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Masayuki Okada - One of the best experts on this subject based on the ideXlab platform.
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Stem Cell Factor c kit signaling promotes the survival migration and capillary tube formation of human umbilical vein endothelial Cells
Journal of Biological Chemistry, 2004Co-Authors: Junji Matsui, Toshiaki Wakabayashi, Makoto Asada, Kentaro Yoshimatsu, Masayuki OkadaAbstract:c-kit receptor tyrosine kinase is a marker of progenitor Cells, which differentiate into blood and/or vascular endothelial Cells, and has an important role in the amplification/mobilization of progenitor Cells. c-kit is expressed in mature endothelial Cells, but its role there is unclear. Stem Cell Factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial Cells. These effects mimicked those of vascular endothelial growth Factor, except that Stem Cell Factor did not sufficiently support proliferation of these Cells. After exposing Cells to this Factor, Akt, Erk1/2, and c-kit were immediately (≤5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited Stem Cell Factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial Cells at a locus downstream to Stem Cell Factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with Stem Cell Factor than with vascular endothelial growth Factor. Phospholipase Cγ was phosphorylated only with the latter, indicating that Stem Cell Factor/c-kit signaling is somewhat different.
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Stem Cell Factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial Cells.
The Journal of biological chemistry, 2004Co-Authors: Junji Matsui, Toshiaki Wakabayashi, Makoto Asada, Kentaro Yoshimatsu, Masayuki OkadaAbstract:c-kit receptor tyrosine kinase is a marker of progenitor Cells, which differentiate into blood and/or vascular endothelial Cells, and has an important role in the amplification/mobilization of progenitor Cells. c-kit is expressed in mature endothelial Cells, but its role there is unclear. Stem Cell Factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial Cells. These effects mimicked those of vascular endothelial growth Factor, except that Stem Cell Factor did not sufficiently support proliferation of these Cells. After exposing Cells to this Factor, Akt, Erk1/2, and c-kit were immediately (≤5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited Stem Cell Factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial Cells at a locus downstream to Stem Cell Factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with Stem Cell Factor than with vascular endothelial growth Factor. Phospholipase Cγ was phosphorylated only with the latter, indicating that Stem Cell Factor/c-kit signaling is somewhat different.
Robert Roskoski - One of the best experts on this subject based on the ideXlab platform.
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structure and regulation of kit protein tyrosine kinase the Stem Cell Factor receptor
Biochemical and Biophysical Research Communications, 2005Co-Authors: Robert RoskoskiAbstract:Abstract Signaling by Stem Cell Factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast Cell development and function, and melanogenesis. Moreover, human and mouse embryonic Stem Cells express Kit transcripts. Stem Cell Factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of Stem Cell Factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-Cell lymphomas. Binding of Stem Cell Factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cγ, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extraCellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control αC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites.
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signaling by kit protein tyrosine kinase the Stem Cell Factor receptor
Biochemical and Biophysical Research Communications, 2005Co-Authors: Robert RoskoskiAbstract:Signaling by Stem Cell Factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast Cell development and function, and melanogenesis. Moreover, human and mouse embryonic Stem Cells express Kit transcripts. Stem Cell Factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of Stem Cell Factor or Kit is lethal. Deficiencies of either produce defects in red and white blood Cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extraCellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of Stem Cell Factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.
