Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell factor (SCF)/c-kit system is critical for human mast cell development. We thus examined the effects of STI571, an inhibitor of the c-kit tyrosine kinase receptor, on the proliferation and function of human mast cells. STI571 at concentrations of 10(-6) M or higher almost completely abolished the SCF-dependent progeny generation from cord blood-derived cultured mast cells through an inhibition of the tyrosine phosphorylation of c-kit. The compound also suppressed the early phase of mast cell development. The extinction of mast cell growth induced by STI571 may be due largely to apoptosis according to the flow cytometric analysis and gel electrophoresis. Two-hour exposure to STI571 that failed to influence the total viable cell number suppressed adhesion of the cells to fibronectin in the presence of SCF without altering the expressions of integrin molecules. Our results may provide a fundamental insight for the clinical application of STI571 in allergic disorders.
 ...
PMID:STI571 inhibits growth and adhesion of human mast cells in culture. 1296 Feb 56

Mast cells (MC) are highly granulated tissue dwelling cells, widely distributed throughout the body in connective tissues and on mucosal surfaces. They are derived from bone marrow progenitors that migrate into the blood and subsequently into the tissues, where they undergo final maturation. Mast cell proliferation, differentiation, survival and activation are regulated by stem cell factor, the ligand for the c-kit tyrosine kinase receptor, expressed on the mast cell surface. They release a large number of pro-inflammatory and immunoregulatory mediators after activation induced by either immunoglobulin E-dependent or immunoglobulin E-independent mechanisms. Mast cells have been most widely studied in the context of allergic reactions and parasite infections, but there is now compelling evidences that they are important players in innate and acquired immunity, wound healing, fibrosis, tumors and autoimmune diseases. This review will discuss current advances in these fields.
 ...
PMID:Mast cells in allergy and beyond. 1296 99

Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl-2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease-related D816V-mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future.
 ...
PMID:On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts. 1529 5

Administration of 1,2-dimethylhydrazine (DMH) induces intestinal epithelial tumors in mice. Increased numbers of mast cells have been reported to occur both within and near a variety of different neoplasms, including DMH-induced intestinal tumors. We investigated the role of the tyrosine kinase receptor, c-kit, and mast cells, in this model by administering DMH to c-kit mutant mast cell-deficient mice and the congenic normal mice. We attempted to induce colonic tumors by administering DMH (20 mg/kg body weight, s.c., weekly for 20 weeks) to WBB6F1-Kit+/+ (+/+) wild-type mice, the congenic mast cell-deficient WBB6F1-Kit(W)/Kit(W-v) (W/W(v)) mice and W/W(v) mice that had been repaired of their mast cell deficiency by adoptive transfer of bone marrow cells derived from the congenic +/+ mice. The susceptibility to the development of DMH-induced colonic tumors, and the numbers of mast cells associated with these tumors, was evaluated. Normal (+/+) mice exhibited significantly higher numbers of mast cells in DMH-induced intestinal tumors than in macroscopically normal colonic mucosa. Treatment with DMH induced development of colonic tumors in 97% of +/+ mice, but in only 32% of the W/W(v) mice. W/W(v) mice that had been repaired of their mast cell deficiency by transfer of +/+ bone marrow cells expressed susceptibility to the development of colonic tumors that was similar to that of wild-type mice. These results show that genetic impairment of c-kit function reduces the susceptibility of mice to DMH-induced colonic tumors, and that defects in bone marrow-derived cells in the W/W(v) mice contribute significantly to this result. Our findings also are consistent with the possibility that mast cells promote the development of DMH-induced colonic epithelial tumors in mice.
 ...
PMID:Decreased susceptibility of mast cell-deficient Kit(W)/Kit(W-v) mice to the development of 1, 2-dimethylhydrazine-induced intestinal tumors. 1569 91

