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)

Human skin xenografted to mice with severe combined immunodeficiency syndrome (SCID) was evaluated to determine the integrity and fate of human dermal mast cells. There was an approximately 3-fold increase in number of dermal mast cells by 3 mo after engraftment (p < 0.05). These cells were responsive to conventional mast cell secretagogues and were confirmed to be of human origin by ultrastructural characterization of granule substructure and by reactivity for the human mast cell proteinase, chymase. CD1a+ Langerhans cells, also bone marrow-derived cells, failed to show evidence of concomitant hyperplasia, and increased mast cell number was not associated with alterations in number of dermal vascular profiles identified immunohistochemically for human CD31. RT-PCR analysis demonstrated human but not murine stem cell factor (SCF; also termed mast cell growth factor, c-kit ligand) mRNA in xenografts. Epidermal reactivity for stem cell factor protein shifted from a cytoplasmic pattern to an intercellular pattern by 3 mo after engraftment, suggesting a secretory phenotype, as previously documented for human cutaneous mastocytosis. The majority (>90%) of mast cells demonstrated membrane reactivity for human SCF at the time points of peak hyperplasia. These data establish SCID mouse recipients of human skin xenografts as a potential in vivo model for cutaneous mast cell hyperplasia.
J Invest Dermatol 1997 Jul
PMID:Human skin/SCID mouse chimeras as an in vivo model for human cutaneous mast cell hyperplasia. 920 63

Mast cell hyperplasia is often observed in dermatoses characterized by fibrosis. Evidence has accumulated showing that a potent fibrogenic cytokine, platelet-derived growth factor (PDGF), plays a pathogenic role in dermal fibrosis. To clarify the mechanism of mast cell hyperplasia associated with fibrosis, we investigated the effect of PDGF on mast cell proliferation and the expression of stem cell factor (SCF), a potent growth factor for mast cells, in fibroblasts. When mouse bone marrow-derived mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, mast cell proliferation was stimulated in both cell number and total histamine content by all isoforms of PDGF (-AA, -AB, and -BB); however, none of the isoforms had any effect on [3H] thymidine incorporation in BMMC in the absence of fibroblasts. The effect of PDGF-AB and -BB were abrogated either by the addition of anti-PDGF-AB antibody or by the separation of mast cells and fibroblasts by a permeable membrane filter with a pore size of 0.2 microm. Immunoblotting of the NIH/3T3 fibroblasts treated with PDGF revealed an enhanced expression of SCF in the membrane fraction and the effect of PDGF was neutralized by the addition of antibody against SCF. Moreover, no effect of PDGF was observed when BMMC were prepared from W/W(v) mice that lack functional c-kit as the SCF receptor or when 3T3 fibroblasts were prepared from Sl/Sl(d) mice that lack membrane-bound SCF. These results suggest that the fibrogenic cytokine PDGF stimulates mast cell hyperplasia via the expression of membrane-bound SCF by fibroblasts in association with fibrosis of the skin.
J Invest Dermatol 1998 Aug
PMID:A fibrogenic cytokine, platelet-derived growth factor (PDGF), enhances mast cell growth indirectly via a SCF- and fibroblast-dependent pathway. 969 19

Mast cells (MC) are important cellular components of the immune network in diverse organs. The skin MC has likewise been implicated in IgE- and complement-mediated cutaneous reactions. Such reactions supposedly involve specific cell surface membrane receptors. In this study, the cell surface marker profile of human skin MC was established using monoclonal antibodies (MoAb) against defined CD antigens. MC were isolated from juvenile foreskin (n = 55) and adult mammary skin (n = 5). The reactivity of MC with MoAb was assessed by a combined toluidine blue/immunofluorescence staining technique. Confirming our previous analyses on lung MC, foreskin MC reacted with MoAb against CD9, CD29, CD33, CD43, CD44, CD45, CD46, CD51, CD54, CD55, CD58, CD59, CD61, and CD117 (c-kit). Foreskin MC were also recognized by MoAb to CD47, CD48, CD49d, CD53, CD60, CD63, CD81, CD82, CD84, CD87, CD92, CD97, CD98, and CD99. Recently clustered CD antigens detectable on foreskin MC were CD147 (neurothelin), CD149 (MEM133), CD151 (PETA-3), and CD157 (BST-1). In contrast to lung MC and MC from adult skin, foreskin MC were found to express CD88 (C5aR). Also, cutaneous MC (from both juvenile foreskin and adult mammary skin), but not lung MC, were found to bind the CD32 MoAb IV.3, 2E1, and FLI8.26 (Fc gammaRII). The CD50 antigen (ICAM-3) was detectable on lung MC, but not on foreskin MC or MC of adult mammary skin. In summary, our data show that cutaneous MC and lung MC express an almost identical phenotype; however, in contrast to lung MC, cutaneous MC appear to express substantial amounts of CD32 and to lack CD50. In addition, foreskin MC, unlike MC from adult skin or lung, express CD88.
J Invest Dermatol 1998 Oct
PMID:Phenotypic characterization of human skin mast cells by combined staining with toluidine blue and CD antibodies. 976 55

