Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During development, the interaction of stem cell factor (SCF) with its receptor, KIT, is critical for the survival of melanocytes. Limited in vivo human studies have suggested a possible activating role of SCF on adult human melanocytes. In order to study the impact of this pathway on normal melanocyte homeostasis, human skin xenografts were treated with serial injections of recombinant human SCF or a KIT-inhibitory antibody (K44.2). On histologic evaluation, SCF injection increased, whereas KIT inhibition decreased the number, size, and dendricity of melanocytes. Immunohistochemical expression of melanocyte differentiation antigens, including tyrosinase-related-protein-1 and gp100/pmel17, was markedly increased by treatment with SCF, and decreased by K44.2 treatment. The number of Ki67-positive melanocytes was increased in the SCF-treated tissue, suggesting a direct proliferative effect of SCF; conversely, treatment with K44.2 resulted in melanocyte loss, which did not appear reversible with prolonged treatment. These findings demonstrate that the SCF/KIT pathway remains critical in adult human skin, and that pharmacologic modulation of this single pathway can control cutaneous melanocyte homeostasis.
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PMID:The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. 1041 34

The etiology and pathogenesis of idiopathic guttate hypomelanosis (IGH) are largely unknown. To investigate whether the pathologic alteration in IGH involves changes in melanocytic differentiation, cell number, or both, we studied nine lesions of IGH by immunoperoxidase, using monoclonal antibodies against the KIT receptor and a panel of melanocyte differentiation antigens (tyrosinase-related protein-1, tyrosinase, and gp100/pme117). In each case, compared with grossly normal non-lesional skin, IGH lesions showed markedly reduced numbers both of KIT+ cells and of cells expressing melanocyte differentiation antigens (p < 0.0001). Double immunofluorescence labeling of lesions revealed only scattered cells with a less-differentiated phenotype, i.e. cells positive for KIT but having low or undetectable TRP-1. These results indicate that the pathogenesis of IGH involves an absolute decrease in the number of melanocytes; a block in melanocyte differentiation does not appear to be a major component of the process.
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PMID:Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis. 976 23

On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.
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PMID:A cascade of genes related to Waardenburg syndrome. 1053 86

The proportion of unpigmented coat on the trunk was determined from photographs of 38 German Simmental and 627 German Holstein bulls distributed over three generations. All 665 animals were members of 18 Holstein and 3 Simmental half-sib families. A Bayesian estimation of heritability yielded a posterior mean of 0.88 and a standard error of 0.08. A quantitative trait loci (QTL) scan over all chromosomes covered by 229 microsatellite marker loci (2926 cM) was performed by fitting a multiple marker regression model to 625 observations from the youngest generation in 18 families. On chromosome 6 a QTL for the proportion of white coat with large effects (experiment-wise error probability < .0001) was found and a less important one on chromosome 3 (chromosome-wise error probability < .009). Chromosome 6 is known to harbor the KIT locus (receptor tyrosinase kinase), which is associated with various depigmentation phenotypes in mice, humans, and pigs. Similarity of phenotypic KIT effects in other species and synteny with the reported QTL suggest that KIT is a serious candidate gene for the degree of spotting in cattle. The results are also discussed with respect to resistance to solar radiation, heat stress, and photosensitization.
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PMID:A QTL for the degree of spotting in cattle shows synteny with the KIT locus on chromosome 6. 1058 13

Stem cell factor (SCF) and endothelin-3 (ET3) are both necessary for melanocyte development. In order to obtain immortal cell populations of melanoblasts that can survive without feeder cells, we first obtained an immortal cell population of neural crest cells (NCCs) from Sl/+ and +/+ mice of strain WB by incubating with a culture medium supplemented with SCF and ET3, and then we designated them as NCC-SE3 cells. NCC-SE3 cells were bipolar, polygonal, or round in shape and possessed melanosomes of stages I-III (mainly stage I). They were positive to dihydroxyphenylalanine (DOPA) reaction and expressed KIT (a receptor tyrosine kinase), tyrosinase, tyrosinase-related protein-1 (TRP1), tyrosinase-related protein-2 (TRP2), and endothelin-B receptor (ETRB) as determined by immunostaining. We next cultured NCC-SE3 cells by changing culture medium from the one supplemented with SCF + ET3 to the one supplemented with SCF or ET3. NCC-SE3 cells cultured with ET3 alone, designated as NCC-E3 cells, were bipolar in shape and had mainly stage II melanosomes and expressed the same proteins as did NCC-SE3 cells. However, NCC-SE3 cells cultured with SCF alone, designated as NCC-S4.1 cells, were polygonal in shape and had mainly stage I melanosomes. They are thought to be more immature because they were positive to KIT, TRP1, and TRP2, but not to ETR(B), tyrosinase, and DOPA reaction. When 12-O-tetradecanoylphorbol 13-acetate and cholera toxin were added to the culture medium, NCC-S4.1 cells changed shape from polygonal to bipolar and became DOPA-positive. This suggests that NCC-S4.1 cells are melanoblasts that have the potential to differentiate into melanocytes. These cell populations will be extremely useful to study factors that affect melanocyte development and melanogenesis.
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PMID:Stem cell factor and/or endothelin-3 dependent immortal melanoblast and melanocyte populations derived from mouse neural crest cells. 1104 61

