mast cells and in some neoplastic mast cells, KIT appeared mainly on the cell membrane. However, in many canine MCTs, KIT is accumulated in the cytoplasm, usually near the cell nucleus. The meaning of these two patterns is not clear. Expression of KIT could not be detected immunohistochemically in any of the other neoplasias investigated. According to our results, it can be concluded that most, if not all, canine MCT express KIT. Furthermore, there is an inverse correlation between the degree of differentiation and the expression of KIT. Moreover, according to our results, KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors.
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PMID:Canine mast cell tumors express stem cell factor receptor. 1069 17

Eosinophils, the major immune effector cells contributing to allergic inflammation and asthma, are profoundly affected by interleukin (IL) 5 with respect to their differentiation, viability, recruitment, and cytotoxic effector functions. IL-5 enhances eosinophil responsiveness to a variety of chemotactic factors via a process called priming, although the molecular mechanism is unknown. In this study, we report that, following IL-5 priming of eosinophils, chemotactic agents including fMet-Leu-Phe, IL-8, and RANTES, promote vigorous transient activation of ERK1 and ERK2. In contrast, these chemotactic factors stimulate weak or indiscernible ERK activation in unprimed eosinophils. Furthermore, this intracellular marker of priming is selective for IL-5-related cytokines, in that it is observed following exposure to IL-5 and granulocyte macrophage-colony stimulating factor but not to interferon-gamma, stem cell factor, tumor necrosis factor alpha, or IL-4. Interestingly, priming of chemoattractant-induced ERK activation is accompanied by an increase in association of tyrosine-phosphorylated proteins with the adapter protein Grb2. The biological relevance of ERK activation to IL-5 priming is supported by the observation that inhibition of ERK activity by treatment with the MEK inhibitors PD98059 or U0126 inhibited the release of leukotriene C(4) stimulated by fMet-Leu-Phe in IL-5-primed eosinophils. These data provide evidence for a previously undescribed fundamental mechanism by which stimulation of IL-5 family receptors induces a rapid phenotypic alteration in the signal transduction pathways of chemotactic receptors, enabling their activation of the ERK1 and ERK2 pathway and contributing to the capacity of these cells to synthesize LTC(4).
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PMID:ERK1 and ERK2 activation by chemotactic factors in human eosinophils is interleukin 5-dependent and contributes to leukotriene C(4) biosynthesis. 1075 97

Stem cell factor (SCF) and its receptor KIT play an important role in various biologic phases, such as hematopoiesis, reproduction, and regeneration. It has been possible to measure both soluble SCF and soluble KIT using enzyme-linked immunosorbent assay since 1993 and 1995, respectively. Although the significance of interaction of soluble SCF with soluble KIT has not yet been elucidated, in certain diseases proteins fluctuate in human sera. We found that serum SCF levels were fivefold higher in patients with chronic renal failure than levels in healthy controls. We review the results of the analysis of SCF. In addition, possible pathologic mechanisms in various clinical abnormalities and the clinical potential for recombinant human SCF are discussed.
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PMID:Measurement of KIT ligand/stem cell factor: clinical and biochemical significance. 1078 49

