Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mastocytosis is characterized by accumulations of mast cells in various organs (1). Most cases are indolent and confined to the skin, where discrete mast cell infiltrates are associated increased epidermal melanin, a clinical picture known as urticaria pigmentosa (UP). Other forms of mastocytosis combine UP with aggressive involvement of other organs or with haemotologic abnormalities (1-4). It is not known whether all forms of mastocytosis are true neoplasms or whether some might represent reactive hyperplasias (5-7). The c-KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT) that is critical to the development and survival of mast cells and melanocytes (8-11). The ligand for KIT (KL) can stimulate mast cell development, proliferation, and mediator release (9,12-17), as well as melanocyte proliferation and pigment production (18-20). To determine the role of c-KIT in the pathogenesis of mastocytosis, we examined tissue and cells isolated from a patient with UP and aggressive systemic mastocytosis with massive splenic involvement. We found a mutation that results in constitutive activation and expression of c-KIT in mast cells of both skin and spleen. This is the first in situ demonstration of an activation c-KIT mutation in neoplastic cells. It also demonstrates the clonal and neoplastic nature of this form of mastocytes.
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PMID:Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. 858 24

Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective against KIT with juxtamembrane activating mutations, whereas only SU6577 could suppress KIT containing either juxtamembrane or kinase domain activating mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.
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PMID:Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells. 1065 4

c-kit protooncogene encodes a type III transmembrane receptor kinase, the stem cell factor receptor, or KIT. The ligand of the KIT. stem cell factor, is a cytokine that stimulates mast cell growth and differentiation. We have studied immunohistochemically KIT expression in 23 canine mast cell tumors (MCTs), 10 histiocytomas, 5 malignant melanomas, and in 2 cell lines derived from mast cells (HMC-1, human and C2, canine). As expected, KIT was detected both in the human mast cell leukemia cell line (HMC- ) and in the canine mastocytoma cell line C2. In normal canine skin, KIT expression was confined to mast cells. All canine MCTs expressed KIT, although the intensity of the staining reaction varied considerably among the 23 neoplasms. Grade III tumors showed the highest expression of KIT, whereas grade I tumors showed the lowest expression of KIT. Two patterns of KIT expression were detected in mast cells. In normal canine mast cells and in some neoplastic mast cells, KIT appeared mainly on the cell membrane. However, in many canine MCTs, KIT is accumulated in the cytoplasm, usually near the cell nucleus. The meaning of these two patterns is not clear. Expression of KIT could not be detected immunohistochemically in any of the other neoplasias investigated. According to our results, it can be concluded that most, if not all, canine MCT express KIT. Furthermore, there is an inverse correlation between the degree of differentiation and the expression of KIT. Moreover, according to our results, KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors.
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PMID:Canine mast cell tumors express stem cell factor receptor. 1069 17

C-kit proto-oncogene product (KIT, CD117) is a tyrosine kinase growth factor receptor for stem cell factor. This receptor is important for the development and maintenance of hematopoietic stem cells, mast cells, germ cells, melanocytes, and interstitial cells of Cajal and is constitutively expressed in them. Among mesenchymal tumors, KIT seems to be specific for the gastrointestinal stromal tumors, which consistently express this protein. Activating mutations in the tyrosine kinase or juxtamembrane domains of c-kit gene have been found in mastocytoma, seminoma, and gastrointestinal stromal tumors. Following up our initial observation of KIT expression in one angiosarcoma, we examined 50 angiosarcomas, 13 Kaposi sarcomas, 10 epithelioid hemangioendotheliomas, and 31 hemangiomas of different types for KIT expression using a polyclonal antiserum specific to KIT. Adult and fetal tissues and neovascular endothelia in 20 carcinomas were studied for comparison. More than half (56%) of the angiosarcomas representing different clinicopathologic and histologic subtypes and 2 of 13 Kaposi sarcoma were KIT positive. All epithelioid hemangioendotheliomas and hemangiomas were negative, with the exception of two infantile hemangiomas that showed KIT reactivity. The fetal capillary endothelia of lungs, placenta, and soft tissues were also KIT positive, although in soft tissues and placenta, KIT positivity was more prominent in the first trimester. However, endothelia of adult vessels and neovascular capillaries of carcinomas were negative. None of the four KIT-positive angiosarcomas and one KIT-positive Kaposi sarcomas that were studied showed mutations in the juxtamembrane or tyrosine kinase domains of the c-kit gene. These results indicate that KIT expression occurs in a subset of angiosarcomas, and the expression probably represents oncofetal expression (i.e., reversion of the tumor cell phenotype to that of fetal endothelial cells that may show KIT expression).
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PMID:KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of C-kit. 1082 25

Mastocytosis is defined by a pathological increase in mast cell numbers in tissues. Recent clinical observations on rare manifestations highlight the diversity of this disease. The diagnosis is now aided by new surrogate markers. At the molecular level, recent studies have reinforced the role of activating mutations in KIT in the etiology of mastocytosis. These findings provide a conceptual basis for the development for new therapeutic strategies.
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PMID:Mastocytosis. 1196 26

