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)

Melanocytes are derived from neural crest and migrate along the dorsolateral pathway to colonize the final destination in the skin. Stem cell factor and its receptor c-kit were identified as gene products of Sl and W mutant loci; both of them were known to have defects in melanocytes survival. In this review, we focus on the function of stem cell factor and c-kit in melanocyte migration and survival, which has become clearer in the last decade. By analysis of both molecules in wild-type and white spotting mutant mice, ligand and receptor set were shown to play multiple roles in the development of melanocytes in mouse ontogeny. Functional blockade of c-kit by specific monoclonal antibody illustrated distinct c-kit dependent and independent stages in melanocyte development. Finally, SCF transgene expression demonstrated that part of the c-kit dependent step is regulated by spatiotemporally specific ligand expression and also indicated the presence of c-kit independent melanocyte stem cells in postnatal skin.
J Investig Dermatol Symp Proc 2001 Nov
PMID:Review: melanocyte migration and survival controlled by SCF/c-kit expression. 1176 76

Microphthalmia-associated transcription factor (MITF) regulates the differentiation and development of melanocytes and retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the MITF gene cause auditory-pigmentary syndromes. MITF consists of at least five isoforms, MITF-A, MITF-B, MITF-C, MITF-H, and MITF-M, differing at their N-termini and expression patterns. Here we show a remarkable similarity between the N-terminal domain of MITF-A and cytoplasmic retinoic acid-binding proteins. To date, four isoform-specific first exons have been identified in the MITF gene: exons 1A, 1H, 1B, and 1M in the 5' to 3' direction, each of which encodes the unique N-terminus of a given isoform. The 5'-flanking regions of these isoform-specific exons are termed A, H, B, and M promoters, respectively. Among these promoters, the M promoter has received particular attention, because it is functional only in melanocyte-lineage cells and is upregulated by Wnt signaling via the functional LEF-1-binding site. Moreover, the M promoter is upregulated by other transcription factors, PAX3, SOX10, and CREB. The activity and degradation of MITF-M are regulated by extracellular signals via protein phosphorylation, such as c-Kit signaling. Together, multiple signals appear to converge on the M promoter as well as on MITF proteins, leading to the proper regulation of MITF-M in melanocytes and other MITF isoforms in many cell types.
J Investig Dermatol Symp Proc 2001 Nov
PMID:Microphthalmia-associated transcription factor (MITF): multiplicity in structure, function, and regulation. 1176 95

Mastcytosis is a rare disease characterized by an abnormal increase of mast cells in tissues. The skin is the organ most frequently involved, but mast cells also accumulate in the bone marrow, gastrointestinal tract, lymph nodes, spleen, and liver. Recent studies suggest that activating mutations of c-kit, a protooncogene encoding for the receptor (kit) of stem cell factor, are a possible cause of some forms of mastocytosis. In addition, an increased rate of chromosomal aberrations has been found. Despite significant advances in research on mastocytosis, curative treatment is not yet available. Current management is based on avoidance of mediator-releasing triggers and symptomatic treatment.
J Investig Dermatol Symp Proc 2001 Nov
PMID:Mastocytosis: review of clinical and experimental aspects. 1176 3

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the mechanisms involved in the pathogenesis of these conditions remains largely uninvestigated, it is speculated that mediators produced in the lesional skin provide a favorable microenvironment for mast cell growth. Among the proinflammatory mediators, leukemia inhibitory factor (LIF), which shares a receptor component (gp130 subunit) with interleukin-6 (IL-6), has been identified as a mast cell growth-enhancing factor produced by cells of the keratinocyte-derived cell line (KCMH-1). In this study, we investigated the effect of four IL-6 family cytokines, IL-6, IL-11, oncostatin M (OSM) and LIF on mast cell growth in a mast cell/fibroblast co-culture system. When mouse bone marrow-derived cultured mast cells (BMMC) were maintained on a NIH/3T3 fibroblast monolayer, these cytokines induced proliferation of the mast cells, but none of the cytokines had any effect on mast cell proliferation in the absence of fibroblasts. mRNA for gp130 and receptors for the four IL-6 family cytokines were detected in NIH/3T3 fibroblasts by reverse transcriptase-mediated polymerase chain reaction. In contrast, only mRNA for the IL-11 receptor and gp130 were detected in BMMC. Tyrosine phosphorylation of gp130 was observed in NIH/3T3 fibroblasts after stimulation with all the cytokines. Some IL-6 family cytokines enhanced the production of stem cell factor (SCF), a potent mast cell growth factor, from NIH/3T3 fibroblasts, but the amount of SCF produced by NIH/3T3 fibroblasts was not paralleled by the mast cell growth-enhancement induced by the IL-6 family cytokines. When anti-SCF antibody was added with the IL-6 family cytokines in the BMMC/fibroblast coculture system, a significant effect of these cytokines remained, although the growth-enhancing activity was markedly reduced. A similar result was obtained when BMMC were prepared from W/W(V)-mice, which lack functional c-kit, in the BMMC/ fibroblast coculture system. These results suggest that IL-6 family cytokines stimulate mast cell growth by a fibroblast-dependent mechanism, and also suggest the existence of another pathway between BMMC and NIH/3T3 fibroblasts cooperating with the SCF/c-kit pathway. IL-6 family cytokines may thus contribute to mast cell hyperplasia in skin diseases.
Arch Dermatol Res 2001 Nov
PMID:The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice. 1182 Jul 27