C-kit proto-oncogene product (KIT, CD117) is a tyrosine kinase growth factor receptor for stem cell factor. This receptor is important for the development and maintenance of hematopoietic stem cells, mast cells, germ cells, melanocytes, and interstitial cells of Cajal and is constitutively expressed in them. Among mesenchymal tumors, KIT seems to be specific for the gastrointestinal stromal tumors, which consistently express this protein. Activating mutations in the tyrosine kinase or juxtamembrane domains of c-kit gene have been found in mastocytoma, seminoma, and gastrointestinal stromal tumors. Following up our initial observation of KIT expression in one angiosarcoma, we examined 50 angiosarcomas, 13 Kaposi sarcomas, 10 epithelioid hemangioendotheliomas, and 31 hemangiomas of different types for KIT expression using a polyclonal antiserum specific to KIT. Adult and fetal tissues and neovascular endothelia in 20 carcinomas were studied for comparison. More than half (56%) of the angiosarcomas representing different clinicopathologic and histologic subtypes and 2 of 13 Kaposi sarcoma were KIT positive. All epithelioid hemangioendotheliomas and hemangiomas were negative, with the exception of two infantile hemangiomas that showed KIT reactivity. The fetal capillary endothelia of lungs, placenta, and soft tissues were also KIT positive, although in soft tissues and placenta, KIT positivity was more prominent in the first trimester. However, endothelia of adult vessels and neovascular capillaries of carcinomas were negative. None of the four KIT-positive angiosarcomas and one KIT-positive Kaposi sarcomas that were studied showed mutations in the juxtamembrane or tyrosine kinase domains of the c-kit gene. These results indicate that KIT expression occurs in a subset of angiosarcomas, and the expression probably represents oncofetal expression (i.e., reversion of the tumor cell phenotype to that of fetal endothelial cells that may show KIT expression).
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PMID:KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of C-kit. 1082 25

To address the value of ex vivo expanded haematopoietic cells for shortening cytopenia in autologous haematopoietic transplantation, we designed an ex vivo expansion protocol based on a cocktail of early acting cytokines and short-term culture and tested it in a baboon model. Expansion involved enriched CD34+ peripheral blood haematopoietic cells cultured for 6 d with a combination of FLT3-L, stem cell factor (SCF), thrombopoietin (TPO) and interleukin (IL)-3 (50 ng/ml each); CD34+ cells, granulocyte-macrophage colony-forming units (GM-CFU) and megakaryocytic colony-forming units (MK-CFU) were amplified, respectively, 10.5-, 20.5- and 17.9-fold. Baboons were submitted to a myeloablative regimen consisting of cyclophosphamide plus total body irradiation (TBI; 6 Gy) and were then grafted with either 2 x 106/kg unmanipulated CD34+ cells (control group, n = 4) or cells cultured from 2 x 106/kg CD34+ cells (expansion group, n = 4). No cytokines were administered after transplantation. All the animals engrafted. The mean times to white blood cell (WBC), granulocyte and platelet recovery were significantly shorter in the expansion group than in the control group: WBC (> 1 x 109/l) and neutrophil (> 0.5 x 109/l) recovery occurred on days 8 (range 6-9) and 9 (range 6-11), respectively, compared with days 12 (range 10-15) and 14 (range 11-16); platelets recovered (> 20 x 109/l) on day 9 (range 7-12) compared with day 13 (range 11-15) in the control group (P < 0.05). No toxicity was observed after reinfusion. No secondary hypoplasia was observed during more than 12 months of follow-up. Functions of both neutrophils and platelets produced from expanded cells were normal in terms of oxidative metabolism, chemotaxis and the bleeding time. This study shows that in comparison with unmanipulated cells peripheral blood haematopoietic cells expanded from similar doses of CD34+ cells, under the conditions defined here, accelerated both neutrophil and platelet recovery without impairing long-term haematopoiesis.
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PMID:Ex vivo expanded mobilized peripheral blood CD34+ cells accelerate haematological recovery in a baboon model of autologous transplantation. 1084 96