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Signaling by Kit protein-tyrosine kinase—The Stem Cell Factor receptor
Biochemical and biophysical research communications, 2005Co-Authors: Robert RoskoskiAbstract:Signaling by Stem Cell Factor and Kit, its receptor, plays important roles in gametogenesis, hematopoiesis, mast Cell development and function, and melanogenesis. Moreover, human and mouse embryonic Stem Cells express Kit transcripts. Stem Cell Factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a receptor protein-tyrosine kinase. The complete absence of Stem Cell Factor or Kit is lethal. Deficiencies of either produce defects in red and white blood Cell production, hypopigmentation, and sterility. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, and mastocytomas. Kit consists of an extraCellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of Stem Cell Factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. The adaptor protein APS, Src family kinases, and Shp2 tyrosyl phosphatase bind to phosphotyrosine 568. Shp1 tyrosyl phosphatase and the adaptor protein Shc bind to phosphotyrosine 570. C-terminal Src kinase homologous kinase and the adaptor Shc bind to both phosphotyrosines 568 and 570. These residues occur in the juxtamembrane segment of Kit. Three residues in the kinase insert domain are phosphorylated and attract the adaptor protein Grb2 (Tyr703), phosphatidylinositol 3-kinase (Tyr721), and phospholipase Cgamma (Tyr730). Phosphotyrosine 900 in the distal kinase domain binds phosphatidylinositol 3-kinase which in turn binds the adaptor protein Crk. Phosphotyrosine 936, also in the distal kinase domain, binds the adaptor proteins APS, Grb2, and Grb7. Kit has the potential to participate in multiple signal transduction pathways as a result of interaction with several enzymes and adaptor proteins.
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Structure and regulation of Kit protein-tyrosine kinase—The Stem Cell Factor receptor
Biochemical and biophysical research communications, 2005Co-Authors: Robert RoskoskiAbstract:Abstract Signaling by Stem Cell Factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast Cell development and function, and melanogenesis. Moreover, human and mouse embryonic Stem Cells express Kit transcripts. Stem Cell Factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of Stem Cell Factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-Cell lymphomas. Binding of Stem Cell Factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cγ, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extraCellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control αC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites.
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Breakthroughs and Views Structure and regulation of Kit protein-tyrosine kinase—The Stem Cell Factor receptor q
2005Co-Authors: Robert RoskoskiAbstract:Signaling by Stem Cell Factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast Cell development and function, and melanogenesis. Moreover, human and mouse embryonic Stem Cells express Kit transcripts. Stem Cell Factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of Stem Cell Factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-Cell lymphomas. Binding of Stem Cell Factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cc, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extraCellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control aC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites. 2005 Elsevier Inc. All rights reserved.
Junji Matsui - One of the best experts on this subject based on the ideXlab platform.
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Stem Cell Factor c kit signaling promotes the survival migration and capillary tube formation of human umbilical vein endothelial Cells
Journal of Biological Chemistry, 2004Co-Authors: Junji Matsui, Toshiaki Wakabayashi, Makoto Asada, Kentaro Yoshimatsu, Masayuki OkadaAbstract:c-kit receptor tyrosine kinase is a marker of progenitor Cells, which differentiate into blood and/or vascular endothelial Cells, and has an important role in the amplification/mobilization of progenitor Cells. c-kit is expressed in mature endothelial Cells, but its role there is unclear. Stem Cell Factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial Cells. These effects mimicked those of vascular endothelial growth Factor, except that Stem Cell Factor did not sufficiently support proliferation of these Cells. After exposing Cells to this Factor, Akt, Erk1/2, and c-kit were immediately (≤5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited Stem Cell Factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial Cells at a locus downstream to Stem Cell Factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with Stem Cell Factor than with vascular endothelial growth Factor. Phospholipase Cγ was phosphorylated only with the latter, indicating that Stem Cell Factor/c-kit signaling is somewhat different.
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Stem Cell Factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial Cells.
The Journal of biological chemistry, 2004Co-Authors: Junji Matsui, Toshiaki Wakabayashi, Makoto Asada, Kentaro Yoshimatsu, Masayuki OkadaAbstract:c-kit receptor tyrosine kinase is a marker of progenitor Cells, which differentiate into blood and/or vascular endothelial Cells, and has an important role in the amplification/mobilization of progenitor Cells. c-kit is expressed in mature endothelial Cells, but its role there is unclear. Stem Cell Factor, a c-kit ligand, dose-dependently promoted survival, migration, and capillary tube formation of human umbilical vein endothelial Cells. These effects mimicked those of vascular endothelial growth Factor, except that Stem Cell Factor did not sufficiently support proliferation of these Cells. After exposing Cells to this Factor, Akt, Erk1/2, and c-kit were immediately (≤5 min) and dose-dependently tyrosinephosphorylated. STI-571, a c-kit inhibitor, dose-dependently attenuated these phosphorylations and inhibited Stem Cell Factor-promoted survival and capillary tube formation over the same dose range. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase, and PD98059, an inhibitor of MEK, abrogated survival and capillary tube formation, indicating that Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial Cells at a locus downstream to Stem Cell Factor/c-kit signaling. Akt was more strongly phosphorylated, whereas Erk1/2 and p38 were more weakly phosphorylated with Stem Cell Factor than with vascular endothelial growth Factor. Phospholipase Cγ was phosphorylated only with the latter, indicating that Stem Cell Factor/c-kit signaling is somewhat different.
