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)

Microinjection in mouse eggs of tr-kit, a truncated form of the c-kit tyrosine kinase present in mouse spermatozoa, causes resumption of meiosis through activation of phospholipase Cgamma1 (PLCgamma1) and Ca(2+) mobilization from intracellular stores. We show that the Src-like kinase Fyn phosphorylates Tyr161 in tr-kit and that this residue is essential for tr-kit function. Fyn is localized in the cortex region underneath the plasma membrane in mouse oocytes. Using several approaches, we demonstrate that Fyn associates with tr-kit and that the interaction requires Tyr161. The interaction between tr-kit and Fyn triggers activation of the kinase as monitored by both autophosphorylation and phosphorylation of PLCgamma1. Co-injection of tr-kit with the SH2 domain of Fyn, or pre-treatment with a Fyn inhibitor, impairs oocyte activation, suggesting that activation of Fyn by tr-kit also occurs in vivo. Finally, microinjection of constitutively active Fyn triggers oocyte activation downstream of tr-kit but still requires PLC activity. We suggest that the mechanism by which tr-kit triggers resumption of meiosis of mouse eggs requires a functional interaction with Fyn and phosphorylation of PLCgamma1.
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PMID:Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase. 1237 39

Bone marrow stem cells (BMSC) from adult mice are now believed to generate non-hematopoietic cell types. This newly defined property is referred to as stem cell plasticity. We tested the potential of lineage negative c-kit positive (Lin- c-kit+), GFP+ BMSC to differentiate into cardiac myocytes in myocardial infarcts produced by ligation of the left coronary artery. At 9 days post-transplant the hearts showed a band of developing GFP+ myocytes within the damaged myocardium. These GFP+ myocytes were positive for cardiac specific myosin and early expressed transcription factors. Endothelial cells and smooth muscle cells also developed from the donor bone marrow cells. Left ventricular end diastolic pressure (LVEDP) and left ventricular developed pressure (LVDP) were improved. Lin-c- kit- cells did not regenerate myocardium. We next tested the ability of cytokine-mobilized BMSC to regenerate myocardium. Nuclei in regenerating cardiomyocytes were positive for Csx/Nkx 2.5, GATA-4 and MEF2. Cytoplasmic proteins included desmin, nestin and connexin 43. Regenerating arterioles consisted of endothelial cells and smooth muscle cells positive for Ki67, and flkl. These regenerating vessels contained circulating TER119 positive red blood cells. Repair of infarcted myocardium resulted in improved heart function and survival. At day 27 after cytokine treatment and surgery, 11 of 15 mice survived compared with 9 of 52 non-treated mice. Left ventricular ejection fraction in infarcted hearts in cytokine-treated mice was 48%, 62% and 114% higher than the ejection fraction in non-treated mice at 9, 16 and 26 days following coronary artery occlusion. These findings demonstrate that circulating autologous stem cells traffic to the ischemic, infarcted myocardium and undergo differentiation into cardiomyocytes and vascular structures. We conclude that adult BMSC have the potential for repair in acute, ischemic heart disease.
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PMID:Stem cell repair in ischemic heart disease: an experimental model. 1243 Aug 44

Imatinib mesylate (Gleevec), a small molecule inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFR beta (exons 2-23) and c-kit (exons 1-21) in 6 patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all 4 responding patients had elevated serum interleukin-5 levels. Although the drug was well tolerated in most patients, a previously unrecognized treatment toxicity of acute left ventricular dysfunction occurred in a responding patient with HES within the first week of treatment. Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy.
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PMID:Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. 1456 8

Chronic idiopathic intestinal pseudo-obstruction is a syndrome in which symptoms of intestinal obstruction are present in the absence of mechanical obstruction. Lack of normal pacemaker activity, usually generated by the interstitial cells of Cajal (ICC), could account for the apparent obstruction. ICC are normally located around and between the myenteric plexus ganglia and within muscle and also in the deep muscular plexus of the small bowel and the submuscular plexus of the large intestine, just within the circular muscle. ICC can be demonstrated immunohistochemically with CD117 (c-kit) as well as with CD34, although this is less specific. CD34 also stains a population of fibroblasts that are intimately associated with ICC. To determine whether there is a relative deficiency of ICC and CD34-positive fibroblasts in patients with chronic idiopathic intestinal pseudo-obstruction, tissue from 30 patients of large intestine and eight patients with small intestine pseudo-obstruction was obtained. Controls (large intestinal specimens from 12 patients, small intestinal specimens from six patients) were chosen from resections for Crohn's disease and colorectal neoplasia, both with and without dilatation. Examination of pseudo-obstruction cases identified 10 patients (nine large intestinal and one small intestinal) in which both CD117 and CD34 were absent or severely reduced in all three of the examined areas. In contrast, the control cases, including those with preobstructive dilatation, showed relatively constant ICC staining. These results suggest that there is a proportion of pseudo-obstruction cases in which the ICC are markedly reduced. These results also demonstrate that, in these cases, loss of the kit immunoreactivity is correlated with the loss of CD34 staining: this indicates that both the ICC and the CD34-positive fibroblasts associated with the ICC are absent. These findings will allow surgical pathologists to identify this subpopulation of patients with CIIP using tissue obtained by laparoscopic biopsy of the muscularis propria or surgical resection.
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PMID:Loss of CD117 (c-kit)- and CD34-positive ICC and associated CD34-positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction. 1254 70