The c-KIT protooncogene encodes a tyrosine kinase receptor, KIT, that is expressed in many normal and cancerous tissues. In this study, we have examined the expression of c-KIT and its ligand, stem cell factor (SCF), in human epithelial ovarian tumors, in normal ovaries and in cultured ovarian surface epithelium (OSE). Cultured cells, normal tissues and tumors were analyzed by Northern and Western blot analyses, reverse transcription-polymerase chain reaction and immunohistochemistry. Normal OSE expressed SCF, but not c-KIT; however, epithelial invaginations and inclusion cysts often expressed KIT protein. Of 15 benign ovarian tumors and tumors of low malignant potential, 87% expressed c-KIT, and 92% of these co-expressed SCF, suggesting the possibility of autocrine growth regulation. Of 35 malignant ovarian cancers, 71% expressed c-KIT (92% co-expressed SCF), with a trend for decreased c-KIT expression in advanced stage disease. Of 34 patients with malignant tumors for whom follow-up information was available (median follow-up time of 24 months), 9 had tumors that did not express c-KIT, 8 (89%) of whom have died and the remaining 1 has recurrent disease. Of the 25 patients with tumors expressing c-KIT, 56% are still alive. Eight of the patients have no evidence of disease and all had KIT-expressing tumors. Statistical analysis indicated that patients whose tumors did not express c-KIT had a significantly shorter (p < 0.05) disease-free survival time than patients who had KIT-expressing tumors. Our results suggest that c-KIT may play a role in early ovarian tumorigenesis, and that loss of c-KIT expression is associated with poor prognosis.
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PMID:Lack of expression of c-KIT in ovarian cancers is associated with poor prognosis. 1086

The expression of the Flk2/Flt3 molecule (CD135), the receptor for Flt3 ligand (FL), was investigated in the human thymus. Results showed that there is a high level of expression of CD135 by thymocyte populations, especially by intrathymic T-cell precursor populations. As these results suggested a role for FL in the regulation of thymic T-cell precursor differentiation and/or proliferation, we used an in vitro model of thymic stromal cell cultures in order to delineate the activity of FL on human CD7(high)CD3-CD4-CD8- triple negative intrathymic T-cell precursors. Results showed that FL, either alone or in combination with stem cell factor (SCF) induced the proliferation of CD7(high) precursors, but to a lower extent than interleukin-7 (IL-7) or IL-7 + SCF, used as positive controls. In the presence of FL + SCF, CD7(high) cells developed mainly towards a CD11b+ phenotype whereas IL-7 + SCF preferentially induce a CD3+TcRgammadelta+CD8+ phenotype. Taken together, these data suggest that FL may play a role in inducing the proliferation of CD7(high) human intrathymic T-cell precursors, but also in the induction of a myeloid differentiation pathway within the human thymus.
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PMID:CD135 (Flk2/Flt3) expression by human thymocytes delineates a possible role of FLT3-ligand in T-cell precursor proliferation and differentiation. 1088 84

Stem cell factor (SCF) and endothelin-3 (ET3) are both necessary for melanocyte development. In order to obtain immortal cell populations of melanoblasts that can survive without feeder cells, we first obtained an immortal cell population of neural crest cells (NCCs) from Sl/+ and +/+ mice of strain WB by incubating with a culture medium supplemented with SCF and ET3, and then we designated them as NCC-SE3 cells. NCC-SE3 cells were bipolar, polygonal, or round in shape and possessed melanosomes of stages I-III (mainly stage I). They were positive to dihydroxyphenylalanine (DOPA) reaction and expressed KIT (a receptor tyrosine kinase), tyrosinase, tyrosinase-related protein-1 (TRP1), tyrosinase-related protein-2 (TRP2), and endothelin-B receptor (ETRB) as determined by immunostaining. We next cultured NCC-SE3 cells by changing culture medium from the one supplemented with SCF + ET3 to the one supplemented with SCF or ET3. NCC-SE3 cells cultured with ET3 alone, designated as NCC-E3 cells, were bipolar in shape and had mainly stage II melanosomes and expressed the same proteins as did NCC-SE3 cells. However, NCC-SE3 cells cultured with SCF alone, designated as NCC-S4.1 cells, were polygonal in shape and had mainly stage I melanosomes. They are thought to be more immature because they were positive to KIT, TRP1, and TRP2, but not to ETR(B), tyrosinase, and DOPA reaction. When 12-O-tetradecanoylphorbol 13-acetate and cholera toxin were added to the culture medium, NCC-S4.1 cells changed shape from polygonal to bipolar and became DOPA-positive. This suggests that NCC-S4.1 cells are melanoblasts that have the potential to differentiate into melanocytes. These cell populations will be extremely useful to study factors that affect melanocyte development and melanogenesis.
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PMID:Stem cell factor and/or endothelin-3 dependent immortal melanoblast and melanocyte populations derived from mouse neural crest cells. 1104 61