The nucleotide sequences of the mouse, rat and human cDNAs and genes that encode the fourth member of the Ras guanine nucleotide releasing protein (RasGRP) family of signalling proteins have been deduced. RasGRP4 is a mast cell-restricted, cation-dependent, guanine nucleotide exchange factor (GEF). It is also a diacylglycerol (DAG)/phorbol ester receptor that plays a prominent role in dictating which protease and eicosanoid mediators are expressed in rodent and human mast cell lines. RasGRP4 appears to act downstream of the tyrosine kinase receptor c-Kt/CD117 and upstream of the basic-helix-loop-helix-leucine zipper transcription factor MITE Allelic variants of RasGRP4 have been identified, as have functionally different isoforms that are the result of variable splicing of its gene. Earlier gene-linkage studies revealed a site on chromosome 7A3-B1 that controls intrinsic airway reactivity to methacholine in backcrossed C3H/HeJ and A/J mice. The 18-exon mouse RasGRP4 gene resides on chromosome 7A3-B1, and recent studies revealed that the mast cells developed from the hyporesponsive C3H/HeJ mouse strain preferentially produce a defective isoform of RasGRP4. These and other data suggest that RasGRP4 is of critical importance in mast cell development and that the expression of abnormal isoforms of the protein can lead to mast cell dysfunction.
 ...
PMID:RasGRP4 in mast cell signalling and disease susceptibility. 1660 28

A 20-year-old female horse showed a nodular, firm, focal ulcerated mast cell tumor at the right dorsobuccal face of the tongue. Histologically, the nonencapsulated tumor consisted of dense, infiltrating aggregates of well-differentiated, Cresyl violet-positive mast cells accompanied by numerous eosinophils. Furthermore, they exhibited a strong, diffuse, intracytoplasmatic immunohistochemical signal for tryptase and a faint membrane-associated and perinuclear signal for tyrosine kinase receptor KIT. Confocal laser scanning microscopy confirmed an aberrant spatial colocalization of KIT in the Golgi apparatus, which may be the result of a defective protein processing within the tumor cells. The tumor was not associated with a poor prognosis.
 ...
PMID:Confocal laser scanning analysis of an equine oral mast cell tumor with atypical expression of tyrosine kinase receptor C-KIT. 1731 3

c-kit, the transmembrane tyrosine kinase receptor for stem cell factor, is required for melanocyte and mast cell development, hematopoiesis, and differentiation of spermatogonial stem cells. We show here that in the heart, c-kit is expressed not only by cardiac stem cells but also by cardiomyocytes, commencing immediately after birth and terminating a few days later, coincident with the onset of cardiomyocyte terminal differentiation. To examine the function of c-kit in cardiomyocyte terminal differentiation, we used compound heterozygous mice carrying the W (null) and W(v) (dominant negative) mutations of c-kit. In vivo, adult W/W(v) cardiomyocytes are phenotypically indistinguishable from their wild-type counterparts. After acute pressure overload adult W/W(v) cardiomyocytes reenter the cell cycle and proliferate, leading to left ventricular growth; furthermore in transgenic mice with cardiomyocyte-restricted overexpression of the dominant negative W(v) mutant, pressure overload causes cardiomyocytes to reenter the cell cycle. In contrast, in wild-type mice left ventricular growth after pressure overload results mainly from cardiomyocyte hypertrophy. Importantly, W/W(v) mice with pressure overload-induced cardiomyocyte hyperplasia had improved left ventricular function and survival. In W/W(v) mice, c-kit dysfunction also resulted in an approximately 14-fold decrease (P<0.01) in the number of c-kit(+)/GATA4(+) cardiac progenitors. These findings identify novel functions for c-kit: promotion of cardiac stem cell differentiation and regulation of cardiomyocyte terminal differentiation.
 ...
PMID:c-kit is required for cardiomyocyte terminal differentiation. 1825 57