Genji Imokawa - One of the best experts on this subject based on the ideXlab platform.
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the mechanism of epidermal hyperpigmentation in dermatofibroma is associated with Stem Cell Factor and hepatocyte growth Factor expression
Journal of Investigative Dermatology, 2001Co-Authors: Etsuko Shishido, Satsuki Kadono, Izumi Manaka, Makoto Kawashima, Genji ImokawaAbstract:Dermatofibromas have an increased brownish color due to hyperpigmentation of the overlying skin. To determine paracrine Factors involved in the epidermal hyperpigmentation, we have studied the expression of cytokines in lesional and nonlesional dermatofibroma skin at the transcriptional and protein levels using reverse transcription polymerase chain reaction and immunohistochemistry, respectively. The number of tyrosinase immuno-positive melanocytes in the pigmented dermatofibroma epidermis is significantly increased (2-fold) compared with nonlesional normal epidermis. Reverse transcription polymerase chain reaction analysis of mRNAs encoding Stem Cell Factor and hepatocyte growth Factor demonstrated that there is an accentuated expression of Stem Cell Factor and hepatocyte growth Factor transcripts in the lesional dermatofibroma dermis compared with the nonlesional dermis, although there is no difference in their expression between the lesional and nonlesional epidermis. In contrast, mRNA transcripts encoding endothelin-1, growth-related oncogene α, and basic fibroblast growth Factor are not increased in lesional epidermis or in dermis relative to nonlesional skin. In parallel, immunohistochemical analysis using antibodies to Stem Cell Factor and hepatocyte growth Factor reveal a marked immunostaining in growing fibroblastic tumor Cells in the dermatofibroma lesions with no detectable staining in the nonlesional dermis, but there is no difference in their immunostaining between the lesional and nonlesional epidermis. Interestingly, and consistent with the increased expression of Stem Cell Factor in lesional dermatofibroma dermis, toluidine blue staining in the dermis revealed a 5-fold increase in the number of mast Cells, an indication of their longevity or accumulation induced by Stem Cell Factor. These findings suggest an important role of fibroblastic tumor Cell-derived Stem Cell Factor in the mechanism involved in the hyperpigmentation of the dermatofibroma epidermis.
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the paracrine role of Stem Cell Factor c kit signaling in the activation of human melanocytes in ultraviolet b induced pigmentation
Journal of Investigative Dermatology, 2001Co-Authors: Akira Hachiya, Akemi Kobayashi, Atsushi Ohuchi, Yoshinori Takema, Genji ImokawaAbstract:The interaction of Stem Cell Factor with its receptor, c-kit, is well known to be critical to the survival of melanocytes. Little is known about the role(s) of the Stem Cell Factor/c-kit interaction in epidermal pigmentation, however. To clarify whether the Stem Cell Factor/c-kit signaling has a paracrine role in ultraviolet-B-induced pigmentation, we determined whether the exposure of human keratinocytes, melanocytes, and the epidermis to ultraviolet B light stimulates the expression of Stem Cell Factor or c-kit at the gene and/or protein levels. We further examined whether interrupting the binding of Stem Cell Factor to c-kit by subepidermal injection of a monoclonal antibody to c-kit affects ultraviolet-B-induced pigmentation in brownish guinea pig skin. When human keratinocytes and melanocytes in culture were exposed to ultraviolet B light, transcripts of Stem Cell Factor and c-kit (as assessed by reverse transcription polymerase chain reaction) and expression of those proteins (by enzyme-linked immunosorbent assay and western blotting) increased significantly and peaked at a dose of 20–40 mJ per cm2. In ultraviolet-B-exposed human epidermis, Stem Cell Factor transcripts and protein expression were also markedly enhanced compared with the nonexposed epidermis. Immunohistochemistry with antibodies to Stem Cell Factor revealed an increased staining in the ultraviolet-B-exposed epidermis, which was accompanied by a slight epidermal hyperplasia. In the course of ultraviolet-B-induced pigmentation of brownish guinea pig skin, the subepidermal injection of c-kit inhibitory antibodies completely abolished the induction of pigmentation in the ultraviolet-B-exposed area, and there was no increase in the number of dihydroxyphenylalanine-positive melanocytes. These findings indicate that the Stem Cell Factor/c-kit signaling is critically involved in the biologic mechanism of ultraviolet-B-induced pigmentation.