The c-kit proto-oncogene plays a dual role in the control of male fertility in mice through two alternative gene products: (1). c-kit [the transmembrane tyrosine kinase receptor for stem cell factor (SCF)], which is expressed and functional in differentiating spermatogonia of the postnatal testis, in which c-kit is essential for pre-meiotic proliferation; and (2). tr-kit, an intracellular protein which is specifically accumulated during spermiogenesis through the use of an alternative intronic promoter, and which is able to trigger mouse egg activation when microinjected into the cytoplasm of metaphase II arrested oocytes. Here, we summarize the most recent findings about the molecular pathways through which c-kit regulates cell cycle progression in mitotic germ cells, and those through which sperm-derived tr-kit triggers parthenogenetic completion of meiosis II and pronuclear formation in microinjected mouse eggs.
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PMID:Molecular mechanisms utilized by alternative c-kit gene products in the control of spermatogonial proliferation and sperm-mediated egg activation. 1255 31

The proto-oncogene c-kit is a transmembrane-tyrosine-kinase receptor that is structurally related to the platelet-derived growth-factor receptor (PDGFR) and is involved in cell differentiation. C-kit has been found to be expressed in certain solid tumors and may play a role in their tumorigenesis. Recently, a tyrosine-kinase inhibitor specific for the PDGFR family, bcr-abl, and c-kit (STI571) has been reported to have therapeutic effects in tumors expressing the aberrant forms or high quantities of target proteins. Expression of c-kit has not been well evaluated in endometrial adenocarcinomas. In this study, c-kit immunoreactivity was evaluated on paraffin sections of 72 endometrial adenocarcinomas (57 endometrioid, 10 serous, and 5 clear cell) with a polyclonal antibody. Immunoreactivity of c-kit was analyzed semiquantitatively and correlated with various clinicopathologic factors. Cytoplasmic c-kit immunoreactivity was detected in 42 (58%) tumors. Thirty-four (60%) endometrioid, 8 (80%) serous, and 0 of the 5 clear-cell adenocarcinomas were c-kit positive. There was a significant correlation between c-kit positivity and the depth of myometrial invasion. Patients with c-kit-positive endometrial adenocarcinomas more frequently had metastases and shorter disease-free survival. Expression of c-kit may be a potentially adverse prognostic feature in endometrial adenocarcinoma. Patients with c-kit-positive advanced endometrial adenocarcinoma might benefit from tyrosine-kinase-inhibitor therapy.
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PMID:C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance. 1264 69

Interstitial cells of Cajal (ICC) in the stomach of wild-type and Ws/Ws mutant rats that are deficient in c-kit were studied by immunohistochemistry and electron microscopy to elucidate their regional specialization in the gastric antrum. Immunohistochemistry for Kit protein demonstrated that in wild-type rats ICC were located at the submucosal border of the circular muscle layer (ICC-SM) in a limited extension of the antrum from the pyloric sphincter towards the corpus, as well as within both the circular (ICC-CM) and longitudinal (ICC-LM) muscle layers and in the myenteric plexus region (ICC-AP). In c-kit mutant Ws/Ws rats while ICC-CM and ICC-LM were not observed, but unexpectedly, a few ICC-SM and ICC-AP were found. By electron microscopy, ICC-SM and ICC-AP were characterized by abundant mitochondria, many caveolae, a distinct basal lamina and formed gap junctions with other ICC or with smooth muscle cells and make close contacts with nerves. Thus, ICC-SM and ICC-AP of the rat antrum were classified as Type 3 ICC, the type most similar to smooth muscle cells. The functional significance of ICC-SM and their survival in the c-kit mutant animals is discussed in reference to the role of the c-kit/stem cell factor system for their cellular maturation.
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PMID:Distribution and ultrastructure of interstitial cells of Cajal in the gastric antrum of wild-type and Ws/Ws rats. 1270 Aug 99