Eosinophils are present in parasitic, allergic, various immunological, and malignant disorders as well as in a variety of idiopathic hypereosinophilic syndromes. However, their exact role in some of these conditions remains elusive. They can be activated both in vivo and in vitro by various agonists, such as Igs, lipid mediators, and cytokines. By phenotyping the surface of the eosinophils, it may be possible to better define their function(s) in different pathophysiological settings. In the present work we screened eosinophils with a panel of Abs recognizing CD2 subfamily receptors usually present on a number of hemopoietic cells. We have demonstrated that human peripheral blood eosinophils, but not basophils or neutrophils, express NTB-A. In addition eosinophils express 2B4, CD84, CD58, and CD48, but not signaling lymphocytic activation molecule or CD2, on their surface (FACS). Cross-linking of 2B4 on eosinophils elicited a significant release of eosinophil peroxidase (30 min), IFN-gamma, and IL-4 (18 h). Moreover, activation of eosinophils via 2B4 induced eosinophil-mediated cytotoxicity toward two malignant cell lines, i.e., mouse mastocytoma P815 and EBV-infected 721.221 B cell lines. Cross-linking of 2B4 on the surface of eosinophils or pervenadate treatment elicited ERK and tyrosine phosphorylation, respectively. Furthermore, we showed that eosinophils express slam-associated protein. The demonstration that human eosinophils express a functional 2B4 receptor indicates a broader role for these cells in health and disease.
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PMID:2B4 (CD244) is expressed and functional on human eosinophils. 1561 Dec 33

The P815 and P198 cell lines are clonally related mouse mastocytoma cell lines. They differ in their biologic behavior in that P815 is a progressive tumor cell line, whereas P198 is a regressive one. These cell lines have been extensively used as models for the study of tumor-host relationships and tumor immunology. Although some of their biological properties have been well documented, the molecular mechanisms underlying tumor progression or regression have not been completely elucidated. In this study, we characterized the growth behavior and immunophenotype of these two cell lines, and analyzed their gene profiles using a complementary deoxynucleic acid (cDNA) microarray composed of 514 immunologically relevant genes. Our data showed that the two cell lines exhibited quite dissimilar and contrasting growth characteristics when inoculated into syngeneic mice. P815 tumors grew unremittingly, while P198 tumors gradually regressed. From a molecular viewpoint, P815 cells showed a higher expression of genes promoting tumor growth, such as IGF-1, IL-8R, FGFR1, VEGF-A, and VEGF-B. On the other hand, P198 tumor cells expressed CD11b and CD80, which favor the recruitment of lymphocytes and antigen-presenting cells (APCs), as well as the elicitation of antitumor immunity. P198 tumor cells also depicted a higher expression of genes inhibiting tumor growth, such as TNF-alpha, SOCS-1, CIS1, 4-1BB, and GDF-10. In conclusion, our results contribute further information in the understanding of the molecular mechanisms associated with the regression and progression of P815 and P198 tumor cells.
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PMID:Molecular and immunophenotypical characterization of progressive and regressive leukemia cell lines. 1598 74

Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.
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PMID:Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. 1643 89

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are rare but devastating diseases, for which no effective specific therapy is currently available. Most patients harbor the D816V mutant of KIT (KIT(D816V)), a constitutively active tyrosine kinase that is essential for pathogenesis, raising hopes that specific inhibition of KIT(D816V) may be therapeutically efficacious. To facilitate testing of new inhibitors in an animal model with similarity to human ASM/MCL, we developed a murine model that is based on retro-orbital injection of P815 cells, a murine mastocytoma line expressing the homologous D814Y mutant of KIT, into syngeneic DBA/2 mice. We found that the systemic disease induced by this approach is highly reproducible and resembles human ASM/MCL. Malignant mast cells were consistently detected in the peripheral blood by morphology and fluorescence-activated cell sorting after a stable latency whose length could be modulated by inoculum size. This easy and inexpensive tumor model should be useful for testing potential drugs with activity against KIT(D816V).
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PMID:Establishment of a murine model of aggressive systemic mastocytosis/mast cell leukemia. 1654 62

KIT receptor, the c-kit gene product, is thought to play a major role in canine mastocytoma, one of the most common neoplastic diseases in dogs. In the present study, the expression of c-kit proto-oncogene in blood and in tumor biopsies from 41 dogs with histologically confirmed mastocytoma at different grades of cellular differentiation and 5 negative control dogs was investigated using real-time (quantitative) reverse transcription-polymerase chain reaction (RRT-PCR). The animals were followed up for over 1 year after surgery in order to characterize the kinetics of c-kit expression in blood. Transcript mRNAs extracted from blood at different time points after surgery and from tumor tissue surgically removed from each dog were used in a quantitative RRT-PCR assay targeting the extracellular coding region of the c-kit gene. Tissues constitutively expressing c-kit (brain and spleen) were used as positive controls. Levels of expression of c-kit were higher in tumor biopsies than in blood; the blood level decreased in the patients between 1 and 3 months after surgery. No KIT expression was detected in blood from the 5 dogs not affected by mastocytoma (negative controls). The RRT-PCR appears to be a suitable method for sensitive and quantitative detection of c-kit gene expression in canine blood and neoplastic tissues. Although c-kit expression levels measured by RRT-PCR do not correlate with prognosis, they confirm that surgery remains the main treatment to reduce circulating mastocytes and that circulating mast cells can be detected even in benign highly differentiated forms of mastocytoma such as grade I.
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PMID:Expression of c-kit proto-oncogene in canine mastocytoma: a kinetic study using real-time polymerase chain reaction. 1692 72


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