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)

The activation or the inhibition of melanocyte-specific receptors offers novel means of augmenting normal melanocyte function, skin color, and photoprotection, or treating melanocytic disorders, namely at this time, metastatic melanoma. Melanocyte-specific receptors include melanocortin-1 (MCR1) and melatonin receptors. Other receptors that play an important role in melanoma progression are G-protein couple receptors such as Frizzled 5 and receptor tyrosine kinases such as c-Kit and hepatocyte growth factor (HGF) receptor. These receptors activate two crucial cell-signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT, integral to melanoma cell survival, and can serve as targets for therapy of disseminated melanoma. Activation of death receptors is another pathway that can be exploited with targeted therapeutics to control advanced melanoma. This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology.
Dermatol Clin 2007 Oct
PMID:Melanocyte receptors: clinical implications and therapeutic relevance. 1790 13

Mast cells are traditionally viewed as effector cells of allergic reactions and parasitic diseases, but their importance in host defense against bacteria, in tissue remodelling, their bone marrow and stem cell origin and a central role of the stem cell factor (SCF) as mast cell growth and chemotactic factor has been worked out only in recent years. Despite this, major aspects about the nature of the cells and their role in disease remain unclear. This holds in particular for the identification of mast cell precursors and the role of growth factors that stimulate specific mast cell commitment from stem cells, such as nerve growth factor, neutrotrophin-3 and certain interleukins, alone and during interaction with SCF. Early data suggesting also an involvement of specific transcription factors need to be expanded in this process. Furthermore, although mast cell proliferative disease (mastocytosis) has been shown to be often associated with SCF receptor c-kit mutations, reasons for the development of this disease remain unclear. This holds also for mast cell release mechanisms in many types of mast cell-dependent urticaria. Exciting new insights are emerging regarding the role of mast cells in bacterial infections, in defense against tumors, in wound healing and in the interplay with the nervous system, with hormones, and in the neurohormonal network. The aim of this reflection is to delineate the many known and unknown aspects of mast cells, with a special focus on their development, and to discuss in detail two mast cell-related diseases, namely mastocytosis and urticaria.
Exp Dermatol 2008 Feb
PMID:Exploring the mast cell enigma: a personal reflection of what remains to be done. 1820 12

Although the exact molecular mechanisms of Merkel cell carcinoma (MCC) tumorigenesis are unknown, they likely involve complex genetic alterations and mutations similar to those seen in many other cancers. In this study, we obtained MCCs from 21 elderly patients (19 women, 2 men) and analyzed their DNA for mutation of exons of interest in several tumor-suppressor genes or oncogenes known to be frequently mutated in skin cancer: p53 (exons 4-8), Ras (exons 1 and 2), c-Kit (exon 11), and the INK4a-ARF locus (encoding p14 and p16) (exons 1 and 2). Direct sequence analysis revealed p53 mutations (that is, at codons 224, 234, and 294) in three tumors (14%) and p16INK4a mutations (that is, at codon 6) in one (5%). No mutations were detected in Ha-Ras, Ki-Ras, N-Ras, c-Kit, or p14ARF. On the other hand, methylation-specific PCR revealed methylation of p14ARF promoter DNA in eight of 19 analyzable tumor samples (42%) and p16INK4a promoter DNA in one of 19 analyzable tumor samples (5%). Together, these findings suggest that p14ARF silencing may be an important mechanism in MCC tumorigenesis, and thus a potential target for therapeutic intervention in this highly aggressive tumor type.
J Invest Dermatol 2008 Jul
PMID:p14ARF hypermethylation is common but INK4a-ARF locus or p53 mutations are rare in Merkel cell carcinoma. 1821 79

Regional lymph node involvement by a cellular blue nevus has been reported. However, it has recently been suggested that specific cases with "benign metastasizing" cellular blue nevi are actually rare. This study describes a typical case of a cellular blue nevus with nevus cells in a sentinel lymph node. We demonstrated that a cellular blue nevus clearly involved the regional lymph node and investigated the immunohistochemical profiles of such nodal cellular blue nevus cells. The location of the nevus cells fundamentally indicated a benign type, with limitation to the capsule and the fibrous trabeculae. However, only a few, isolated nevus cells were also seen in the parenchyma of the lymph node. The nevus cells in the capsule and the fibrous trabeculae were positive for c-kit, like the migrating melanocytes from the neural crest. In cellular blue nevi or lesions with similar histopathological features, it may be appropriate to consider the predominant involvement of the capsule as well as the benign cytological features and the immunohistochemical profiles (Ki-67-, PCNA-, and c-kit+) of the nodal cells to be a benign sign.
Eur J Dermatol
PMID:Cellular blue nevus with nevus cells in a sentinel lymph node. 1869 67

Imatinib mesylate, a tyrosine kinase inhibitor targeting the Bcr-Abl protein, c-kit (KIT) and the platelet-derived growth factor receptors (PDGFR), is an important part of the therapeutic armamentarium used in chronic myelogenous leukemia and gastrointestinal stromal tumors. A multitude of dermatological toxicities occur with the clinical use of this drug, ranging from various acute rashes to Steven-Johnson syndrome. Hyperpigmentation of the skin is a less frequent side effect. This phenomenon may be linked to alterations in the c-kit signaling pathway, which plays an important role in melanogenesis. A similar cutaneous phenotypic expression is manifested in families carrying congenital tyrosine II domain mutations of c-kit. We present a unique case of long-term persistent hyperpigmentation that occurred after the treatment with imatinib and describe the possible pathogenetic mechanisms involved. Elucidation of the mechanisms of action of imatinib in the skin may open future directions for the treatment of pigmentary disorders.
Dermatol Online J 2008 Jul 15
PMID:Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST. 1871 91

