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)

Interstitial cells of Cajal (ICCs) are postulated to serve as pacemakers that physiologically generate electrical slow waves in the gastrointestinal tract. Imatinib is a novel and potent inhibitor of c-Kit tyrosine kinase and a new therapeutic agent for gastrointestinal stromal tumors (GIST) which presumably arise from ICCs. The effects of imatinib on the basal rhythmic mechanical activities of small intestinal circular muscles were investigated in ring preparations of the gut. The small intestinal rings of BALB/c mice exhibited spontaneous contractile activity at a rate of 40.8 +/- 4.9 contractions/min. Imatinib (1- 81 micromol/l) dose-dependently abolished spontaneous contractile activity in the 9- to 27-micromol/l concentration range. Contraction was restored by washing imatinib out with a fresh buffer. High K(+)-induced contraction was not affected by imatinib, suggesting that the drug does not have nonspecific inhibitory actions on the smooth muscles. The small intestinal rings of adult W/W(v)mice, which lack a functional c-Kit activity,exhibited only small and irregular spontaneous contractions. These results demonstrate that imatinib affects bowel contractions, and suggest that the c-Kit signaling of ICCs plays an essential role in the spontaneous movements in circular muscles of the mouse small intestine.
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PMID:Imatinib blocks spontaneous mechanical activities in the adult mouse small intestine: possible inhibition of c-Kit signaling. 1572 47

The prostate exhibits electric activity in the form of slow waves (SWs) and action potentials (APs). As the interstitial cells of Cajal (ICCs) are considered the pacemaker cells which generate the electric waves, we investigated the hypothesis that the prostate contains ICC. Prostatic biopsies were obtained from 15 healthy volunteers (mean age 36 +/- 3.8 SD years). They were subjected to c-kit immunohistochemistry. Controls for the specificity of the antisera consisted of tissue incubated with normal rabbit serum substituted for the primary antiserum. C-kit-positive cells were identified as fusiform with dendritic processes. The cytoplasm was granular and the nucleus large and oval. Mast cells, also c-kit-positive, were round and lacked the dendritic processes. Immunoreactivity was absent in the negative controls. There were cells in the prostate with morphological and immunological phenotypes similar to ICCs of the gut. We predict an abnormal distribution of these cells in prostatic diseases. The study of the integrity of these cells may prove to be a useful investigative tool in the diagnosis of prostatic diseases and in the planning of an appropriate treatment.
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PMID:Identification of c-kit-positive cells in the human prostate: the interstitial cells of Cajal. 1608 62

It is postulated that the propagated electric activity of the gut is generated by the interstitial cells of Cajal (ICCs). We investigated the hypothesis of the presence of ICCs in the Fallopian tube (FT) as initiators of the tubal electric activity. Specimens from various parts of the FT were obtained from 21 female cadavers (mean age 38.2 +/-10.9 years) from the PostMortem Department of the Cairo University, Faculty of Medicine. Fixed sections were prepared and stained for c-kit. Controls for antisera specificity consisted of tissue incubated with normal rabbit serum substituted for the primary antiserum. Dendritic, c-kit-positive, ICC-like cells were detected in the tubal musculature of the studied specimens. They were distinguishable from the c-kit-positive nonbranching mast cells and from the c-kit-negative smooth muscle cells (SMC). Immunoreactivity was absent in the negative controls. We have for the first time identified cells in the FT with morphologic and immunologic phenotypes similar to the ICCs of the gut. These cells may be responsible for initiating the slow waves (SWs) recorded from the SMC of the FT. This is a preliminary study, and further studies are needed to investigate the functional role of these cells.
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PMID:Specialized pacemaking cells in the human Fallopian tube. 1612 78

Mice carrying certain mutations in the white spotting (W) locus (ie, c-kit) exhibit reduced c-kit tyrosine kinase-dependent signaling that results in mast cell deficiency and other phenotypic abnormalities. The c-kit mutations in Kit(W/W-v) mice impair melanogenesis and result in anemia, sterility, and markedly reduced levels of tissue mast cells. In contrast, Kit(W-sh/W-sh) mice, bearing the W-sash (W(sh)) inversion mutation, have mast cell deficiency but lack anemia and sterility. We report that adult Kit(W-sh/W-sh) mice had a profound deficiency in mast cells in all tissues examined but normal levels of major classes of other differentiated hematopoietic and lymphoid cells. Unlike Kit(W/W-v) mice, Kit(W-sh/W-sh) mice had normal numbers of TCR gammadelta intraepithelial lymphocytes in the intestines and did not exhibit a high incidence of idiopathic dermatitis, ulcers, or squamous papillomas of the stomach, but like Kit(W/W-v) mice, they lacked interstitial cells of Cajal in the gut and exhibited bile reflux into the stomach. Systemic or local reconstitution of mast cell populations was achieved in nonirradiated adult Kit(W-sh/W-sh) mice by intravenous, intraperitoneal, or intradermal injection of wild-type bone marrow-derived cultured mast cells but not by transplantation of wild-type bone marrow cells. Thus, Kit(W-sh/W-sh) mice represent a useful model for mast cell research, especially for analyzing mast cell function in vivo.
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PMID:Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. 1612 61

