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)

Little is known about the signals downstream of PI3K which regulate mast cell homeostasis and function following FcepsilonRI aggregation and Kit ligation. In this study, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1) pathway in these responses. In human and mouse mast cells, stimulation via FcepsilonRI or Kit resulted in a marked PI3K-dependent activation of the mTORC1 pathway, as revealed by the wortmannin-sensitive sequential phosphorylation of tuberin, mTOR, p70S6 kinase (p70S6K), and 4E-BP1. In contrast, in human tumor mast cells, the mTORC1 pathway was constitutively activated and this was associated with markedly elevated levels of mTORC1 pathway components. Rapamycin, a specific inhibitor of mTORC1, selectively and completely blocked the FcepsilonRI- and Kit-induced mTORC1-dependent p70S6K phosphorylation and partially blocked the 4E-BP1 phosphorylation. In parallel, although rapamycin had no effect on FcepsilonRI-mediated degranulation or Kit-mediated cell adhesion, it inhibited cytokine production, and kit-mediated chemotaxis and cell survival. Furthermore, Rapamycin also blocked the constitutive activation of the mTORC1 pathway and inhibited cell survival of tumor mast cells. These data provide evidence that mTORC1 is a point of divergency for the PI3K-regulated downstream events of FcepsilonRI and Kit for the selective regulation of mast cell functions. Specifically, the mTORC1 pathway may play a critical role in normal and dysregulated control of mast cell homeostasis.
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PMID:Activation and function of the mTORC1 pathway in mast cells. 1835 81

Cutaneous mastocytosis (CM) in children is a usually benign skin disorder caused by mast cell proliferation. Progressive disease leading to systemic involvement and fatal outcomes has been described. C-kit receptor mutations have been identified as causative for CM, some of which potentially respond to imatinib treatment as described for patients with systemic mastocytosis. We report successful therapy of progressive CM with imatinib in a 23-month-old boy. KIT gene analysis revealed not only a somatic deletion of codon 419 in exon 8 (c.1255_1257delGAC) which responds to imatinib therapy, but also a novel germ line p. Ser840Asn substitution encoded by exon 18 in the c-kit kinase domain. Family history suggests this exchange does not affect receptor function or cause disease. Imatinib therapy was well tolerated, stopped symptoms and disease progression, and appeared to shorten the course of the disease. Imatinib could possibly represent a novel therapeutic option in patients with progressive CM.
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PMID:Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation. 1856 37

TGF-beta has pleiotropic effects on many cell types at different stages of their development, including mast cells. The present study examines the effects of TGF-beta on human skin mast cells of the MC(TC) type. The expression of TGF-beta receptors (TGF-R) was verified at the mRNA and protein levels for TGF-RI and TGF-RII, and at the mRNA level for accessory molecules beta-glycan and endoglin. TGF-beta did not affect mast cell viability after 1 wk at concentrations < or = 10 ng/ml, but at 50 ng/ml caused significant cell death. TGF-beta inhibited surface and total expression of Kit in a dose-dependent manner, whereas the surface expression of Fc epsilonRI, Fc gammaRI, and Fc gammaRII was not affected. TGF-beta inhibited degranulation and cytokine production, but not PGD(2) production. TGF-beta diminished surface Kit expression through a TGF-RI kinase/Smad-dependent pathway by inhibiting new synthesis of Kit protein, which became evident following internalization and degradation of Kit after mast cells were exposed to the Kit ligand, stem cell factor. In contrast, addition of TGF-beta had no discernible effect on surface Kit expression when administered 3 days after stem cell factor, by which time surface Kit levels had returned to baseline. Although both transcription and translation are important for de novo expression of Kit, Kit mRNA levels were not affected by TGF-beta. Therefore, transcription of a gene other than Kit might be involved in Kit expression. Finally, activation of mast cells increased their susceptibility to TGF-beta-mediated apoptosis, a process that might regulate the survival of activated mast cells in vivo.
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PMID:TGF-beta1 attenuates mediator release and de novo Kit expression by human skin mast cells through a Smad-dependent pathway. 1898 Nov 48