Mastocytosis represents a mast cell proliferative disease that generally runs a benign clinical course, with spontaneous remissions mostly by puberty in childhood-onset disease, although rare forms, particularly in adult-onset disease, can be associated with (pre)malignant hematologic disorders and very rarely present as mast cell leukemia or malignant mastocytosis. Reasons for this divergent clinical behavior of childhood- versus adult-onset disease are unknown. Recently, two activating mutations in the intracellular domain of the proto-oncogene c-kit, which encodes a tyrosine kinase receptor for the mast cell growth factor stem cell factor, have been detected in the human leukemic mast cell line HMC-1. We have therefore studied lesional skin biopsies from patients with adult- and childhood-onset indolent mastocytosis for the presence of these codon 560 and 816 mutations. C-kit coding DNA sequences were amplified and analyzed by mutation-specific restriction analyses, and mutated polymerase chain reaction products were additionally cloned and sequenced. The codon 816 mutation was found in all six samples from adult patients, but not in any of the 11 specimens from children. In addition, the codon 560 mutation could be demonstrated for the first time in indolent mastocytosis, namely in two of four specimens from adult patients, but not in those from two children. These data thus provide a possible explanation for the divergent clinical behavior of adult- versus childhood-onset indolent mastocytosis, with the first being associated with an activating mutation, possibly as part of a neoplastic process, and the latter representing most likely a reactive process of an as yet unknown pathogenesis.
J Invest Dermatol 1998 Dec
PMID:Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavior. 985 47

We investigated the effects of glucocorticoids on IL-3-dependent proliferation and c-kit expression of cells of the mouse mast cell line, MC/9. Glucocorticoids (dexamethasone, prednisolone, and hydrocortisone) inhibited IL-3-dependent MC/9 cell proliferation, whereas sex steroids (progesterone, beta-estradiol, and testosterone) had no effect. Flow cytometric analysis revealed that glucocorticoids reduced the expression of the IL-3 receptor on MC/9 cells. Immunoblot and Northern blot analyses indicated that glucocorticoids also reduced the expression of both c-kit protein and c-kit mRNA transcript. Furthermore, the adhesion of MC/9 cells to stem cell factor-expressing NIH/3T3 cells was reduced following glucocorticoid treatment. Our results indicate that glucocorticoids inhibit IL-3-dependent MC/9 mast cell proliferation, with an accompanying decrease in IL-3 receptor expression. Glucocorticoids also reduced c-kit expression on MC/9 cells resulting in a decreased adhesion to NIH/3T3 fibroblasts.
Arch Dermatol Res 1999 Apr
PMID:Glucocorticoids inhibit proliferation and adhesion of the IL-3-dependent mast cell line, MC/9, to NIH/3T3 fibroblasts, with an accompanying decrease in IL-3 receptor expression. 1033 20

Skin hyperpigmentation and itching are characteristic findings in systemic sclerosis (SSC) patients. Stem cell factor (SCF, c-kit ligand) is a multifunctional cytokine which can promote melanocyte and mast cell development. We investigated the SCF expression histopathologically in normal and SSC skin, and compared the expression with the serum SCF levels measured with a specific enzyme-linked immunosorbent assay. The epidermal and dermal immunoreactive SCF expression was markedly higher in the forearm skin of edematous phase SSC patients than in that of normal subjects. Tissue SCF expression declined from the sclerotic phase to the atrophic phase, where it was close to the normal level. In contrast, the elevated serum SCF level seen in the edematous phase samples was further increased in the sclerotic phase samples. The serum SCF level decreased in the atrophic phase, but it still remained at a level higher than that of the normal controls. Itching and increase of dermal mast cell number are characteristic of edematous phase SSC, and are in bears a parallel to the presently observed dermal SCF expression profile. Pigmentation is significant in sclerotic phase SSC and lasts to the atrophic phase, which may correspond to the serum SCF level observed here. These results indicate a contribution of the fibroblast membrane integral SCF in dermal mast cell development, and of the soluble serum SCF to melanocyte activation in SSC.
J Dermatol Sci 1998 May
PMID:Increased cutaneous immunoreactive stem cell factor expression and serum stem cell factor level in systemic scleroderma. 1034 50

Somatic mutations within c-kit have been reported in individuals with mastocytoses, including urticaria pigmentosa (UP). We have identified three siblings with UP. We aimed to determine whether the c-kit proto-oncogene was playing a part in the aetiology of UP in these three siblings. Using seven microsatellite repeat markers spanning an 8-cM interval encompassing the c-kit gene we followed the transmission of the c-kit gene in this family. Furthermore, single-strand conformation polymorphism analysis was used to scan exon 17 of the c-kit gene for mutations in genomic DNA of all family members and somatic DNA extracted from skin of the eldest affected sibling, the proband. No mutations were found in exon 17 in either genomic DNA of all family members or somatic DNA of the proband. Patients with UP have been shown to possess somatic mutations of the c-kit gene. However, this locus has been excluded as playing a part in the three siblings examined here in whom a second gene locus must be determining their UP. Therefore, this study emphasizes genetic heterogeneity in UP. Future study to identify primary molecular determinants of UP should include affected sib-pair studies.
Br J Dermatol 1999 May
PMID:Lack of c-kit mutation in familial urticaria pigmentosa. 1035 21