A 62-year-old obese woman presented with a malignant melanoma (Stage la). In addition, she had disseminated telangiectatic macules on both thighs. Intensive rubbing of lesions resulted in wheals. Biopsy revealed increased numbers of mast cells. We diagnosed telangiectasia macularis eruptiva perstans, a rare clinical form of adult maculopapular cutaneous mastocytosis, a group which also includes urticaria pigmentosa. No evidence was found for systemic involvement. Possible associations with malignant tumors and the possible role of c-kit mutations both in development of melanoma and mastocytosis are discussed.
J Dtsch Dermatol Ges 2009 Apr
PMID:Telangiectasia macularis eruptiva perstans, a form of cutaneous mastocytosis, associated with malignant melanoma. 1905 27

We report a case of vitiligo with localized repigmentation induced by imatinib mesylate. An elderly Chinese man has been characterized with recurrent gastrointestinal stromal tumors originated from interstitial cells of Cajal with gain-of-function c-kit mutation. His recurrent tumors have responded to imatinib mesylate therapy. To our surprise, his decade-long vitiligo was dramatically ameliorated by localized repigmentation, which is considered to be the side effect of imatinib mesylate. Hypopigmentation induced by imatinib mesylate with possible molecular blockage to a melanin-dependent KIT signal has been well documented; however, our case with repigmentation suggested that KIT signal of melanin formation would be much more sophisticated than we have believed.
J Am Acad Dermatol 2008 Nov
PMID:Imatinib mesylate-induced repigmentation of vitiligo lesions in a patient with recurrent gastrointestinal stromal tumors. 1911 32

Childhood cutaneous melanoma is a rare disease with increasing incidence. It is not clear whether it differs from adult melanoma in etiology and clinical evolution. To genetically characterize childhood melanoma, 21 pediatric patients were studied by germ-line analysis of CDKN2A, CDK4, and MC1R genes. In addition, alterations in CDKN2A, c-Kit, BRAF, and NRAS genes were evaluated at the somatic level by direct gene sequencing, fluorescence in situ hybridization analysis, and immunohistochemistry. As a control group of susceptible patients, we studied patients from 23 melanoma-prone families. At the germ-line level, CDKN2A and MC1R gene variants were detected in 2/21 and 12/21 pediatric patients and in 9/23 and 19/22 in familial patients. At the somatic level, most lesions (9/14) from pediatric patients showed CDKN2A locus homozygous deletions and a null p16 immunophenotype, whereas most lesions (5/8) from familial patients were disomic and immunoreactive. A c-Kit low-polysomy profile seems to parallel CDKN2A homozygous deletions in pediatric melanoma whereas the single activating mutation observed segregates with familial patients. Loss of KIT protein expression was frequent (7/14) in pediatric melanomas, where metastatic cases were prevalent. BRAF(V600E) mutation occurred at a similar rate (approximately 50%) in lesions from pediatric and familial patients, whereas no NRAS mutations were detected.
J Invest Dermatol 2009 Jul
PMID:Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. 2071 Dec 7

Hair depigmentation has been shown to occur with disruption of the interaction between the ligand stem cell factor (SCF) with its class III receptor tyrosine kinase c-kit, also called the stem cell factor receptor. This article reports the case of a patient who experienced depigmentation of her eyelashes, eyebrows, and temporal scalp hair six-to-eight weeks after initiating treatment with dasatinib (BMS-354825 or Sprycel), a novel dual Bcr-Abl/Src family tyrosine kinase inhibitor for chronic myeloid leukemia (CML). This case illustrates a previously unreported side-effect of dasatinib that is most likely due to the drug's inhibition of the c-kit, Src family, and platelet-derived growth factor receptor beta (PDGFRbeta) tyrosine kinases. Further study of hair depigmentation as a side effect of multi-kinase inhibitors can provide useful information on hair and melanocyte physiology.
J Drugs Dermatol 2009 Apr
PMID:Hair depigmentation during chemotherapy with dasatinib, a dual Bcr-Abl/Src family tyrosine kinase inhibitor. 1936 59

We describe a patient with a solitary mastocytoma arising at a site of trauma. The patient was born with the umbilical cord wrapped around her right thigh and subsequently developed a solitary mastocytoma in the exact site and distribution of this injury. The pathogenesis of mast cell proliferation in solitary mastocytoma is not completely understood. Cytokines released after injury, such as stem cell factor, may stimulate the proliferation of mast cells, as well as fibroblasts and melanocytes to form a mastocytoma. Mast cells in a newborn may be more sensitive to stem cell factor in the presence of cytokines released after injury due to an increased density of c-kit receptors. We present our patient and review the literature to support a hypothesis that this condition represents a reactive, and not neoplastic, process.
Australas J Dermatol 2009 May
PMID:Solitary mastocytoma occurring at a site of trauma. 1939 69


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