Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.
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PMID:Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors. 769 40

The ear, skin, and purified serosal mast cells of WBB6F1/J-(+/+) (WB-(+/+)) and WCB6F1/J-(+/+) (WC-(+/+)) mice contain high steady-state levels of the transcripts that encode mouse mast cell protease (mMCP) 2, mMCP-4, mMCP-5, mMCP-6, and mouse mast cell carboxypeptidase A (mMC-CPA). In contrast, no mast cell protease transcripts are present in abundance in the ear and skin of WBB6F1/J-W/Wv (W/Wv) and WCB6F1/J-Sl/Sld (Sl/Sld) mice which are mast cell-deficient in vivo due to defects in their c-kit and c-kit ligand genes, respectively. We now report that the immature bone marrow-derived mast cells (mBMMC) obtained in vitro with recombinant interleukin 3 (rIL-3) or WEHI-3 cell conditioned medium from WB-(+/+), WC-(+/+), W/Wv, and Sl/Sld mice all contain high steady-state levels of the mMCP-2, mMCP-4, mMCP-5, mMCP-6, and mMC-CPA transcripts. As assessed immunohistochemically, mMCP-2 protein and mMCP-5 protein are also present in the granules of mBMMC from WB-(+/+), WC-(+/+), and W/Wv mice. That Sl/Sld and W/Wv mBMMC contain high steady-state levels of five granule protease transcripts expressed by the mature serosal, ear, and skin mast cells of their normal +/+ littermates suggests that c-kit-mediated signal transduction is not essential for inducing transcription of these protease genes. Because rIL-4 inhibits the rIL-10-induced expression of mMCP-1 and mMCP-2 in BALB/cJ mBMMC, the ability of rIL-4 to influence protease mRNA levels in WC-(+/+) mBMMC and W/Wv mBMMC was investigated. Although rIL-10 induced expression of the mMCP-1 transcript in WC-(+/+) and W/Wv mBMMC, rIL-4 was not able to suppress the steady-state levels of the mMCP-1 transcript or any other protease transcript in these cultured mast cells. Thus, not only do BALB/cJ mBMMC express fewer granule proteases than mBMMC from mast cell-deficient strains and their normal littermates but the subsequent induction of late-expressed proteases in BALB/cJ mBMMC is more tightly regulated by IL-3 and IL-4.
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PMID:Mouse bone marrow-derived mast cells (mBMMC) obtained in vitro from mice that are mast cell-deficient in vivo express the same panel of granule proteases as mBMMC and serosal mast cells from their normal littermates. 800 1

We report that blood cell autografts, collected by single leukapheresis in cancer patients (n = 11) at the time of mobilization of hematopoietic progenitors into peripheral blood following anticancer therapy with high-dose cyclophosphamide (HD-CTX) plus interleukin-3 (IL-3) and granulocyte colony-stimulating factor (G-CSF/filgrastim), comprise 1.98 +/- 0.39 x 10(5)/kg (mean +/- SE) CD34+ progenitors of dendritic cells (DCs). This number corresponds to 140-fold more progenitors than in a control autograft collected in the steady state. DCs derived from mobilized CD34+ cells, morphologically and immunophenotypically undistinguishable from skin Langerhans cells and DCs from bone marrow and cord blood CD34+ cells, are shown to be powerful stimulators of allogeneic T cell proliferation in primary MLR and of autologous HLA-DR-restricted CD4+ T cell proliferation in response to presentation of xenogenic antigens. We show that the GM-CSF-plus-TNF-alpha-dependent ex vivo generation of DCs from mobilized CD34+ cells is 2.5-fold enhanced by flk-2/flt-3 ligand or c-kit ligand (stem cell factor) and five-fold enhanced by a combination of these growth factors. In addition, the optimal serum for the generation of DCs is autologous HD-CTX recovery-phase serum rather than fetal calf serum (FCS) or steady-state human serum, which are clinically inadequate and ineffective, respectively. In practice, the stimulation of CD34+ cells in a blood cell autograft (15.75 +/- 2.46 x 10(6)/kg) provided by the above four growth factors should permit ex vivo generation of approximately 40 x 10(9) DCs in an adult patient. These new findings provide advantageous tools for the large-scale generation of DCs that are potentially usable for clinical protocols of immunotherapy or vaccination in patients undergoing cancer treatment.
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PMID:Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. 854 32