Genetic and cell culture analyses have shown that the development of melanocytes from neural crest-derived precursor cells critically depends on the tyrosine kinase receptor KIT and the basic-helix-loop-helix-leucine zipper transcription factor MITF. KIT and MITF show complex interactions in that MITF is needed for the maintenance of Kit expression in melanoblasts and KIT signaling modulates MITF activity and stability in melanocyte cell lines. Using primary neural crest cell cultures from embryos homozygous for a Kit null allele marked by an inserted LacZ gene (Kit(W-LacZ)), we show that the onset of Mitf expression in melanoblasts does not require KIT. In fact, provided that the melanocyte growth factor endothelin-3 is present, a small number of MITF/beta-Gal-positive cells can be maintained for at least 2 weeks in Kit(W-LacZ)/Kit(W-LacZ) cultures. These cells express several pigment cell-specific genes that are thought or have been shown to be activated by MITF, including dautochrome tautomerase, pMel 17/Silver and tyrosinase-related protein-1, but lack expression of the MITF target gene tyrosinase, which encodes the rate-limiting enzyme in melanin synthesis. Consequently, the cells remain unpigmented. Addition of cholera toxin, which elevates cAMP levels and mimics part of the KIT signaling pathway, increases the number of MITF-positive cells in Kit(W-LacZ)/Kit(W-LacZ) cultures, leads to tyrosinase expression, and induces the differentiation of melanoblasts into mature, pigmented melanocytes. Even when added on day 5-6 of culture, cholera toxin still rescues tyrosinase expression and differentiation. The results thus demonstrate that the presence of MITF is not sufficient for tyrosinase expression in melanoblasts and that KIT signaling influences gene expression during melanocyte development in a gene-selective manner.
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PMID:Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. 1107 59

Stem cell factor (SCF) and endothelin 3 (EDN3) are both necessary for melanocyte development. We have established an immortal cell population of neural crest cells from C57BL/6 mice, cultivating them with SCF, EDN3 and 15% fetal calf serum without feeder cells, and have designated that line as C57NCC SE. C57NCC SE consists of a population of melanocytes in various stages of differentiation. We used a single-cell cloning method, in which only one cell is transferred to each new culture plate, and succeeded in establishing an immortal cell line named NCCmelan5. All NCCmelan5 cells were positive for KIT (SCF receptor), HMB45 (human melanosomal antigen), tyrosinase-related protein-1 (TYRP1), tyrosinase-related protein-2 (TYRP2), tyrosinase and endothelin receptor B (EDNRB) and all could oxidize 3,4-dihydroxyphenylalanine (DOPA) to form melanin. Measurement of their DNA content revealed that 88.6% of the cells were in the G0-G1 phase, suggesting that they retained normal DNA ploidy. Thus, NCCmelan5 cells have the characteristics of mature melanocytes except that they are immortal; these cells may prove useful to study factors that directly affect melanogenesis and melanocyte development without the influence of feeder cells. It is clear that our attempt to establish immortal cell lines from murine neural crest cells would have never been successful without the addition of SCF and EDN3, since C57NCC SE and NCCmelan5 cells require those factors to proliferate.
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PMID:Establishment and characterization of a mouse neural crest derived cell line (NCCmelan5). 1154 10

