Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the hair follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and hair follicle levels. FM is stringently coupled to the anagen stage of the hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper hair follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and hair follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color.
J Invest Dermatol 2005 Jan
PMID:Hair follicle pigmentation. 1565 48

A 45-year-old man presented with lesions clinically and histologically consistent with telangiectasis macularis eruptiva perstans (TMEP). TMEP is a rare form of mastocytosis, which is localized to the skin, although systemic involvement has been reported. A mutation in the c-kit proto-oncogene is thought to be involved in mast cell hyperplasia in some patients with mastocytosis. Treatment depends on the presence of systemic involvement or clinical symptoms. In case reports, therapeutic benefit has been reported in TMEP with the use of the 585-flashlamp pumped dye lasers and of electron beam radiation.
Dermatol Online J 2004 Nov 30
PMID:Telangiectasia macularis eruptiva perstans. 1574 71

Human skin substitutes (HSS) have been developed for repairing burns and other acute or chronic wounds. But although the clinical utility of HSS is well known, scant attention has been paid to their cosmetic properties, especially with regard to color compatibility with the patient's complexion. In this study, we generated an HSS from mixed cell slurries containing keratinocytes and fibroblasts with and without melanocytes on the back of severe combined immunodeficient mice by means of a spontaneous cell-sorting technique. At 16 wk after grafting, Caucasian donor-derived HSS with melanocytes were macroscopically clearly darker than those without melanocytes, and a more darkly pigmented HSS was produced when cells from donors of African descent were seeded. Immunohistochemistry of c-kit, S-100, and HMB45, as well as Fontana-Masson staining and transmission electron microscopy (TEM) demonstrated that melanocytes spontaneously localized to the basal layer. Melanosome transfer to keratinocytes was correctly reorganized, and melanin was evenly dispersed in the basal and suprabasal layers. Colorimetric analysis showed a significantly lower L-value by day 14 following irradiation with 120 mJ per cm2 ultraviolet-B (UVB) (p<0.01), whereas epidermal thickness increased by 50% 1 d after exposure (p<0.01), indicating a normal physiological response to UVB irradiation. These findings suggest that HSS with spontaneously sorted melanocytes offer a means of treating both the structural and cosmetic aspects of skin conditions and trauma, such as pigmentary disorders and skin wounds, by allowing manipulation of the color and population of donor melanocytes.
J Invest Dermatol 2005 Aug
PMID:An in vivo mouse model of human skin substitute containing spontaneously sorted melanocytes demonstrates physiological changes after UVB irradiation. 1609 48

Melanin synthesis in the hair follicle (HF) is strictly coupled to the growth stage of the hair cycle and is interrupted during follicle regression (catagen) and resting. Using tyrosine-related protein 2 (Trp)2-LacZ transgenic mice as a model, we show that distinct melanocyte subpopulations of the HF display distinct patterns of apoptosis and survival during catagen. Melanocytes located in the outer root sheath express Bcl-2 and are TUNEL-negative. Part of the pigment-producing melanocytes located above the follicular papilla expresses Fas, TUNEL, and is likely to undergo apoptosis, whereas the other part of these melanocytes expresses c-kit, Bcl-2, and becomes visible in the follicular papilla. During late catagen, TUNEL and Ki-67 negative melanocytes expressing Bcl-2 are seen in the secondary germ of the HF. Lack of proliferation in the follicular melanocytes during catagen suggests that secondary hair germ of late catagen HF is most likely repopulated by melanocytes arising from the outer root sheath or follicular papilla of early/mid-catagen HF. Taken together, these data suggest a possible scenario and mechanisms of the remodeling of the follicular pigmentary unit during HF anagen-catagen-telogen transition and may be used for the establishing in vivo models for pharmacological modulation of melanocyte apoptosis and survival during the hair cycle.
J Invest Dermatol 2005 Dec
PMID:Changes in different melanocyte populations during hair follicle involution (catagen). 1635 97

Telangiectasia macularis eruptiva perstans (TMEP) is an uncommon form of cutaneous mastocytosis that occurs exclusively in adults. Histologically, TMEP presents with scattered mast cells lined up around the dilated capillaries and venules of the superficial vascular plexus. In some cases, the number of mast cells falls within the range observed in normal skin and therefore cannot be detected by routine histologic examination. We used immunohistochemical staining for c-kit (CD 117) for the definitive diagnosis in two patients with TMEP. One of them was successfully treated with topical application of pimecrolimus.
J Dermatol 2005 Oct
PMID:Two cases of telangiectasia macularis eruptiva perstans demonstrated by immunohistochemistry for c-kit (CD 117). 1636 34

Imatinib mesylate (Gleevec, also known as STI-571), is an approved oral treatment for patients with chronic myeloid leukemia (CML). It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans. One report notes its effectiveness for treating HIV related Kaposi's sarcoma; imatinib has not been effective for the treatment of melanoma.
J Drugs Dermatol 2006 Feb
PMID:A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases. 1648 79

