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 biological effects of c-kit ligand (stem-cell factor: SCF) on an immortalized human megakaryocytic cell line (CMK) was evaluated using methods including the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, surface marker analysis, DNA cell-cycle analysis and immunoblotting. SCF stimulated the growth of CMK cells. Incubation with SCF resulted in increased expression of IIb/IIIa platelet-related glycoprotein (gpIIb, IIIa), indicating enhanced differentiation of CMK cells. Treatment of CMK cells with SCF resulted in a decrease in the subpopulation in the G1 phase, with a reciprocal increase in those in the S phase and the G2 + M phase. Moreover, SCF significantly increased cellular expression of cyclin A, a regulatory subunit of cyclin-dependent protein kinase (CDK), and the ratio of phosphorylated/dephosphorylated retinoblastoma gene product (RB protein). These results suggest that SCF stimulates the growth and differentiation of megakaryocytic cells possibly through mechanisms related to the activation of cell-cycle-dependent serine/threonine kinase and inactivation of the nuclear tumor-suppressor gene product.
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PMID:Stem-cell factor regulates the expression of cyclin A and retinoblastoma gene product in the growth and differentiation pathway of human megakaryocytic cells. 869 43

We sought to determine the functional significance of the c-kit receptor (Kit) in melanoma, breast carcinoma, and non-small cell lung cancer (NSCLC). To explore these issues, we first screened cell lines of each type for c-kit mRNA expression using a reverse-transcription polymerase chain reaction. We found that WM-39 melanoma cells, HTB-22 breast carcinoma cells, and A549 NSCLC cells all expressed c-kit mRNA. Of interest, all of these cells expressed the c-kit ligand, Steel factor (SF). We then assessed the functional significance of c-kit and SF expression by disrupting the gene's expression with antisense (AS) oligodeoxynucleotides (ODN) targeted to c-kit mRNA codons 1-6 and SF mRNA codons 2-7, respectively. Nonhybridizing sequences [sense (5) and scrambled (SCR)] were also employed as controls. WM-39, HTB-22, and A549 cells were exposed to ODN (approximately 25 microM) for 5-7 days. Downregulation of c-kit and SF mRNA, and c-kit protein was demonstrated in cells treated with AS ODN. Effects on viable cell growth were demonstrated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) or 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 -sulfophenyl)- 2H-tetrazolium (MTS) assay. In fact, c-kit antisense ODN inhibited the viable cell growth of A549 cells 66% and 79% compared to sense and untreated controls (P = .0003; P < .0001). Additionally, WM-39 cell growth was inhibited 48% and 21% (P < .0001, P < .03) and HTB-22 cell growth was inhibited 50% (P < .001) compared to sense and untreated controls. Viable cell growth was also significantly inhibited by SF AS ODN compared to S and SCR controls in all cell lines. These results demonstrate that WM-39, HTB-22, and A549 NSCLC cells all express the c-kit and SF protooncogenes and suggest that the encoded receptor and ligand are important for cell growth. By finding the presence, and functional importance, of both the receptor and ligand in these cells, this study suggests the existence of an autocrine loop growth mechanism worthy of further study.
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PMID:Evidence for a functional kit receptor in melanoma, breast, and lung carcinoma cells. 917 36

This study determines the effect of hepatocyte growth factor (HGF) on post-infarction left ventricular (LV) remodeling and cardiac function. In mice, on day 1 after myocardial infarction (MI), HGF (0.45 mg/kg per day) was injected into the tail vein for 7 days (n = 12). In the control mice (n = 12), 0.9% sodium chloride was injected instead of HGF. Hemodynamic data were obtained in vehicle treated control and HGF-treated hearts 4 weeks after the onset of MI. In the HGF-treated group, cardiac function was well preserved as indicated by LV pressure-volume relationship. These mice exhibited better LV systolic and diastolic function. The infarcted LV wall in HGF-treated heart was thicker as compared to vehicle treated group. Fibrosis and infarct size of the ventricular wall was significantly reduced in the HGF-treated hearts. 5-Bromo-2'-deoxy-uridine (BrdU) and Ki67 positive cardiomyocytes were observed in the border area of the HGF-treated infarcted hearts. c-Met and c-kit positive cardiomyocytes were observed in the border area and epicardium. Angiogenesis was significantly enhanced in HGF-treated hearts as determined by vessel density per unit area. A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. Treatment with HGF improved heart function through angiogenesis, ventricular wall thickening, and hypertrophy of cardiomyocytes. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway.
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PMID:Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis. 1552 81

Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in t he hepaticprogenitor cell population in 16 patients with non-responding chronic hepatitis C Interferon alpha-based treatment significantly reduced the numbers of c-kit-positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murinehepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validatethese results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha-based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation. Supplementay material for this article can
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PMID:Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo. 1662 47

Histone deacetylases (HDACs) play a critical role in the regulation of gene transcription, cardiac development, and diseases. The aim of this study was to test whether inhibition of HDACs induces myocardial repair and cardiac function restoration through c-kit signaling in mouse myocardial infarction models. Myocardial infarction in wild type Kit(+/+) and Kit(W)/Kit(W-v) mice was created following thoracotomy by applying permanent ligation to the left anterior descending artery. The HDAC inhibitor, trichostatin A (TSA, 0.1 mg/kg), was intraperitoneally injected daily for a consecutive 8 weeks after myocardial infarction. 5-Bromo-2-deoxyuridine (BrdU, 50 mg/kg) was intraperitoneally delivered every other day to pulse-chase label in vivo endogenous cardiac replication. Eight weeks later, inhibition of HDACs in vivo resulted in an improvement in ventricular functional recovery and the prevention of myocardial remodeling in Kit(+/+) mice, which was eliminated in Kit(W)/Kit(W-v) mice. HDAC inhibition promoted cardiac repairs and neovascularization in the infarcted myocardium, which were absent in Kit(W)/Kit(W-v) mice. Re-introduction of TSA-treated wild type c-kit(+) CSCs into Kit(W)/Kit(W-v) myocardial infarction heart restored myocardial functional improvement and cardiac repair. To further validate that HDAC inhibition stimulates c-kit(+) cardiac stem cells (CSCs) to facilitate myocardial repair, GFP(+) c-kit(+) CSCs were preconditioned with TSA (50 nmol/liter) for 24 h and re-introduced into infarcted hearts for 2 weeks. Preconditioning of c-kit(+) CSCs via HDAC inhibition with trichostatin A significantly increased c-kit(+) CSC-derived myocytes and microvessels and enhanced functional recovery in myocardial infarction hearts in vivo. Our results provide evidence that HDAC inhibition promotes myocardial repair and prevents cardiac remodeling, which is dependent upon c-kit signaling.
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PMID:Inhibition of histone deacetylase-induced myocardial repair is mediated by c-kit in infarcted hearts. 2302 62

Our previous study demonstrated that natriuretic peptides (NPs) play an inhibitory role in regulation of gastric smooth muscle motility. However, it is not clear whether NPs are involved in diabetics-induced loss of gastric interstitial cell of Cajal (ICC). The present study was designed to investigate the relationship between diabetics-induced loss of gastric ICC and natriuretic peptide signaling pathway in streptozotocin (STZ)-induced diabetic mice. The results showed that the protein expression levels of c-Kit and membrane-bound stem cell factor (mSCF) in gastric smooth muscle layers were decreased in STZ-induced diabetic mice. However, both mRNA and protein expression levels of natriuretic peptide receptor (NPR)-A, B and C were increased in the same place of the diabetic mice. The amplitude of spontaneous contraction in gastric antral smooth muscles was inhibited by C-type natriuretic peptide (CNP) dose-dependently and the inhibitory effect was potentiated in diabetic mice. Pretreatment of the cultured gastric smooth muscle cells (GSMCs) with different concentration of CNP can significantly decrease the mSCF expression level. 8-Bromoguanosine-3',5'-cyclomo-nophosphate (8-Br-cGMP), a membrane permeable cGMP analog, mimicked the effect of CNP but not cANF (a specific NPR-C agonist). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay showed that high concentration of cANF (10(-6) mol/L) inhibited cell proliferation in cultured GSMCs. These findings suggest that up-regulation of NPs/NPR-A, B/cGMP and NPs/NPR-C signaling pathways may be involved in diabetes-induced loss of gastric ICC.
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PMID:Diabetes-induced loss of gastric ICC accompanied by up-regulation of natriuretic peptide signaling pathways in STZ-induced diabetic mice. 2335 81