Because in humans mast cells and basophils tend to possess nonsegmented and segmented/multi-lobular nuclei, respectively, nuclear morphology has been a major criterion for assessing the lineage of metachromatic cells of hematopoietic origin. Immature metachromatic cells with mono- and multi-lobular nuclei were both obtained when bone marrow cells from BALB/c mice were cultured for 3 weeks in the presence of interleukin-3. Analogous to the indigenous mature mast cells that reside in the peritoneal cavity and skin, both populations of in vitro-derived cells expressed the surface receptor c-kit, the chymase mouse mast cell protease (mMCP) 5, the tryptase mMCP-6, and the exopeptidase carboxypeptidase A (mMC-CPA). Immunogold electron microscopy confirmed the granule location of mMC-CPA and mMCP-6 in both populations of cells, and cytochemical analysis confirmed the presence of chymotryptic enzymes in the granules. Because mature mast cells possessing multi-lobular nuclei also were occasionally found in the skeletal muscle and jejunum of the BALB/c mouse, the V3 mouse mast cell line was used to investigate the developmental relationship of mast cells that have very different nuclear structures. After the adoptive transfer of V3 mast cells into BALB/c mice, v-abl-immortalized mast cells with mono- and multi-lobular nuclei were detected in the lymph nodes and other tissues of the mastocytosis mice that expressed c-kit, mMCP-5, mMCP-6, and mMC-CPA. These studies indicate that mouse mast cells can exhibit varied nuclear profiles. Moreover, the nuclear morphology of this cell type gives no insight as to its protease phenotype or stage of development.
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PMID:Mouse mast cells that possess segmented/multi-lobular nuclei. 920 74

Tissue mast cell development requires stem cell factor (SCF), whereas helminth-induced intestinal mucosal mast cell hyperplasia also requires T cell-derived factors such as IL-3. We generated progenitor mast cells (PrMC) from mouse bone marrow cells (BMC) in vitro with a triad of SCF, IL-6, and IL-10 that exhibit IL-3-mediated mitogenic and maturation responses. SCF/IL-6/IL-10 transiently elicited a cell subpopulation with the phenotype (c-kit(high)Thy-1(low)) of fetal blood promastocytes at 3 wk of culture that progressed within 1 wk to FcepsilonRI-bearing PrMC, designated PrMCTriad. PrMCTriad lacked mouse mast cell carboxypeptidase A (mMC-CPA) protein, required SCF for IL-3-driven thymidine incorporation, and responded to SCF plus IL-3 with strong mMc-CPA immunoreactivity, clarifying distinct sequential roles for SCF and IL-3 in mast cell development. PrMCTriad, arising from BMC through promastocytes, are metamastocytes that acquire microenvironmentally determined phenotypic features.
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PMID:Generation of a novel stem cell factor-dependent mast cell progenitor. 982 Apr 83

Chemotherapy alters the structure and function of hair follicle melanocytes. Molecular mechanisms controlling melanocyte responses during chemotherapy-induced hair loss, however, remain largely unknown. Using immunohistology and multicolor confocal microscopy, we show here that cyclophosphamide administration to C57BL/6 mice alters the activity and fate of hair follicle melanocytes. After 24-48 h, hair bulb melanocytes expressing Fas undergo apoptosis. The number of apoptotic follicular melanocytes is significantly reduced (p<0.01) in cyclophosphamide-treated Fas knockout mice compared to wild-type controls, suggesting that Fas signaling contributes to chemotherapy-induced melanocyte death. After 3-5 d, surviving hair bulb melanocytes express c-kit receptor, proliferate, and appear to migrate up the outer root sheath. Tyrosinase-positive and melanogenically active cells then appear in the epidermis. By Western blotting and immunohistochemistry, expression levels of the c-kit ligand, stem cell factor, in skin and epidermis are strongly increased after cyclophosphamide treatment. Cyclophosphamide-induced migration of the hair follicle melanocytes into epidermis is completely abrogated by administration of c-kit neutralizing antibody. These data suggest that chemotherapy induces a complex response in the hair follicle melanocytes, which includes apoptosis, proliferation, and migration. Pharmacologic manipulation of Fas and c-kit signaling pathways might be useful for the correction of skin hyperpigmentation as a side-effect of chemotherapy.
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PMID:Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss. 1253 95

This study shows for the first time the presence of interstitial cells of Cajal (ICC) and their possible role in the initiation of spontaneous excitation in the corporal tissue of the guinea-pig penis. ICC, which were identified by their c-kit immunoreactivity, were abundantly distributed in the corporal smooth muscle meshwork. Spontaneous increases in the intracellular calcium concentration ([Ca(2+)](i); calcium transients) were visualized in preparations loaded with the fluorescent dye fura-2. Ca transients originated from the boundary of muscle bundles and then spread throughout the meshwork (Ca waves). Ca waves were strongly suppressed by either CPA (10 microm), ryanodine (50 microm) or 2-APB (10 microm), and their synchronicity was disrupted by 18beta-GA (30 microm). These results suggest that ICC in the corporal tissue may have a role as pacemakers to drive the bulk of smooth muscles, and that intracellular Ca(2+) stores and gap junctions are critical for the generation of spontaneous excitation.
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PMID:Identification of interstitial cells of Cajal in corporal tissues of the guinea-pig penis. 1475 68

