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)

Studies of mice containing mutations in the genes for a receptor tyrosine kinase, c-kit, or its cognate ligand, Steel factor (SLF), establish that this signaling pathway is required for the development of melanocytes from their precursors in the embryonic neural crest (NC). In order to define the mechanism of this requirement, we have labeled cells expressing c-kit with an anti-c-kit antibody (ACK2) and studied the action of SLF on these cells in cultures of murine trunk NC. c-kit positive (c-kit+) cells first appeared after 2 days in culture and were morphologically indistinguishable from other NC cells. These cells subsequently expressed tyrosinase-related protein, an early marker for the melanocyte lineage, and became pigmented in the presence of a phorbol ester. Further, elimination of the c-kit+ population, by incubating the cultures in ACK2, resulted in the ablation of the melanocyte population, but had no effect on the generation of other neural crest derivatives. These data indicate that c-kit+ cells arising from the neural crest are melanocyte progenitors. The addition of SLF to these cultures stimulated an increase in the number of c-kit+ cells, and further studies indicated that SLF acts as both a survival and a proliferative factor for c-kit+ cells. These findings provide a mechanism of regulation of melanocyte development, whereby c-kit is exclusively expressed by melanocyte progenitors within the neural crest precursor population, and subsequent survival and proliferation of these progenitors is regulated by SLF.
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PMID:Steel factor directs melanocyte development in vitro through selective regulation of the number of c-kit+ progenitors. 754 Jan 55

In this article we describe the rapid advances made in the molecular genetics of three inherited pigmentation disorders: albinism, piebaldism, and vitiligo, all of which throw light on normal pigment cell function. The focus is on studies in mice, with comparison of data in humans. The critical role of tyrosinase (c-locus or human tyrosinase protein) in normal pigmentation and albinism has been reinforced by the cloning and identification of mutations in tyrosinase and two other melanocyte-specific oxidoreductases structurally related to but functionally different from tyrosinase: the (b) brown-locus protein/gp75/catalase B and dopachrome tautomerase. Each possesses a distinct enzyme activity and yet the three share homology in strategic regions. Most of the point mutations that reduce or abrogate the respective enzyme activities are located in those regions. Tyrosinase-negative albinism is caused only by defects in tyrosinase. A locus for human tyrosinase-positive albinism has been recently mapped to chromosome 15q11.2-->q12, at a gene identified in mice as pink-eyed dilution. On the other hand, several genes encoding proteins critical for the proliferation of melanocytes are known to control the piebald phenotype. So far identified are two membrane-receptor tyrosine kinases, c-Kit and PDGF-R/alpha, and the ligand for c-kit, MGF (mast-cell growth factor, also known as stem-cell factor, c-Kit-ligand, or steel factor). Mutations in W/c-kit (white spotting), Ph/Pdgfr/a (patch), and Sl/MGF (steel), lead to a reduction in receptor kinase activity and failure of melanocytes to thrive and reach the skin during embryogenesis. Finally, mouse mutant models suggest at least two possible causes for vitiligo, a progressive loss of pigmentation that occurs after birth. In one mutant, the Blt (light) mouse, the cyclic death of hair melanocytes may be due to the toxicity of intermediates and byproducts of melanogenesis in the presence of a dysfunctional b-locus protein. In the other model, the "vitiligo mouse," in which the allele vit has been assigned to the microphthalmia (mi) locus, the loss of melanocytes may be caused by defective signal transduction, because in addition to vitiligo mivit/mivit mice have extensive piebaldism.
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PMID:White mutants in mice shedding light on humans. 843 6

The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented.
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PMID:Molecular bases of congenital hypopigmentary disorders in humans and oculocutaneous albinism 1 in Japan. 1104 70

Cells positive to the dopa reaction (melanocytes) as well as to the combined dopa-premelanin reaction (melanoblasts and melanocytes) in the epidermis of C57BL/10JHir-p/p (pink-eyed dilution) mice were fewer and less reactive than in C57BL/10JHir (black, P/P) mice, suggesting that the proliferation and differentiation of p/p melanocytes are inhibited. To confirm the inhibitory effects of p gene on the proliferation and differentiation of epidermal melanocytes, we cultured epidermal cell suspensions of neonatal skins from P/P and p/p in a serum-free medium. The proliferation and differentiation of p/p melanoblasts/melanocytes in primary culture were greatly inhibited as compared to P/P melanoblasts/melanocytes. The morphology of p/p melanoblasts/melanocytes cultured in melanocyte growth medium, though non-pigmented, was similar to P/P melanocytes; namely, dendritic, polygonal, or epithelioid. About 8% of p/p cells cultured in melanocyte growth medium were positive to the dopa reaction, and about 25% were reactive to the combined dopa-premelanin reaction. Eumelanin content in p/p was extremely reduced compared to P/P. The immunocytochemical staining of p/p melanoblasts/melanocytes revealed that they are negative to tyrosinase, but reactive to tyrosinase-related protein (TRP)-1, TRP-2, and c-kit. However, the reactivities in p/p were lower than in P/P. Although the differentiation of p/p melanoblasts was not induced by endothelin (ET)-1, ET-2, and ET-3, the proliferation of p/p melanoblasts was stimulated by them. These results suggest for the first time that p gene exerts its influence on the proliferative activities of mouse epidermal melanoblasts by affecting the regulatory mechanisms dependent on the function of ETs.
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PMID:Effects of genic substitution at the pink-eyed dilution locus on the proliferation and differentiation of mouse epidermal melanocytes in vivo and in vitro. 1185 69

Hermansky-Pudlak Syndrome-type 3 (HPS-3) is a relatively mild subtype of HPS with minimal cutaneous and ocular depigmentation. The HPS-3 gene encodes a novel protein of unknown function with a predicted molecular weight of 114 kd. To assess the role of the HPS3 protein in melanization, cultured melanocytes developed from HPS-3 patients were evaluated biochemically and histologically for activity and localization of melanocyte-specific proteins. Endogenous tyrosinase activity of HPS-3 melanocytes was substantial, but tyrosinase activity and melanin synthesis was suppressed in intact melanocytes. However, the level of suppression, as well as extent to which up-regulation by isobutylmethylxanthine and cholera toxin was muted, was less that in HPS-1 melanocytes. Ultrastructurally, HPS-3 melanocytes contained morphologically normal melanosomes, predominantly of stage I and II with minimal stage III and few stage IV melanosomes. Dihydroxyphenylalanine (DOPA) histochemistry demonstrated an increase in melanization of melanosomes. Unique to HPS-3 melanocytes were numerous DOPA-positive 50-nm vesicles and tubular elements present throughout the cell body and dendrites. Tyrosinase, tyrosinase-related protein-1 (Tyrp1), dopachrome tautomerase (Dct), and LAMP1 and 3 localization in HPS-3 melanocytes, as evaluated by immunocytochemistry and confocal microscopy, demonstrated a fine, floccular distribution in contrast to the coarse, granular distribution characteristic of control melanocytes. The localization profile of other proteins expressed by melanocytes (ie, Silver/Pmel17, Melan-A/MART-1, LAMP2, Rab 27, transferrin, c-kit, adaptin-3, and the HPS1 protein) appeared normal. These results suggest that a specific subset of melanocyte proteins are aberrantly trafficked throughout the HPS-3 melanocyte and may be responsible for the reduction in melanin synthesis.
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PMID:Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3. 1563 15