Mastocytosis is a heterogeneous entity that may present as either a cutaneous or systemic disease. Progression of pediatric cutaneous mastocytosis (CM) is uncommon, but in adults, this condition persists and often progresses to systemic disease. Mast cell proliferation and differentiation from stem cell precursors depend on a number of factors, including a mast cell tyrosine kinase receptor (kit) and its ligand (the stromal cell-derived cytokine stem cell factor). A gain-of-function mutation in codon 816 of c-kit is frequently present in mast cells of patients with systemic mastocytosis (SM). The diagnostic approach for a patient with suspected mast cell disease includes a thorough skin examination, a skin biopsy, a serum tryptase level, and bone marrow aspiration and biopsy. The treatment is directed toward avoidance of triggers of mast cell mediator release and management of symptoms. Aggressive cases are managed with cytoreductive therapies, such as interferon alfa-2b and cladribine. Research has been directed at more specific treatment modalities, including specific kit tyrosine kinase inhibitors.
 ...
PMID:Systemic mastocytosis: classification, pathogenesis, diagnosis, and treatment. 1927 68

Masitinib is the first veterinary drug recently approved in Europe to treat mast cell tumours in dogs (Hahn et al. JVIM, Masivet). This inhibitor is selective and highly efficient in blocking c-Kit, PDGFR, and Lyn tyrosine kinase activities. It showed good efficacy and acceptable toxicity in several animal studies such as mice, rats, rabbits and dogs (Dubreuil P, et al. submitted, and Hahn et al. (J Vet Intern Med 22(6):8, 2008)). C-kit is a tyrosine kinase receptor that plays a critical role in the biology of mast cells including differentiation, survival, migration and cytokine/mediator release. Mast cells are involved in a number of allergy-and immune-related diseases in cats such as asthma (Reinero Carol et al. Vet Immunol Immunopathol 121(3-4):9, 2008), inflammatory bowel disease, (Janeczko et al. Vet Mic 128(1-2):15, 2008), and feline mast cell tumours (Rassnick et al. J Am Vet Med Assoc 232(8):1200-1205, 2008). Therefore, there might be a strong rationale to use masitinib in these indications. Here, we report the results of a preliminary pharmacokinetic study of masitinib in cats which showed a good bioavailability of ~60% in both sexes. We propose that an oral dose of 10-15 mg/kg masitinib is appropriate to achieve adequate plasma concentrations.
 ...
PMID:Pharmacokinetics of masitinib in cats. 1953 3

Mastocytosis (MC) encompasses a range of disorders characterized by a clonal, pathological accumulation of mast cells having a somatic activating mutation of the tyrosine kinase receptor Kit (exon 17, codon 816; D816V) in more than 90 % of adult patients. The mutation is much less common in children. Skin and bone marrow are most often affected. Symptoms and clinical course are very heterogeneous due to a variable degree of local or systemic mediator release or organ dysfunction as a result of mast cell infiltrates. Pruritus, wheals, flushing and gastrointestinal symptoms are often reported. The majority of pediatric patients experience spontaneous remission of MC. Adults usually have chronic disease, rarely transforming into an aggressive or lethal type. Indolent systemic MC with involvement of skin and bone is the most common type. In MC the risk for anaphylactic reactions following an insect sting (and other causes of mast cell activation) is increased significantly. Diagnostic hallmarks are biopsies from skin and bone marrow using tryptase antibodies for staining as well as serum tryptase levels. At present a curative treatment for MC is not available. Systemic histamine H(1) receptor antagonists are widely used. Aggressive types of MC respond partially to IFN-alpha or cladribine. A variety of receptor tyrosine kinase inhibitors is still under critical evaluation for systemic treatment of MC. After introduction of the WHO classification for MC and the development a German MC guideline, as well as the foundation of national and international competence networks for MC, a significantly improved quality of medical care for MC patients can be expected for the future.
 ...
PMID:Mastocytosis - an update. 2067 51


<< Previous 1 2 3 4 Next >>