The effects of all-trans retinoic acid on the differentiation and proliferation of immature melanocyte precursors were studied. NCC-melb4 cells are an immortal cloned cell line established from mouse neural crest cells using a single-cell cloning method. These cells were positive for tyrosinase-related protein 1, tyrosinase-related protein 2 and KIT, but were negative for tyrosinase and had no dihydroxyphenylalanine reaction. They contained only stage I melanosomes without any melanosomes in more advanced stages. After treatment with all-trans retinoic acid, many of the cells became tyrosinase- and dihydroxyphenylalanine-reaction-positive, changed from polygonal to dendritic in shape, and had stage III to IV melanosomes. These findings indicate that treatment with all-trans retinoic acid induced the differentiation of NCC-melb4 cells. Reverse transcription polymerase chain reaction analysis revealed a marked increase in expression of microphthalmia-associated transcription factor mRNA after all-trans retinoic acid treatment, suggesting that microphthalmia-associated transcription factor may be the key molecule in this event. Enhanced expression of protein kinase Calpha following treatment with all-trans retinoic acid was also demonstrated. The proliferation of NCC-melb4 cells was inhibited by all-trans retinoic acid in a dose-dependent manner. Increased apoptosis after all-trans retinoic acid treatment was observed by electron microscopy, the TUNEL method, DNA fragmentation assay, and flow cytometry. All-trans retinoic acid upregulated caspase-3 and downregulated bcl-2. Electron microscopy showed that apoptotic cells contained melanosomes of advanced stages, suggesting that mature melanocytes may tend to undergo apoptosis after all-trans retinoic acid treatment. This study provides important clues towards understanding the roles and working mechanisms of retinoic acids in melanocyte development and melanogenesis.
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PMID:All-trans retinoic acid induces differentiation and apoptosis of murine melanocyte precursors with induction of the microphthalmia-associated transcription factor. 1185 73

Angiomyolipoma is a unique mesenchymal tumor postulated to arise from perivascular epithelioid cells. Immunohistochemical studies have shown that angiomyolipomas express the melanocytic markers HMB-45, MART-1 (Melan A), microphthalmia transcription factor, and tyrosinase, in addition to smooth muscle actin. KIT (CD117) is a transmembrane growth factor receptor expressed in cells of melanocytic and a variety of other cell lineages. To date, KIT immunoreactivity has not been systematically studied in angiomyolipoma. In this study we immunohistochemically analyzed a series of 21 angiomyolipomas (15 hepatic, six renal) with KIT. All were KIT positive: 14 of 21 (67%) with 3+ staining (>50% of tumor cells), 4 of 21 (19%) with 2+ staining (25-50% of tumor cells), and 3 of 21 (14%) with 1+ staining (<25% of tumor cells). In comparison, the percent of angiomyolipomas showing 3+ staining with HMB-45 was 62% and with Melan A was 52%. Positive KIT staining was detected in the epithelioid, spindle, and intermediate small round cells. Most cases showed diffuse cytoplasmic positivity. Strong perinuclear staining was present in the vacuolated clear epithelioid cells. There was focal KIT staining of fat cells. KIT was not detected in the endothelial cells lining blood vessels within the tumor. KIT may be a useful ancillary marker for the diagnosis of angiomyolipoma. Angiomyolipoma should be included in the differential diagnosis of KIT-positive tumors.
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PMID:Expression of KIT (CD117) in angiomyolipoma. 1191 28

To evaluate the etiologic role of ultraviolet (UV) radiation in acquired dermal melanocytosis (ADM), we investigated the effects of UVA and UVB irradiation on the development and differentiation of melanocytes in primary cultures of mouse neural crest cells (NCC) by counting the numbers of cells positive for KIT (the receptor for stem cell factor) and for the L-3,4-dihydroxyphenylalanine (DOPA) oxidase reaction. No significant differences were found in the number of KIT- or DOPA-positive cells between the UV-irradiated cultures and the non-irradiated cultures. We then examined the effects of UV light on KIT-positive cell lines derived from mouse NCC cultures. Irradiation with UVA but not with UVB inhibited the tyrosinase activity in a tyrosinase-positive cell line (NCCmelan5). Tyrosinase activity in the cells was markedly enhanced by treatment with alpha-melanocyte-stimulating hormone (alpha-MSH), but that stimulation was inhibited by UVA or by UVB irradiation. Irradiation with UVA or UVB did not induce tyrosinase activity in a tyrosinase-negative cell line (NCCmelb4). Levels of KIT expression in NCCmelan5 cells and in NCCmelb4 cells were significantly decreased after UV irradiation. Phosphorylation levels of extracellular signal-regulated kinase 1/2 in cells stimulated with stem cell factor were also diminished after UV irradiation. These results suggest that UV irradiation does not stimulate but rather suppresses mouse NCC. Thus if UV irradiation is a causative factor for ADM lesions, it would not act directly on dermal melanocytes but may act in indirect manners, for instance, via the overproduction of melanogenic cytokines such as alpha-MSH and/or endothelin-1.
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PMID:Effects of ultraviolet light on melanocyte differentiation: studies with mouse neural crest cells and neural crest-derived cell lines. 1501 4


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