Genomic DNA extracted from peripheral blood mononuclear cells of monozygotic twin patients with urticaria pigmentosa was investigated for mutations of proto-oncogene c-kit. Neither the patients nor their families had genomic mutations in exon 11 or exon 17 of c-kit. The patients did not have any systemic involvement or bone marrow abnormalities. There are indications that some genetic factors may participate in the pathogenesis of urticaria pigmentosa in monozygotic twins. In the present patients, factors other than genomic faults in exon 11 and exon 17 of c-kit may be responsible for the pathogenesis.
Br J Dermatol 1999 Jun
PMID:Analysis of c-kit exon 11 and exon 17 of urticaria pigmentosa that occurred in monozygotic twin sisters. 1035 83

Murine mast cell proliferation and maturation are regulated by two distinct cytokines, interleukin-3 (IL-3) and the c-kit ligand, stem cell factor (SCF). In this study using cells of the mouse mast cell line, MC/9, the effects of two immunosuppressants, FK506 and cyclosporin A (CsA), were investigated. Withdrawal of IL-3 from the culture medium resulted in loss of viability of MC/9 cells. The addition of SCF in the absence of IL-3 maintained MC/9 cell survival but no cell proliferation was detected. The combined addition of IL-3 and SCF to the culture medium resulted in a more marked MC/9 cell proliferation than the addition of IL-3 alone. FK506 and CsA inhibited the SCF-dependent, but not the IL-3 dependent, stimulatory effects on MC/9 cell proliferation/survival. Apoptotic changes were analyzed using fluorescent staining with acridine orange and DNA electrophoresis. FK506 and CsA inhibited the SCF-dependent rescue effect from apoptosis. Flow cytometry showed that FK506 and CsA did not affect IL-3 receptor expression. However, immunoblot and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses indicated that c-kit protein and c-kit mRNA transcripts were increased following the FK506 and CsA treatments in the presence of IL-3. In addition, MC/9 cells pretreated with FK506 or CsA showed an increased adhesiveness to NIH/3T3 cells that express membrane-bound SCF. Neither FK506 nor CsA affected c-kit tyrosine phosphorylation or MAP kinase nuclear translocation of MC/9 cells following SCF stimulation. These results indicate that FK506 and CsA, while inducing c-kit of MC/9 cells, selectively inhibit the SCF-dependent stimulatory effects on MC/9 cell proliferation/survival by a mechanism independent of, or at point(s) distal to, the c-kit-MAP kinase pathway.
Arch Dermatol Res 1999 May
PMID:FK506 and cyclosporin A inhibit stem cell factor-dependent cell proliferation/survival, while inducing upregulation of c-kit expression in cells of the mast cell line MC/9. 1036 10

The melanoma cell adhesion molecule was identified as a human melanoma-associated antigen that increases in expression as tumors increase in thickness and begin to acquire metastatic potential. Clinical and experimental evidences suggest that the development of metastatic capacity might be the consequence of increased melanoma cell adhesion molecule expression. The mechanisms for upregulation of the melanoma cell adhesion molecule during melanoma progression are, however, still poorly understood. In this study, we show that melanoma cell adhesion molecule expression is tightly regulated at the transcriptional level. Using a combination of CAT reporter assays and semiquantitative reverse transcriptase-polymerase chain reaction, we observed that cyclic adenosine monophosphate significantly increases transcription of the melanoma cell adhesion molecule in nonmetastatic melanoma cells. In metastatic cells, transcription of the gene was constitutive and could not be further increased by cyclic adenosine monophosphate. On the other hand, melanoma cell adhesion molecule promoter activity was impeded upon treatment with phorbol esters or in the presence of stem cell factor, a phenomenon which was protein kinase C-dependent. Promoter-deletion studies demonstrated that the first 196 nt of the melanoma cell adhesion molecule promoter region are sufficient to get full expression in metastatic melanoma cells. This fragment contains five binding sites for the transcription factor Sp1 and DNA mobility shift experiments showed direct binding of Sp1 to the promoter. In conclusion, our results indicate that Sp1 is sufficient to drive constitutive melanoma cell adhesion molecule expression in metastatic melanoma cells. In nonmetastatic cells, however, melanoma cell adhesion molecule expression is repressed and we speculate that stem cell factor/c-Kit signaling might be responsible for the control of melanoma cell adhesion molecule synthesis, and thus, perhaps, of melanoma progression and metastasis.
J Invest Dermatol 1999 Nov
PMID:Regulation of the melanoma cell adhesion molecule gene in melanoma: modulation of mRNA synthesis by cyclic adenosine monophosphate, phorbol ester, and stem cell fFactor/c-kKit signaling. 1057 24


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