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The Paracrine Role of Stem Cell Factor/c-kit Signaling in the Activation of Human Melanocytes in Ultraviolet-B-Induced Pigmentation
The Journal of investigative dermatology, 2001Co-Authors: Akira Hachiya, Akemi Kobayashi, Atsushi Ohuchi, Yoshinori Takema, Genji ImokawaAbstract:The interaction of Stem Cell Factor with its receptor, c-kit, is well known to be critical to the survival of melanocytes. Little is known about the role(s) of the Stem Cell Factor/c-kit interaction in epidermal pigmentation, however. To clarify whether the Stem Cell Factor/c-kit signaling has a paracrine role in ultraviolet-B-induced pigmentation, we determined whether the exposure of human keratinocytes, melanocytes, and the epidermis to ultraviolet B light stimulates the expression of Stem Cell Factor or c-kit at the gene and/or protein levels. We further examined whether interrupting the binding of Stem Cell Factor to c-kit by subepidermal injection of a monoclonal antibody to c-kit affects ultraviolet-B-induced pigmentation in brownish guinea pig skin. When human keratinocytes and melanocytes in culture were exposed to ultraviolet B light, transcripts of Stem Cell Factor and c-kit (as assessed by reverse transcription polymerase chain reaction) and expression of those proteins (by enzyme-linked immunosorbent assay and western blotting) increased significantly and peaked at a dose of 20–40 mJ per cm2. In ultraviolet-B-exposed human epidermis, Stem Cell Factor transcripts and protein expression were also markedly enhanced compared with the nonexposed epidermis. Immunohistochemistry with antibodies to Stem Cell Factor revealed an increased staining in the ultraviolet-B-exposed epidermis, which was accompanied by a slight epidermal hyperplasia. In the course of ultraviolet-B-induced pigmentation of brownish guinea pig skin, the subepidermal injection of c-kit inhibitory antibodies completely abolished the induction of pigmentation in the ultraviolet-B-exposed area, and there was no increase in the number of dihydroxyphenylalanine-positive melanocytes. These findings indicate that the Stem Cell Factor/c-kit signaling is critically involved in the biologic mechanism of ultraviolet-B-induced pigmentation.
I. K. Mcniece - One of the best experts on this subject based on the ideXlab platform.
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Stem Cell Factor.
Journal of leukocyte biology, 1995Co-Authors: I. K. Mcniece, Robert A. BriddellAbstract:Stem Cell Factor (SCF) is the ligand for the tyrosine kinase receptor c-kit, which is expressed on both primitive and mature hematopoietic progenitor Cells. In vitro, SCF synergizes with other growth Factors, such as granulocyte colony-stimulating Factor (G-CSF), granulocyte macrophage-colony-stimulating Factor, and interleukin-3 to stimulate the proliferation and differentiation of Cells of the lymphoid, myeloid, erythroid, and megakaryocytic lineages. In vivo, SCF also synergizes with other growth Factors and has been shown to enhance the mobilization of peripheral blood progenitor Cells in combination with G-CSF. In phase I/II clinical studies administration of the combination of SCF and G-CSF resulted in a two- to threefold increase in Cells that express the CD34 antigen compared with G-CSF alone. Other potential clinical uses include ex vivo expansion protocols and in vitro culture for gene therapy.
