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

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
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PMID:Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. 795 56

The generation of blood cells, haematopoiesis, in the mouse embryo begins with the development of primitive nucleated erythroid cells in the yolk sac followed by the appearance of precursors for multiple definitive haematopoietic lineages. The later developing lineages arise from multipotential stem cells, but the relationship of primitive erythroid cells to these other haematopoietic populations is unknown. Using an in vitro embryonic stem (ES) cell differentiation system, we show that primitive erythrocytes and other haematopoietic lineages arise from a common multipotential precursor that develops within embryoid bodies generated from differentiated ES cells. In response to vascular endothelial growth factor and c-kit ligand these precursors give rise to colonies containing immature cells (blasts) expressing marker genes characteristic of haematopoietic precursors. Many blast colonies also expressed betaH1 and beta major globins but not Brachyury, a mesodermal marker. Kinetic analysis demonstrated that the blast colony-forming cells represent a transient population, preceding the establishment of the primitive erythroid and other lineage-restricted precursors. This precursor population may represent the earliest stage of embryonic haematopoietic commitment.
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PMID:A common precursor for primitive erythropoiesis and definitive haematopoiesis. 908 6

We have recently identified a novel ligand of the vascular endothelial growth factor (VEGF) family termed VEGF-related protein (VRP), which specifically binds to the FLT4 receptor. To characterize the signaling events after VRP engagement of its cognate receptor in hematopoietic cells, a population of human erythroleukemia (HEL) cells, termed HEL-JW, expressing high levels of FLT4 receptor was isolated. Stimulation of HEL-JW cells with VRP alone and in combination with the c-kit ligand/stem cell factor increased cell growth. VRP induced tyrosine phosphorylation of various proteins, including the FLT4 receptor. Further characterization of these tyrosine phosphorylated molecules revealed that Shc, Grb2, and SOS form a complex with the activated FLT4 receptor. HEL-JW cells also expressed RAFTK, a recently identified member of the focal adhesion kinase family. RAFTK was phosphorylated and activated upon VRP treatment, and there was an enhanced association of this kinase with the adaptor protein Grb2. Furthermore, the c-Jun NH2-terminal kinase (JNK), involved in growth activation and shown to mediate RAFTK signaling in other cell types, was activated by VRP stimulation. We also observed that VRP treatment of HEL-JW cells resulted in the phosphorylation of the cytoskeletal protein paxillin. This treatment resulted in an increased association of paxillin with RAFTK, which was mediated by the C-terminal region of RAFTK. These studies indicate that VRP stimulation induced the formation of a signaling complex at its activated receptor as well as activation of RAFTK. VRP-mediated activation of RAFTK may facilitate signal transduction to the cytoskeleton and downstream to the JNK pathway in FLT4-expressing blood cells.
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PMID:Signal transduction in human hematopoietic cells by vascular endothelial growth factor related protein, a novel ligand for the FLT4 receptor. 934 34

Vascular permeability factor/vascular endothelial cell growth factor (VPF/VEGF) can both potently enhance vascular permeability and induce proliferation of vascular endothelial cells. We report here that mouse or human mast cells can produce and secrete VPF/VEGF. Mouse mast cells release VPF/VEGF upon stimulation through Fcepsilon receptor I (FcepsilonRI) or c-kit, or after challenge with the protein kinase C activator, phorbol myristate acetate, or the calcium ionophore, A23187; such mast cells can rapidly release VPF/VEGF, apparently from a preformed pool, and can then sustain release by secreting newly synthesized protein. Notably, the Fc epsilonRI-dependent secretion of VPF/VEGF by either mouse or human mast cells can be significantly increased in cells which have undergone upregulation of Fc epsilonRI surface expression by a 4-d preincubation with immunoglobulin E. These findings establish that at least one cell type, the mast cell, can be stimulated to secrete VPF/VEGF upon immunologically specific activation via a member of the multichain immune recognition receptor family. Our observations also identify a new mechanism by which mast cells can contribute to enhanced vascular permeability and/or angiogenesis, in both allergic diseases and other settings.
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PMID:Mast cells can secrete vascular permeability factor/ vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression. 974 32

This study examined the relationship between blastomere fragmentation in cultured human embryos obtained by in-vitro fertilization and the effect of fragmentation on the distribution of the following eight regulatory proteins found to be: (i) localized in the mature oocyte in subplasmalemmal, polarized domains; and (ii) unequally inherited by the blastomeres during cleavage: leptin, signal transducer and activator of transcription 3 (STAT3), Bax, Bcl-x, transforming growth factor beta 2 (TGF beta 2), vascular endothelial growth factor (VEGF), c-kit and epidermal growth factor R (EGF-R). Four basic patterns of fragmentation were observed. The severity of the impact of each type of fragmentation on the affected blastomere(s) and the developmental competence of the embryo appeared to be a function of the unique temporal and spatial features associated with the particular fragmentation pattern(s) involved in each instance. The findings demonstrate that certain patterns of fragmentation can result in the partial or near total loss of the eight regulatory proteins from specific blastomeres and that the developmental potential of the affected embryo can be particularly compromised if it occurs during the 1- or 2-cell stages. In contrast, fragmentation from portions of a fertilized egg or a blastomere(s) in a 2-cell embryo that do not contain the protein domains, or the complete loss by fragmentation of a regulatory protein domain-containing blastomere after the 4-cell stage does not necessarily preclude continued development to the blastocyst, although the normality and developmental potential of the embryo may be compromised. The possible association between fragmentation and apoptosis was examined by annexin V staining of plasma membrane phosphatidylserine and TUNEL analysis of blastomere DNA. No direct correlation between fragmentation and apoptosis was found following the analyses of fragmented embryos with these two markers. However, while we suggest that changes in cell physiology unrelated to apoptosis are the more likely causes of fragmentation, we cannot exclude the possibility that fragmentation itself may be an initiator of apoptosis if critical ratios or levels of developmentally important proteins are altered by partial or complete elimination of their polarized domains. The findings are discussed with respect to the possible developmental significance of regulatory protein polarization in human oocytes and preimplantation stage embryos.
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PMID:Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. 1009 91

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
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PMID:PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. 1078 82

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.
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PMID:Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy. 1118 30

SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC(50)] 0.1-1 microM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML.
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PMID:The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. 1122 88

Angiogenesis plays a critical role in the growth and metastasis of solid and hematologic malignancies. This complex and highly regulated process involves numerous different cell types and mediators. Vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor are among the soluble factors that stimulate this process. They are ligands for specific tyrosine kinase receptors that are important in transduction of intracellular signals and induction of angiogenesis. SU6668 is a novel molecule that competitively inhibits the tyrosine kinase of the receptors for vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, and c-kit. In vitro studies have confirmed that SU6668 inhibits growth factor-stimulated tyrosine phosphorylation. SU6668 also has significant antitumor activity against many types of tumor xenograft explants in athymic mice. SU6668 inhibits angiogenesis through several mechanisms, including the induction of apoptosis in vascular endothelial cells and tumor cells. Currently, Phase 1 studies are being initiated to evaluate the potential of SU6668 as an anticancer agent for humans.
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PMID:SU6668, a multitargeted angiogenesis inhibitor. 1177 84

Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
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PMID:Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. 1201 61


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