Imatinib mesylate is a drug that has been recently approved for the treatment for chronic myeloid leukemia. It acts as a potent and selective inhibitor of BCR-ABL tyrosine kinase. It also inhibits both c-kit and platelet-derived growth factor receptor tyrosine kinases. Hypopigmentation of the skin in patients receiving this drug has been recently reported. We report a 17-year-old Caucasian patient affected by chronic myeloid leukemia in therapy with imatinib mesylate who developed hypopigmented vitiligo-like patches and generalized lightening of the skin. In order to evaluate the lightening observed clinically, we measured the progressive skin color hypopigmentation by using a colorimeter over several months. The colorimetric evaluation confirmed the generalized and gradual lightening of patient's skin over treatment with imatinib mesylate. We believe that this is the first reported instance of vitiligo-like lesions in a pediatric patient treated with imatinib mesylate, and the second in a Caucasian patient.
Pediatr Dermatol
PMID:Vitiligo-like lesions and diffuse lightening of the skin in a pediatric patient treated with imatinib mesylate: a noninvasive colorimetric assessment. 1665 Feb 31

The receptor tyrosine kinase c-Kit is fundamental to mast cell (MC) development and maintenance. Its regulation can occur at various levels, but nothing is known about how this is accomplished in normal human tissue MC. Likewise, the baseline turnover of c-Kit has not been addressed yet. We used mature MC from human skin, along with the MC lines LAD-2 and HMC-1 and treated them with stem cell factor (SCF), cycloheximide, actinomycin D (AD) and combinations thereof, and determined expression levels of c-Kit and other surface receptors by flow cytometry. Ligand-induced internalization of c-Kit was found to be a universal mechanism and detectable in all MC subtypes. By Western blot analysis of LAD-2 cells, c-Kit was found to nearly disappear 3 h after the addition of SCF to slowly recover thereafter. Investigations into the baseline turnover of c-Kit expression revealed that c-Kit is strongly affected by the inhibition of de novo translation in all MC subsets, while a suppression of transcription had a weaker effect and displayed greater cell-to-cell variation. Only a minor impact on other cell surface receptors (CD29, CD50 and CD54) was noted. On combined treatment, cycloheximide, AD and SCF displayed additive effects, resulting in a complete disappearance of c-Kit from the cell surface. In conclusion, c-Kit represents a rapidly cycling cell surface receptor. It is not only immediately internalized upon binding of its ligand, but it is also heavily affected by the inhibition of translation or transcription when viewed against an average background. Interestingly, c-Kit regulation seems largely independent of the MC subtype.
Exp Dermatol 2006 Jul
PMID:Baseline and stimulated turnover of cell surface c-Kit expression in different types of human mast cells. 1676 62

Mastocytosis refers to a group of disorders characterized by the pathologic proliferation of mast cells. We present a 70-year-old white man with a rare presentation of nodular mastocytosis, characterized by disseminated nodular lesions, myelodysplastic syndrome, and a c-kit V560G receptor mutation. The patient presented to the clinic after initial presentation 6 months earlier, with ear pruritus, associated hearing loss, and widespread rash.
J Am Acad Dermatol 2006 Aug
PMID:Nodular mastocytosis. 1684 28

It was previously reported that telomere homologue oligonucleotides (T-oligos) can induce a variety of cellular responses in skin including increased melanogenesis. To assess the effects of T-oligos on hair pigmentation, we administered thymidine dinucleotide (pTT), one-third of the TTAGGG telomere repeat sequence, intradermally at distinct time points of the depilation-induced hair cycle in C3H/HeJ mice. Penetration of T-oligos into the hair follicle (HF) was monitored by using FITC-labelled pTT and confocal microscopy. pTT treatment on days 1-5 after depilation, during early anagen, did not significantly alter the number and proliferation of melanocytes (Trp-2-positive cells), compared with vehicle-treated controls. However, pTT treatment on days 5-12 after depilation, during mid- to late anagen, resulted in the formation of darker hairs, that showed a significantly increased eumelanin/total melanin ratio in their sub-apical agouti band region, compared with vehicle-treated controls (P < 0.05). By RT-PCR and western blot, full thickness skin of pTT-treated mice showed increases in Trp-1, Trp-2 and tyrosinase mRNA and protein levels, compared with control mice. Western blot analyses of two receptors that positively regulate eumelanogenesis, melanocortin type 1 receptor (MC-1R) and kit, showed increased expression of MC-1R protein in pTT-treated versus control skin, while the levels of c-kit receptor remained unchanged. These data demonstrate that pTT treatment increases eumelanogenesis in HFs, associated with increased tyrosinase, TRP-1 and MC-1R expression. These data also raise the possibility of using T-oligos to modulate hair pigmentation.
Exp Dermatol 2007 Aug
PMID:Oligonucleotide treatment increases eumelanogenesis, hair pigmentation and melanocortin-1 receptor expression in the hair follicle. 1762 94


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