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

Interleukin-15/T(IL-15) is a growth factor that utilizes IL-2 receptor (IL-2R) components in addition to its private binding protein IL-15R(alpha) in T-cells. Here, we report that IL-15 induces mast cell proliferation in the absence of IL-2R alpha and beta. Using transfectants of these cells with a cytoplasmic-truncated mutant of gamma(c), we demonstrated that IL-15 signaling in mast cells does not involve gamma(c). Cross-linking of mast cells with [(125)I]IL-15 revealed a 60-65 kDa IL-15 binding protein that is distinct from known components of T-cell IL-15 receptors. Mast cell IL-15 receptors recruit JAK-2 and STAT-5, instead of JAK1/3 and STAT3/5 that are activated in T-cells. Thus IL-15 is a mast cell growth factor that utilizes a novel receptor and distinct signaling pathway.
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PMID:Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. 889 Jan 66

Interleukin-9 (IL-9) is a Th2 cytokine whose overexpression is associated with asthma and T cell lymphomagenesis. All the IL-9 activities studied so far are mediated by a specific hemopoietin receptor that activates a Jak/STAT pathway. Searching for genes specifically modulated by IL-9, we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL-9 stimulation. 24P3 is a member of the lipocalin family, and has been reported to bind N-formyl-Met-Leu-Phe, a potent neutrophil chemoattractant, and possibly other lipophilic mediators of inflammation. A similar 24P3 induction was observed in other T cell lymphomas (EL4 and TH201) in response to IL-9, as well as in EL4 cells stimulated with IL-6 or IL-1. By contrast, other IL-9-responsive cells such as mast cell line MC9 and B cell lymphoma A20 showed no 24P3 induction upon IL-9 stimulation. Experiments using IL-9R mutants indicated that STAT transcription factors, particularly STAT3, are involved in this process. However, 24P3 gene induction was slow, reaching a plateau from 36 to 72 hours after stimulation and was inhibited if cells were treated with cycloheximide during the first 8 hours of IL-9 stimulation, suggesting an indirect induction requiring new protein synthesis.
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PMID:Interleukin-9 induces 24P3 lipocalin gene expression in murine T cell lymphomas. 1128 60

In vitro and in vivo evidence suggest that microphthalmia transcription factor (MITF) plays a key regulatory role in tissue-specific gene regulation in several cell types, including melanocytes, osteoclasts, and mast cells. A yeast two-hybrid search, using a portion of a nonmutated MITF gene as the bait in the screening of a mast cell library, resulted in the isolation of the STAT3 inhibitor, PIAS3. PIAS3 is a transcriptional inhibitor that acts by specifically inhibiting STAT3's DNA binding activity. We found that it can directly associate with MITF using an in vitro pull-down assay. Immunoprecipitation of MITF from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of PIAS3. Co-transfection of MITF with PIAS3 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94% inhibition of MITF-mediated transcriptional activation. Using a gel-shift assay, it was shown that PIAS3 can block DNA binding activity. It was also found that STAT3 does not interfere, either in vitro or in vivo, with the interaction between PIAS3 and MITF. These data suggest that PIAS3 functions in vivo as a key molecule in supressing the transcriptional activity of MITF, a role of considerable importance in mast cell and melanocyte development.
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PMID:A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor. 1170 56

Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer.
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PMID:17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. 1455 Nov 38

Mutation of microphthalmia transcription factor (MITF) results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. A search for MITF-associated proteins, using a mast cell library that was screened with a construct that encodes the basic helix-loop-helix leucine zipper (Zip) domain of MITF, resulted in the isolation of the STAT3 inhibitor, PIAS3. PIAS3 functions in vivo as a key molecule in suppressing the transcriptional activity of MITF. Here, we report that the Zip domain is the region of MITF that is involved in the direct interaction between MITF and PIAS3. Additionally, we investigated the effect of phosphorylation of MITF on its interaction with PIAS3. We found that phosphorylation of MITF on serines in positions 73 and 409 plays an important role in its association with PIAS3. This effect was profound with phosphorylation on Ser409, which significantly reduced the inhibitory effect of PIAS3 on MITF and also modulated the transcriptional activity of MITF. Thus, phosphorylation of MITF could be considered a fine, and alternative, tuning of its transcriptional machinery.
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PMID:Role played by microphthalmia transcription factor phosphorylation and its Zip domain in its transcriptional inhibition by PIAS3. 1464 19

Microphthalmia transcription factor (MITF) and STAT3 are two transcription factors that play a major role in the regulation of growth and function of mast cells and melanocytes. We have previously provided experimental evidence regarding the functional cross-talk between MITF, protein inhibitor of activated STAT3, and STAT3 in response to cytokine activation of mast cells. Recent studies have demonstrated that binding of different IgE molecules to their FcepsilonRI induces a spectrum of intracellular events in the absence of specific Ag. In this work, we show for the first time that, in mouse bone marrow-derived mast cells and in rat basophilic leukemia cells, monomeric IgE alone can induce the MITF-protein inhibitor of activated STAT3-STAT3 network of interactions and leads to phosphorylation of MITF at S73 and of STAT3 at both tyrosine 705 and S727. This phosphorylation increases the transcriptional activity of MITF and STAT3 as indicated by mRNA accumulation of their target genes such as Bcl-2, granzyme B, and c-Myc. Interestingly, MITF and STAT3 were not found to be obligatory factors in the anti-apoptotic response induced by IgE. Thus, the phenomenon that IgE alone was able to induce transcription factors that are essential for mast cell function could contribute to our understanding of the pathogenesis of allergy and its associated diseases.
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PMID:Immunological trigger of mast cells by monomeric IgE: effect on microphthalmia transcription factor, STAT3 network of interactions. 1603 81

Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KIT(D816V) autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KIT(D816V). Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KIT(D816V) expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KIT(D816V) and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KIT(D816V)mutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KIT(D816V) mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.
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PMID:Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. 1898 3

Interleukin (IL)-10 is an important immunoregulatory cytokine with multiple biologic effects on different cell types. This cytokine also affects mast cell development, survival and activity. Mast cells are well known for their role in diverse pathophysiological processes including inflammatory events. Mast cell number in tissues is high and relatively constant. However, it is well established that these cells accumulate at the sites of inflammation in response to chemoattractants, e.g. RANTES, tumour necrosis factor (TNF) and nerve growth factor (NGF). In the present study, we examined whether IL-10 influenced RANTES-, TNF- and NGF-induced rat peritoneal mast cell migration. We also studied whether IL-10 could act as mast cell chemoattractant. We provided evidence, for the first time ever, that IL-10 influenced mature mast cell migration, i.e. it strongly decreased RANTES-induced mast cell migration and completely inhibited mast cell migratory response to TNF and NGF. The effective concentration of IL-10 that inhibited RANTES-, TNF- and NGF-induced mast cell migratory response was in the nanomolar range. The inhibitory effect of IL-10 on cytokine-stimulated mast cell migration was specific, as it was completely blocked by anti-IL-10R antibodies, and STAT3-dependent. In addition, our results have shown that IL-10 was not a mast cell chemoattractant. Thus, our findings clearly demonstrated that IL-10 may affect mast cell number within tissue by inhibiting local mast cell accumulation stimulated by chemotactic factors.
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PMID:Interleukin (IL)-10 inhibits RANTES-, tumour necrosis factor (TNF)- and nerve growth factor (NGF)-induced mast cell migratory response but is not a mast cell chemoattractant. 1942 51

Histone hypoacetylation occurs in many cancers and inhibition of histone deacetylation is a promising approach to modulate these epigenetic changes. Our laboratory previously demonstrated that the histone deacetylase inhibitors (HDACis) vorinostat and AR-42 reduced the viability of a canine malignant mast cell line. The purpose of this study was to further investigate the mechanisms of pan-HDAC inhibition in normal and malignant mast cells. Mouse and canine malignant mast cell lines expressing various Kit mutations, normal canine mast cells, and primary canine malignant mast cells were treated with AR-42 (a novel HDACi) and effects on cell viability, cycling, and signaling were evaluated. Treatment with AR-42 induced growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7. AR-42 promoted hyperacetylation of H3, H4, and alpha-tubulin, and up-regulation of p21. Down-regulation of Kit occurred after AR-42 treatment via inhibition of Kit transcription. Disassociation between Kit and heat shock protein 90 (HSP90) and up-regulation of HSP70 were observed after AR-42 treatment, suggesting potential loss of HSP90 chaperone function. Lastly, AR-42 down-regulated the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. In summary, AR-42 exhibits in vitro and ex vivo biologic activity against malignant mast cells, representing a promising therapeutic approach for malignant mast cell disease.
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PMID:AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. 2023 74

Mutations in the c-kit gene occur in the vast majority of mastocytosis. In adult patients as well as in the cell line derived from mast cell neoplasms, the mutations occur almost exclusively at amino acid 816 within the kinase domain of KIT. Among the downstream effectors of KIT signaling, STAT3 and STAT5 have been shown to be critical for cell proliferation elicited by the KIT-Asp(816) mutant protein. However, little is known about the mechanisms of activation of STAT proteins. In this study, we identify and clarify the contribution of various STAT kinases in two widely used neoplastic mast cell lines, P815 and HMC-1. We show that STAT1, -3, and -5 proteins are activated downstream of the KIT-Asp(816) mutant. All three STAT proteins are located in the nucleus and are phosphorylated on serine residues. KIT-Asp(816) mutant can directly phosphorylate STATs on the activation-specific tyrosine residues in vitro. However, within cells, SRC family kinases and JAKs diversely contribute to tyrosine phosphorylation of STAT proteins downstream of the KIT mutant. Using a panel of inhibitors, we provide evidence for the implication or exclusion of serine/threonine kinases as responsible for serine phosphorylation of STAT1, -3, and -5 in the two cell lines. Finally, we show that only STAT5 is transcriptionally active in these cells. This suggests that the contribution of STAT1 and STAT3 downstream of KIT mutant is independent of their transcription factor function.
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PMID:Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells. 2113 90


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