Interstitial cells of Cajal (ICCs) have been reported to play the role of a pacemaker in regulating bowel motility. The relationship between neurons and ICCs, however, remains unclear. Hirschsprung's disease (HD) is an ideal model for investigating this relationship. The operated specimens obtained from 6 short and 3 long segment aganglionosis patients and 3 controls were used as the subject materials in this study. ICCs were immunohistochemically identified using a specific antiserum c-kit, a tyrosine kinase receptor expressing ICCs. Nitrergic nerves were demonstrated by NADPH-diaphorase (NADPH-d) histochemistry. C-kit immunohistochemistry was also combined with protein gene product 9.5 (PGP 9.5; as a general neuronal marker). In the normoganglionic segment of HD, numerous c-kit-positive cells and NADPH-d positive neurons were found in the proper muscle layer, including Auerbach's plexus. In the oligoganglionic segment, the number of c-kit-positive cells and NADPH-d neurons slightly decreased. In the inner border of the circular muscle layer (IBCM), the c-kit-positive cell networks and NADPH-d activities remained in short segment cases, while both of them were absent in the long segment cases. In the aganglionic segment, c-kit positive cells were present universally but the number of them was slightly decreased in the proper muscle layer. The c-kit-positive cell networks of IBCM were seen where extrinsic neurons were present, while they were almost completely absent where extrinsic neurons were absent in the proximal zone of the long segment cases. C-kit positive cells were present universally in the oligoganglionic as well as aganglionic segments of HD. The distribution and properties of c-kit positive cells were related to the presence of extrinsic neurons in aganglionic segment. Based on these findings, aperistalsis is considered not to relate with c-kit positive cells, and c-kit positive cells are not supposed to have a neurogenic origin and can develop without neurons, however the lack of enteric neurons may influence the full differentiation of ICCs.
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PMID:Universal distribution of c-kit-positive cells in different types of Hirschsprung's disease. 1272 30

Total colonic aganglionosis (TCA) is a severe form of ultra long Hirschsprung's disease with an incidence of 2 to 14% among all forms of intestinal aganglionosis. C-kit positive interstitial cells of Cajal (ICCs) are pacemaker cells that play a key role in the motility function of the bowel. The aim of this study was to compare the innervation and ICCs distribution in total colonic and recto-sigmoid HD. Full thickness colonic specimens were obtained from four children with TCA, ten with recto-sigmoid HD and four controls. Single immunohistochemistry using peripherin, neuronal nitric oxide synthase (nNOS) and c-kit antibody was performed and analysed in light microscopy. Additionally, whole-mount preparations were stained using anti c-kit immunohistochemistry and NADPH-diaphorase. In the ganglionic bowel of TCA, recto-sigmoid HD and control patients there was a strong nNOS and peripherin immunoreactivity (IR) in ganglia of myenteric and submucous plexus and in thin nerve fibres in the muscle layers. In the TCA there was weak or lack of nNOS IR in the sparse, short nerve trunks of the myenteric and submucous plexuses and muscle layers, whereas nNOS weakly positive nerve trunks were observed in the recto-sigmoid HD bowel. Peripherin IR was markedly reduced in the TCA specimens compared to recto-sigmoid HD. In the TCA specimens there was a lack of ICCs-MY in the smooth muscle layer in all the specimens, whereas in the recto-sigmoid aganglionic bowel ICCs-MY were markedly reduced. Whole-mount preparations showed lack of ICCs-MY and a markedly reduced number of NADPH-positive nerve trunks in TCA. Our findings demonstrate clear histopathological differences between rectosigmoid Hirschsprung's disease and total colonic aganglionosis.
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PMID:Histopathological differences between recto-sigmoid Hirschsprung's disease and total colonic aganglionosis. 1275 96

Morphologic distinction between adrenal cortical and medullary tumors can be difficult. Previous studies have shown inhibin, melan-A, and BCL-2 to be useful markers for adrenal cortical tumors. We have recently observed a high level of calretinin expression in normal adrenal cortex but not the medulla and therefore evaluated its diagnostic application for adrenal tumors in comparison with inhibin, melan-A, and BCL-2. C-kit is a transmembrane tyrosine kinase receptor. Immunodetection of c-kit expression has been recently used for tumor diagnosis, and c-kit-positive tumors can potentially benefit from kit kinase inhibitor treatment. Although c-kit expression was reported in adrenal medulla and pheochromocytoma, it has not been evaluated in adrenal cortical tumors. In this study, 28 adrenal cortical tumors (12 carcinomas, 16 adenomas), 20 pheochromocytomas, and 20 extraadrenal paragangliomas were evaluated for calretinin, inhibin, melan-A, BCL-2, and c-kit expression by standard immunohistochemical assays on paraffin sections. The percentage of immunoreactivity in adrenal cortical tumors was as follows: calretinin, 96%; melan-A, 89%; inhibin, 92%; BCL-2, 20%; and c-kit, 5%. Normal adrenal medulla did not stain for c-kit but was positive for BCL-2. Eighty-six percent of pheochromocytomas stained for BCL-2 and none for calretinin, with the exception of the ganglioneuromatous areas in composite pheochromocytomas (n = 5). Extraadrenal paragangliomas showed reactivity with calretinin in 25%, melan-A in 5%, inhibin in 16%, BCL-2 in 38%, and c-kit in 8% of the cases. Our results indicate that calretinin is the most sensitive among all the adrenal markers tested. Like melan-A and inhibin, calretinin is also a very specific marker in differentiating cortical from medullary adrenal tumors. In addition, calretinin can be used to confirm a composite pheochromocytoma. BCL-2 does not appear to be useful in differentiating adrenal cortical from medullary tumors. C-kit is not useful in the diagnosis of adrenal tumors, and kit kinase inhibitor might have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.
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PMID:The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study. 1280 65


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