Before stem cell gene therapy can be considered for clinical applications, problems regarding cytokine prestimulation remain to be solved. In this study, a retroviral vector carrying the genes for the enhanced version of green fluorescent protein (EGFP) and neomycin resistance (neo(r)) was used for transduction of CD34+ cells. The effect of cytokine prestimulation on transduction efficiency and the population of uncommitted CD34+CD38- cells was determined. CD34+ cells harvested from umbilical cord blood were kept in suspension cultures and stimulated with combinations of the cytokines stem cell factor (SCF), FLT3 ligand, interleukin-3 (IL-3), IL-6, and IL-7 prior to transduction. Expression of the two genes was assessed by flow cytometry and determination of neomycin-resistant colonies in a selective colony-forming unit (CFU) assay, respectively. The neomycin resistance gene was expressed in a higher percentage of cells than the EGFP gene, but there seemed to be a positive correlation between expression of the two genes. The effect of cytokine prestimulation was therefore monitored using EGFP as marker for transduction. When SCF was compared to SCF in combination with more potent cytokines, highest transduction efficiency was found with SCF and IL-3 and IL-6 (5.05% +/- 0.80 versus 2.66% +/- 0.53 with SCF alone, p = 0.04). However, prestimulation with SCF in combination with IL-3 and IL-6 also reduced the percentage of CD34+ cells (p = 0.02). Then, prestimulation with SCF and FLT3 ligand was compared. Significant difference in transduction efficiency was not found. Interestingly, FLT3 ligand seemed to preserve the population of CD34+CD38- cells compared to SCF (16.56% +/- 2.02 versus 9.39% +/- 2.35, p = 0.03). In conclusion, prestimulation with potent cytokine combinations increased the transduction efficiency, but reduced the fraction of CD34+ cells. Importantly, the use of FLT3 ligand seemed to preserve the population of uncommitted cells.
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PMID:FLT3 ligand preserves the uncommitted CD34+CD38- progenitor cells during cytokine prestimulation for retroviral transduction. 1109 93

Cord blood (CB) stem cell transplantations have been associated with delayed hematopoietic engraftment. This has most likely been due to the limited numbers of hematopoietic short-term repopulating cells in CB. Ex vivo expansion of CB has been attempted, and expansion of CD34-enriched CB has been successful; however, CD34 enrichment procedures are in general associated with substantial cell loss. Thus, we have studied culture conditions for expansion of nonenriched CB. Nonenriched CB cells were cultured for 21 days in the presence of conditioned medium from the HS-5 stromal cell line and FLT3-L or alternatively in the presence of FLT3-L, stem cell factor (SCF), megakaryocite growth and development factor (MGDF), and granulocyte colony-stimulating factor (G-CSF) (FSMG), either on fibronectin fragment CH-296-coated dishes or on uncoated dishes. With all four culture conditions, the number of mononuclear cells initially decreased until day 7 and then increased until the end of the expansion cultures. Overall expansion using HS-5 and FLT3-L resulted in superior expansion of MNC and CFU-C (44-/34-fold) for both cultures with and without CH-296 compared to FSMG (18-/17-fold). Expansion on CH-296 was less efficient than expansion on tissue culture-treated wells without CH-296 for both conditions. We then studied the best time for transduction on nonenriched CB. In contrast to enriched CD34 cells, we found for both conditions, HS-5/FLT3-L and growth factor cocktail, higher transduction efficiencies when cells were transduced on day 7 as compared to day 2. Gene transfer rates up to 45% were achieved with both conditions, which corresponded with the increased number of cells in S phase on day 7 compared to day 2. We conclude that HS-5 and FLT-3L allow efficient expansion and transduction of nonenriched CB.
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PMID:Expansion and transduction of nonenriched human cord blood cells using HS-5 conditioned medium and FLT3-L. 1109


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