The abnormality in mastocytosis is the excessive accumulation of mast cells in the affected tissue. The growth and differentiation of human mast cells are quite dependent on stem cell factor (SCF), the ligand for the protein products of c-kit. Recent studies have demonstrated that all adult patients examined so far carry c-kit point mutations, leading to SCF-independent autophosphorylation of the receptor and autonomous cell growth. On the other hand, typical pediatric patients have been found to bear no activating Asp816Val mutation in c-kit. Although most mastocytosis patients are children, the mechanism by which mast cells proliferate in these pediatric patients remains unclear. Recently, were reported that human mast cells obtained from adult skin could dramatically proliferate when cultured with SCF. From these experimental results, it is speculated that local excessive production of SCF results in the mast cell proliferation in pediatric patients.
J Dermatol 2002 Jan
PMID:A possible mechanism of mast cell proliferation in mastocytosis. 1183 66

Chemotherapy alters the structure and function of hair follicle melanocytes. Molecular mechanisms controlling melanocyte responses during chemotherapy-induced hair loss, however, remain largely unknown. Using immunohistology and multicolor confocal microscopy, we show here that cyclophosphamide administration to C57BL/6 mice alters the activity and fate of hair follicle melanocytes. After 24-48 h, hair bulb melanocytes expressing Fas undergo apoptosis. The number of apoptotic follicular melanocytes is significantly reduced (p<0.01) in cyclophosphamide-treated Fas knockout mice compared to wild-type controls, suggesting that Fas signaling contributes to chemotherapy-induced melanocyte death. After 3-5 d, surviving hair bulb melanocytes express c-kit receptor, proliferate, and appear to migrate up the outer root sheath. Tyrosinase-positive and melanogenically active cells then appear in the epidermis. By Western blotting and immunohistochemistry, expression levels of the c-kit ligand, stem cell factor, in skin and epidermis are strongly increased after cyclophosphamide treatment. Cyclophosphamide-induced migration of the hair follicle melanocytes into epidermis is completely abrogated by administration of c-kit neutralizing antibody. These data suggest that chemotherapy induces a complex response in the hair follicle melanocytes, which includes apoptosis, proliferation, and migration. Pharmacologic manipulation of Fas and c-kit signaling pathways might be useful for the correction of skin hyperpigmentation as a side-effect of chemotherapy.
J Invest Dermatol 2003 Jan
PMID:Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss. 1253 95

Vitiligo vulgaris is a common skin disease, however some cases show poor clinical responses to topical steroid ointment or PUVA therapy. Such regimens are generally avoided in the treatment of facial lesions or in pediatric cases because of the undesirable side effects. To confirm the excellent response to combination therapy with topical vitamin D3 ointment and solar irradiation for vitiligo achieved in the initial patients, we conducted an open trial on other patients, most of whom had poor clinical responses to the prior therapies. Fifteen patients (9 men and 6 women) with vitiligo vulgaris were enrolled in this study. Each patient was instructed to sunbathe for 30 minutes within 1 hour after topical application of the tacalcitol [1 alpha 24(OH)(2)D(3)] ointment or cream to the skin lesions every day. Six of 15 patients showed a fair and excellent clinical response to the combination therapy (more than 30% clearance of the vitiligo). The clinical effect was more apparent in patients with a history of less than 5 years of vitiligo (4 of 6 cases) in contrast to those with a history of more than 5 years (2 of 9 cases). In vitro experiments revealed that tacalcitol upregulated the expression of c-Kit mRNA by melanocytes irradiated with linear polarized infrared, UVA or short period solar irradiation. These results suggest that combination therapy with topical vitamin D(3) ointment and solar irradiation can be used as an alternate therapy for vitiligo vulgaris.
Eur J Dermatol
PMID:Open trial of topical tacalcitol [1 alpha 24(OH)2D3] and solar irradiation for vitiligo vulgaris: upregulation of c-Kit mRNA by cultured melanocytes. 1294 18