Mastocytosis is a rare disease characterized by an elevated whole body mast cell number. Anaphylaxis is a severe, generalized hypersensitivity reaction with rapid onset. The problem of anaphylaxis and mastocytosis is due to strongly increased mediator release from the elevated mast cell number during allergic reactions. This explains the much higher prevalence of anaphylaxis in mastocytosis than in the general population and its severe and sometimes fatal course. Because of the increased risk of anaphylaxis in mastocytosis, all patients with severe or recurrent anaphylaxis should be analyzed for underlying mastocytosis by estimation of baseline serum tryptase. If this is elevated, patients also should be tested via skin examination for cutaneous mastocytosis and with a bone marrow biopsy. All patients with mastocytosis and anaphylaxis must be instructed about avoiding the responsible elicitors and should carry an emergency kit with adrenaline for self-application. In mastocytosis patients with anaphylaxis due to Hymenoptera stings, venom immunotherapy is recommended for life.
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PMID:The problem of anaphylaxis and mastocytosis. 1906 27

It is known that cancer is not a single transformational event. It is rather a multistage process involving complex interactions with the surrounding cellular microenvironment. Mast cells accumulate at sites of tumor growth in response to numerous chemoattractants. Our aim was to investigate the relationship between mast cell density (MCD) and myometrial invasion in endometrial carcinomas. Immunohistochemistry was performed on 35 unselected consecutive hysterectomy specimens from patients with endometrial adenocarcinoma. C-kit-positive mast cell assessment was performed in the myometrium adjacent to tumor tissue. A mean number of <or=15 mast cells per high power field (HPF) were regarded as low mast cell density (L-MCD), and a count of >or=16 mast cells was regarded as high mast cell density (H-MCD). A significant correlation (p=0.018, Pearson Chi-Square test) between H-MCD and the presence of myometrial invasion was demonstrated in endometrial carcinomas. H-MCD was found in 54% of all cases, and 94% of H-MCD cases had myometrial invasion, suggesting a role of mast cells or an interaction with tumor. Therapeutic modalities orientated to these cells or their microenvironment as a new target for adjuvant treatment might determine the prognosis in endometrial carcinomas.
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PMID:The association of mast cell density with myometrial invasion in endometrial carcinoma: a preliminary report. 2018 90

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.
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PMID:Pharmacokinetics of masitinib in cats. 1953 3

The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67.7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.
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PMID:Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours. 1980 53

Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone-bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone-related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease.
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PMID:The role of mast cells in parathyroid bone disease. 2020 Sep 65

Cysteinyl leukotrienes such as LTE(4) are produced by mast cells, neutrophils, eosinophils, and macrophages. LTE(4) levels have not been reported in systemic mastocytosis, a disorder with a large increase in mast cell numbers. Urinary LTE(4) from patients referred for symptoms potentially due to mast cell degranulation or systemic mastocytosis was measured by a commercial cysteinyl leukotriene enzyme immunoassay kit. The diagnosis of systemic mastocytosis was established using current World Health Organization criteria. Compared with a control group of patients with various potential mast cell-related symptoms (e.g., "spells"), patients with systemic mastocytosis had a significant (P=.01) increase in urinary LTE(4) excretion, whether expressed as LTE(4) ng/g creatinine or as LTE(4) ng/24h. There was a moderate correlation of LTE(4) ng/24h with excretion of N-methyl histamine and serum tryptase but not with urinary 11beta-prostaglandin F(2alpha) (11beta-PGF(2alpha)) excretion. LTE(4) excretion is increased in patients with systemic mastocytosis and potentially contributes to clinical symptoms.
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PMID:Increased leukotriene E4 excretion in systemic mastocytosis. 2038 Aug 89

Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.
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PMID:Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. 2083 88


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