Cancer stem cells (CSCs) have been observed to share certain characteristics with normal stem cells. It was an important argument for cancer therapy and a successful progenitor inhibition could show us targeted cell type for a novel strategy. In this study, we aimed to constitute an inhibition in different stages of hepatic stem/progenitor cells (HPCs) with verapamil. Expression patterns of alpha-fetoprotein (AFP), c-kit (CD117) and p-glycoprotein were investigated in developing mouse on the embryonic day (E) 15, E18 and E21 to characterize early and late stages of HPCs. Proliferation inhibition with 5-Bromo-2-Deoxyuridin (BrdU) incorporation and maturation inhibition with PAS staining results were supported by morphometrical analysis during these periods. AFP, c-kit and p-glycoprotein immunoreactivity increased especially in E15 but decreased in E18 and E21 of the control groups during embryonic development. Verapamil treatment effected particularly E15 cells and immunoexpression of HPCs significantly decreased. Proliferation inhibition was observed in all embryonic days of mouse with verapamil and this drug inhibited not only maturation of HPCs in E18 and E21 embryos, but also decreased HPC number in the same embryonic period. According to our results, we estimated that similar to the early and late progenitor stages of HPCs, CSCc can also be in different stages in a heterogenic tumour bulk and the difficulty of CSC inhibition could be the main mechanism of tumour relapses. In this study, HPCs inhibition by verapamil in E15 was not observed in E18 and E21. As similar, CSCs treatments targeting different stages may be impotent to cells in tumour initiating cell stage. We can speculate that ineffectiveness of CSC-specific therapies may be attributed to the highly selective specificity of the treatment (Fig. 6, Ref. 28).
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PMID:Hepatic progenitor cell inhibition during embryonic period with high dose verapamil; liable joint to the cancer therapy. 2382 19

It is well known that natriuretic peptides (NPs) are involved in the regulation of gastrointestinal motility. Interstitial cells of Cajal (ICC) are the pacemaker cells of gastrointestinal motility and gastrointestinal dyskinesia is one of the important digestive tract symptoms of depression. However, it is unclear whether they are involved in depression-induced loss of ICC. The aim of the present study was to investigate the relationship between the natriuretic peptide signaling pathway and depression-induced loss of gastric ICC in depressed rats. These results showed that the expression of c-kit and stem cell factor (SCF) in smooth muscle layers of stomach were down-regulated in depressed rats at the mRNA and protein levels. The expression of natriuretic peptide receptor (NPR)-A, B and C were up-regulated in the stomach of depressed rats at the mRNA and protein levels. NPR-A, B and C can significantly decrease the expression of SCF to treat cultured gastric smooth muscle cells (GSMCs) obtained from normal rats with different concentrations of C-type natriuretic peptide (CNP). Pretreatment of cultured GSMCs with 8-Brom-cGMP (8-Br-cGMP, a membrane permeable cGMP analog), cANF (a specific NPR-C agonist) and CNP (10-6 mol/L) demonstrated that 8-Br-cGMP had a similar effect as CNP, but treatment with cANF did not. The results of the methyl thiazolyl tetrazolium bromide (MTT) assay indicated that high concentrations of cANF (10-6 mol/L) restrained the proliferation of cultured GSMCs. Taken together, these results indicate that the up-regulation of the NPs/NPR-C and NPs/NPR-A, B/cGMP signaling pathways may be involved in depression-induced loss of gastric ICC.
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PMID:NPs/NPRs Signaling Pathways May Be Involved in Depression-Induced Loss of Gastric ICC by Decreasing the Production of mSCF. 2686 59