Gastrointestinal stromal tumours (GIST) are thought to derive from interstitial cells of Cajal (ICCs), which are putative pacemaker cells for gut motility. Isolated cells were obtained by enzymatic treatment of human duodenum GIST tissue having a frequent gain-of-function gene mutation. After cell culturing, c-Kit immunoreactivity was preserved and the cells developed long processes. Whole cell patch clamp recordings revealed voltage-dependent outward currents, without transient inward currents. Intracellular Ca(2+) measurements showed oscillation-like spontaneous activity in some GIST cells. RT-PCR revealed expression of ion channels (Kv1.1, Kv1.6 and KCNH2; IP3R1, and IP3R2; TRPC1, 3, 6 and 7; Cx43), which have been suggested to play important roles in pacemaker activity. However, SCN5A, a TTX-resistant Na(+) channel known to be expressed in human ICCs, was below detectable levels. These data suggest that GIST cells appear to preserve some, but not all ionic mechanisms underlying pacemaker activity in ICC.
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PMID:Inherent pacemaker function of duodenal GIST. 1634 93

We have previously shown the existence of ICLC in human resting mammary gland stroma by means of methylene blue (vital) staining and c-kit immunopositivity (immunofluorescence and immunohistochemistry). In addition, we reported the phenotype characteristics of these ICLC in vitro (primary cell cultures). Since the identification of ICLC outside the gut requires, at this moment, the obligatory use of TEM, we used this technique and provide unequivocal evidence for the presence of ICLC in the intralobular stroma of human resting mammary gland. According to the 'platinum standard' (10 TEM criteria for the certitude diagnosis of ICLC), we found interstitial cells with the following characteristics: 1. location: among the tubulo-alveolar structures, in the non-epithelial space; 2. caveolae: approximately 2.5% of cell volume; 3. mitochondria: approximately 10% of cell volume; 4. endoplasmic reticulum: either smooth or rough, approximately 2-3% of cell volume; 5. cytoskeleton: intermediate and thin filaments, as well as microtubules are present; 6. myosin thick filaments: undetectable; 7. basal lamina: occasionally found; 8. gap junctions: occasionally found; 9. close contacts with targets: nerve fibers, capillaries, immunoreactive cells by 'stromal synapses'; 10. characteristic cytoplasmic processes: i) number: frequently 2-3; ii) length: several tens of mum; iii) thickness: uneven caliber, 0.1-0.5 microm, with dilations, but very thin from the emerging point; iv) aspect: moniliform, usually with mitochondria located in dilations; v) branching: dichotomous pattern; vi) Ca(2+) release units: are present; vii) network labyrinthic system: overlapping cytoplasmic processes. It remains to be established which of the possible roles that we previously suggested for ICLC (e.g. juxta- and/or paracrine secretion, uncommited progenitor cells, immunological surveillance, intercellular signaling, etc.) are essential for the epithelium/stroma equilibrium in the mammary gland under normal or pathological conditions.
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PMID:Interstitial Cajal-like cells (ICLC) in human resting mammary gland stroma. Transmission electron microscope (TEM) identification. 1636 98

Scientists interested in the smooth muscles of the urinary tract, and their control, have recently been studying cells in the interstitium of tissues that express the c-kit antigen (Kit(+) cells). These cells have morphologic features that are reminiscent of the well-described pacemaker cells in the gut, the interstitial cells of Cajal (ICC). The spontaneous contractile behavior of muscles in the urinary tract varies widely, and it is clear that urinary tract Kit(+) interstitial cells cannot be playing an identical role to that played by the ICC in the gut. Nevertheless, there is increasing evidence that they do play a role in modulating the contractile behavior of adjacent smooth muscle, and might also be involved in mediating neural control. This review outlines the properties of ICC in the gut, and gives an account of the discovery of cells in the interstitium of the main components of the urinary tract. The physiologic properties of such cells and the functional implications of their presence are discussed, with particular reference to the bladder. In this organ, Kit(+) cells are found under the lamina propria, where they might interact with the urothelium and with sensory nerves, and also between and within the smooth-muscle bundles. Confocal microscopy and calcium imaging are being used to assess the physiology of ICC and their interactions with smooth muscles. Differences in the numbers of ICC are seen in smooth muscle specimens obtained from patients with various pathologies; in particular, bladder overactivity is associated with increased numbers of these cells.
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PMID:Mechanisms of Disease: specialized interstitial cells of the urinary tract--an assessment of current knowledge. 1647 98