To investigate mechanisms underlying the transmission of spontaneous Ca2+ signals in the bladder, changes in intracellular concentrations of Ca2+ ([Ca2+]i) were visualized in isolated detrusor smooth muscle bundles of the guinea-pig urinary bladder loaded with a fluorescent Ca2+ indicator, fura-PE3 or fluo-4. Spontaneous increases in [Ca2+]i (Ca2+ transients) preferentially originated along the boundary of muscle bundles and then spread to the other boundary (Ca2+ waves). The synchronicity of Ca2+ waves across the bundles was disrupted by 18beta-glycyrrhetinic acid (18beta-GA, 40 microm), carbenoxolone (30 microm) or 2-aminoethoxydiphenylborate (2-APB, 50-100 microm), while CPA (10 microm), ryanodine (100 microm), xestospongin C (3 microm) and U-73122 (10 microm) had no effect. Intracellular recordings using two independent microelectrodes demonstrated that 2-APB (100 microm) blocked electrical coupling between detrusor smooth muscle cells. Nifedipine (10 microm) but not nominal Ca2+-free solution diminished the synchronicity of Ca2+ waves before preventing their generation. Staining for c-kit identified interstitial cells (IC) located along both boundaries of muscle bundles. IC were also scattered amongst smooth muscle cells and were more dominantly distributed in connective tissue between muscle bundles. IC generated nifedipine-resistant spontaneous Ca2+ transients, which occurred independently of those of smooth muscles. In conclusion, the propagation of Ca2+ transients in the bladder appears to be exclusively mediated by the spread of action potentials through gap junctions being facilitated by the regenerative nature of L-type Ca2+ channels, without significant contribution of intracellular Ca2+ stores. IC in the bladder may modulate the transmission of Ca2+ transients originating from smooth muscle cells rather than being the pacemaker of spontaneous activity.
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PMID:Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the guinea-pig urinary bladder. 1523 94

Cyclophosphamide (CY), the agent with cytoreductive activity, is widely exploited in cancer chemotherapy, and can be used alone or in combination with various cytokines and growth factors to stimulate the egress of hematopoietic stem/progenitor cells (HSPC) from the BM compartment. The aim of the present study was to exam the morphology and ultrastructure of the bone marrow, spleen and liver of mice injected intraperitoneally with a single dose of cyclophosphamide (200 mg/kg bw) and the localization of cells expressing markers of early hematopoietic cells in studied organs and the peripheral blood. We observed that the CY-induced morphological changes in the BM and spleen were reconstructed on day 4. of experiment, and the spleen was repopulated by HSPC on the 6th day. In this time, the highest number of c-Kit-R-positive cells was determined by flow cytometry in the peripheral blood. The results confirmed, that the egress of HSPC from the bone marrow into the peripheral blood was delayed compared to mice treated with G-CSF or GCS-F plus CY.
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PMID:Morphology of the bone marrow, spleen and liver during hematopoietic cell mobilization with cyclophosphamide in mice. 1914 5

Cyclophosphamide (CY) is a chemotherapeutic agent used for cancer and immunological diseases. It induces cytotoxicity of bone marrow and causes myelosuppression and extramedullary haematopoiesis (EMH) in treated patients. EMH is characterized with the emergence of multipotent haematopoietic progenitors most likely in the spleen and liver. Previous studies indicated that a Chinese medicine, ginsenoside Rg1, confers a significant effect to elevate the number of lineage (Lin(-) ) Sca-1(+) c-Kit(+) haematopoietic stem and progenitor cells (HSPCs) and restore the function of bone marrow in CY-treated myelosuppressed mice. However, whether the amelioration of bone marrow by Rg1 accompanies an alleviation of EMH in the spleen was still unknown. In our study, the cellularity and weight of the spleen were significantly reduced after Rg1 treatment in CY-treated mice. Moreover, the number of c-Kit(+) HSPCs was significantly decreased but not as a result of apoptosis, indicating that Rg1 alleviated EMH of the spleen induced by CY. Unexpectedly, the proliferation activity of c-Kit(+) HSPCs was only up-regulated in the spleen, but not in the bone marrow, after Rg1 treatment in CY-treated mice. We also found that a fraction of c-Kit(+) /CD45(+) HSPCs was simultaneously increased in the circulation after Rg1 treatment. Interestingly, the effects of Rg1 on the elevation of HSPCs in bone marrow and in the peripheral blood were suppressed in CY-treated splenectomized mice. These results demonstrated that Rg1 improves myelosuppression induced by CY through its action on the proliferation of HSPCs in EMH of the spleen and migration of HSPCs from the spleen to the bone marrow.
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PMID:Ginsenoside Rg1 improves bone marrow haematopoietic activity via extramedullary haematopoiesis of the spleen. 2615 45


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