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-alpha and -beta were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-alpha were expressed on cells with higher metastatic potential, and higher levels of PDGFR-beta were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-alpha and PDGFR-beta in vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit.
J Invest Dermatol 2004 Feb
PMID:Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. 1500 22

Mast cells (MC) are of hematopoietic origin but complete their differentiation exclusively within tissues. The mediators that positively or negatively affect the maturation process are incompletely defined. Here, the human MC line HMC-1 (subclone 5C6) was used along with several treatments (IL-4, IL-6, NGFbeta), either alone or in combination, and MC differentiation was monitored by flow-cytometric analysis of c-kit, tryptase, and FcepsilonRIalpha expression. Of the different treatments, IL-4 displayed the clearest effects by suppressing the expression of the three markers and inhibiting cellular growth, while the other cytokines had no (NGFbeta) or negligible (IL-6) effects only. The downregulating effects of IL-4 could not be overcome by any other treatment. There is some controversy in the literature as to the impact of IL-4 on the MC lineage. To determine whether the effects from IL-4 were differentiation stage dependent, two further human MC subsets (skin MC and LAD 2 cells) were investigated. No effects on c-kit and FcepsilonRIalpha expression were noted when terminally differentiated skin MC were used as target cells, while a modest downregulation of c-kit was observed with intermediately matured LAD 2 cells. In sharp contrast to HMC-1 5C6 cells, the survival of skin MC was significantly enhanced by IL-4 treatment. Our data therefore imply that at a lower maturation stage, IL-4 acts as a negative regulator of the MC lineage, but that this property disappears or is even reversed upon terminal differentiation of the cell. Our study provides direct proof that the effects of IL-4 vary substantially in the course of MC maturation.
Arch Dermatol Res 2004 Aug
PMID:Regulation of mast cell characteristics by cytokines: divergent effects of interleukin-4 on immature mast cell lines versus mature human skin mast cells. 1532 32

In order to better understand the mechanisms governing display of mast cell characteristics in human myeloid cells, we have studied the mast cell phenotype in human promyelocytic (HL-60) and myelocytic (U-937, TPH-1) vs. basophilic (KU-812) and mast cell (HMC-1) lines, in part also in skin mast cells and blood monocytes, at mRNA and protein level before and after stimulation with mast cell growth factors. In unstimulated cells, mRNA for the stem cell factor (SCF) receptor c-kit and the gamma chain of the high-affinity IgE receptor (FcepsilonRI) was noted in all cells studied. Like mast and basophilic cells, THP-1 cells expressed the FcepsilonRIalpha and beta chains and weakly histidine decarboxylase (HDC), but they lacked mRNA for mast cell-specific proteases [tryptase, chymase, carboxypeptidase A (CPA)]. In contrast, HL-60 and U-937 cells lacked FcepsilonRIalpha, but expressed tryptase and chymase, HL-60 cells also CPA. KU-812 cells failed to express the basophil-specific marker 2D7. After a 10-day culture with SCF or fibroblast supernatants, baseline mRNA expression of most mast cell characteristics was upregulated, whereas c-kit mRNA expression decreased in all but THP-1 cells. Differential mRNA expression of FcepsilonRI vs. protease (tryptase) was confirmed at protein level by immunocytochemistry and enzymatic activity. KU-812 cells are thus closest to skin mast cells in that they express all molecules studied, except for chymase, followed by THP-1 cells that lack all mast cell proteases. In contrast, HL-60 and U-937 cells fail to express the FcepsilonRIalpha and beta chains but express most mast cell proteases. The selective and differential expression of mast cell characteristics in human myeloid cell lines suggests that induction of the mast cell phenotype is regulated by several independent genes and that mast cells and basophils branch off at early and distinct points of myeloid development.
Exp Dermatol 2004 Sep
PMID:Differential expression of mast cell characteristics in human myeloid cell lines. 1533 53


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