In a search for novel antiproliferative agents, a series of quinoxaline derivatives containing 2-aminoimidazole (8a-8x) were designed and synthesized. The structures of synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, Mass Spectroscopy and analyzed using HSQC, COSY, ROESY, HMBC techniques. The anticancer activity of all derivatives were evaluated for colon cancer and breast cancer cell lines by the MTT assay and acridine orange/ethidium bromide double staining method. The anti-cancer effect in human colon cancer (HCT-116) and breast cancer (MCF-7) cell lines exhibited that compounds 8a, 8s, 8t, 8w, 8x appeared as potent antiproliferative agents and especially inhibited the human colon cancer cell proliferation with percentage of inhibition by over 50%. The most active compound was (E)-4-phenyl-1-((quinoxalin-2-ylmethylene)amino)-1H-imidazol-2-amine (8a) with the highest inhibition for MCF-7 (83.3%) and HCT-116 (70%) cell lines after 48 and 24h, respectively. Molecular docking studies of these derivatives within c-kit active site as a validated target might be suggested them as appropriate candidates for further efforts toward more potent anticancer compounds.
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PMID:Design, synthesis, biological assessment and molecular docking studies of new 2-aminoimidazole-quinoxaline hybrids as potential anticancer agents. 2931 28

The present study aimed to determine the expression of mast cells, C-C motif chemokine ligand 2 (CCL-2) and C-C motif chemokine receptor 2 (CCR2) in gastric cancer tumor tissue; and the association of mast cells with the proliferation, migration, invasion and apoptosis of gastric cancer cells. In addition, whether the stem cell factor (SCF)/c-Kit pathway was associated with the secretion of CCL-2 by gastric cancer cells was explored. Flow cytometry analysis and immunohistochemistry were used to observe the relative number of mast cells, and reverse transcription-quantitative polymerase chain reaction and western blot analysis were utilized to determine the expression of CCL-2 and CCR2 mRNA and protein. Following the co-culture of the mast cell line HMC-1 and the gastric cancer cell line BGC-823, a Transwell assay was used to validate the effect of mast cells on the migration and invasion of gastric cancer cells. Furthermore, Cell Counting kit-8 and dual acridine orange/ethidium bromide fluorescent staining assays were performed to determine the proliferation and apoptosis of gastric cancer cells, following co-culture with mast cells. The expression of SCF and c-Kit were also determined with a western blot analysis. A specific phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, was used to test the effect of PI3K inhibition on the secretion of CCL-2 in gastric cancer. The results demonstrated that the proportion of infiltrating mast cells, and the mRNA/protein expression of CCL-2 and CCR2, were significantly increased in tumor tissue relative to adjacent tissues. In addition, the migration and invasion of gastric cancer cells were significantly increased when mast cells were used as an attractant. When co-cultured with mast cells, the viability of gastric cancer cells was significantly increased and H2O2-induced apoptosis was inhibited. In gastric cancer tissue samples, the expression of SCF, c-Kit and phosphorylated (p)-Akt protein were significantly increased compared with normal adjacent tissues. It was hypothesized that SCF/c-Kit signaling pathway was activated by PI3K-Akt, resulting in an increase in the expression of CCL-2 mRNA and protein. Furthermore, it was demonstrated that CCL-2 mRNA and protein expression was significantly inhibited by treatment with the PI3K inhibitor wortmannin. Additionally, wortmannin intervention significantly inhibited gastric cancer cell migration and invasion. Therefore, the results of the present study demonstrated that mast cells may promote gastric cancer cell proliferation, migration and invasion, and inhibit apoptosis. In addition, the activation of the SCF/c-Kit signaling pathway was identified to promote the expression of CCL-2, which is associated with the development and metastasis of gastric cancer.
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PMID:Association of mast cell infiltration with gastric cancer progression. 2942 64


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