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.
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PMID:In vitro formation of enteric neural network structure in a gut-like organ differentiated from mouse embryonic stem cells. 1652 1

The so-called interstitial cells of Cajal (ICC) are distributed throughout the muscle coat of the alimentary tract with characteristic intramural location and species-variations in structure and staining. Several ICC sub-types have been identified: ICC-DMP, ICC-MP, ICC-IM, ICC-SM. Gut motility is regulated by ICC and each sub-type is responsible for the electrical activities typical of each gut region and/or muscle layer. The interstitial position of the ICC between nerve endings and smooth muscle cells has been extensively considered. Some of these nerve endings contain tachykinins. Three distinct tachykinin receptors (NK1r, NK2r and NK3r) have been demonstrated by molecular biology. Each of them binds with different affinities to a series of tachykinins (SP, NKA and NKB). In the ileum, SP-immunoreactive (SP-IR) nerve fibers form a rich plexus at the deep muscular plexus (DMP), distributed around SP-negative cells, and ICC-DMP intensely express the SP-preferred receptor NK1r; conversely a faint NK1r-IR is detected on the ICC-MP and mainly after receptor internalization was induced by agonists. ICC-IM are never stained in laboratory mammals, while those of the human antrum are NK1r- IR. RT-PCR conducted on isolated ileal ICC-MP and gastric ICC-IM showed that these cells express NK1r and NK3r. Colonic ICC, except those in humans, do not express NK1r-IR, at least in resting conditions. Outside the gut, NK1r-IR cells were seen in the arterial wall and exocrine pancreas. In the mouse gut only, NK1r-IR is present in non-neuronal cells located within the intestinal villi, so-called myoid cells, which are c-kit-negative and alpha-smooth muscle actin-positive. Immunohistochemistry and functional studies confirmed that ICC receive input from SP-IR terminals, with differences between ICC sub-types. In the rat, very early after birth, NK1r is expressed by the ICC-DMP and SP by the related nerve varicosities. Studies on pathological conditions are few and those on mutant strains practically absent. It has only been reported that in the inflamed ileum of rats the NK1r-IR ICC-DMP disappear and that at the peak of inflammatory conditions ICC-MP are NK1r-IR. In the ileum of mice with a mutation in the W locus, ICC-DMP were seen to express c-kit-IR but not NK1-IR, and SP-IR innervation seems unchanged. In summary, there are distinct ICC populations, each of them under a different tachykininergic control and, likely, having different functions. Further studies are recommended at the aim of understanding ICC involvement in modulating/transmitting tachykininergic inputs.
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PMID:Relationships between neurokinin receptor-expressing interstitial cells of Cajal and tachykininergic nerves in the gut. 1656 19

The concept of lymphoid differentiation in the human gastrointestinal tract is controversial but is the focus of this study, which examined adult human small intestinal tissue for the presence of CD34(+)CD45(+) hemopoietic stem cells (HSCs) and lymphoid progenitors. Flow cytometry demonstrated that over 5% of leukocytes (CD45(+) cells) isolated from human gut were HSCs coexpressing CD34, a significantly higher incidence than in matched peripheral blood or control bone marrow. HSCs were detected in cell preparations from both the epithelium and lamina propria of all samples tested and localized to the intestinal villous and crypt regions using immunofluorescence. A high proportion of gut HSCs expressed the activation marker CD45RA, and few expressed c-kit, indicating ongoing differentiation. The vast majority of intestinal HSCs coexpressed the T cell Ag, CD7 (92% in the epithelium, 80% in the lamina propria) whereas <10% coexpressed the myeloid Ag CD33, suggesting that gut HSCs are a relatively mature population committed to the lymphoid lineage. Interestingly, almost 50% of epithelial layer HSCs coexpressed CD56, the NK cell Ag, compared with only 10% of the lamina propria HSC population, suggesting that the epithelium may be a preferential site of NKR(+) lymphoid differentiation. In contrast, bone marrow HSCs displayed low coexpression of CD56 and CD7 but high coexpression of CD33. The phenotype of intestinal HSCs, which differs significantly from circulating or bone marrow HSCs, is consistent with a role in local lymphoid development.
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PMID:Detection and characterization of hemopoietic stem cells in the adult human small intestine. 1662 84


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