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Stimulation of hematopoiesis in vivo by Stem Cell Factor.
Current opinion in hematology, 1994Co-Authors: Robert G. Andrews, Robert A. Briddell, Fr Appelbaum, I. K. McnieceAbstract:The ligand for c-kit, known as Stem Cell Factor, mast Cell growth Factor, or kit ligand, plays a central role in normal hematopoietic Stem Cell, melanocyte, and gametocyte development and function during embryogenesis and in adult life. In vitro, Stem Cell Factor promotes the survival of hematopoietic progenitors and enhances their proliferation in response to specific growth Factors. Administration of recombinant soluble Stem Cell Factor to rodents, dogs, and baboons produces a broad array of effects on hematopoiesis, though not all lineages are equally stimulated. At doses of more than 100 micrograms/kg/d Stem Cell Factor stimulates neutrophilia, lymphocytosis, basophilia, and reticulocytosis and increases mast Cells in multiple tissues. In vivo mast Cell activation can occur. Marrow Cellularity is increased and progenitor Cells are increased in marrow, spleen, and blood, and marrow-repopulating Cells are increased in the circulation of Stem Cell Factor-treated animals. Stem Cell Factor synergizes with other hematopoietic growth Factors in vivo. Low-dose Stem Cell Factor, 25 micrograms/kg/d, that does not elicit a detectable biological response, enhances the effects of granulocyte colony-stimulating Factor in vivo, increasing the neutrophilia and circulation of progenitor and marrow-repopulating Cells above that which is achieved with either Factor alone. In phase I human trials, dose-limiting toxicities, related to mast Cell activation, were reached at 25 to 50 micrograms/kg/d of recombinant human Stem Cell Factor. At these doses, progenitor and long-term culture-initiating Cells are increased in marrow and increases in circulating levels of progenitor Cells of multiple types are observed. Phase I-II trials of low-dose Stem Cell Factor in combination with granulocyte colony-stimulating Factor show that the combination increases the circulation of CD34+ Cells and colony-forming progenitor Cells. Further studies are needed to determine the therapeutic role of Stem Cell Factor and its effects on expansion and maintenance of hematopoietic Stem Cells in vivo.
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Stem Cell Factor is a potent synergistic Factor in hematopoiesis
Oncology, 1994Co-Authors: George Morstyn, Michael S. Gordon, Sherri Brown, Jeffrey Crawford, George D. Demetri, William J. Rich, Brain Mcguire, Mary Ann Foote, I. K. McnieceAbstract:Stem Cell Factor (SCF), a ligand for c- kit, has a broad range of activities including effects on Cells at or near the level of the multipotential Stem Cell as well as on committed c
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The role of recombinant Stem Cell Factor in early B Cell development: Synergistic interaction with IL-7
Journal of immunology (Baltimore Md. : 1950), 1991Co-Authors: I. K. Mcniece, Keith Langley, Krisztina M. ZseboAbstract:The cDNA for Stem Cell Factor was recently isolated from Buffalo rat liver Cells (BRL-3A) and recombinant rat Stem Cell Factor produced from Escherichia coli (rrSCF164). rrSCF164 synergizes with rhIL-7 to stimulate pre-B clonal growth in agar culture of mouse bone marrow Cells, and in this study we have characterized the role of rrSCF164 in B Cell development. The combination of rrSCF164 plus rhIL-7 stimulated increased colony numbers compared with the sum of colonies stimulated by rrSCF164 and rhIL-7 alone. Also, increased Cell proliferation per colony was stimulated by the combination of rrSCF164 plus rhIL-7 compared with rhIL-7 or rrSCF164 alone. The colonies formed with rrSCF164 plus rhIL-7 and rhIL-7 alone contained exclusively pre-B Cells, which expressed B220 Ag and cytoplasmic mu-chain, but were negative for surface Ig expression. Morphological examination of the Cells in the colonies showed blast-like characteristics. rrSCF164 alone and in combination with rhIL-7 stimulated generation of B220+ Cells in liquid culture of B220- Cells, whereas rhIL-7 alone had no stimulatory effect on B220- Cells. Both Stem Cell Factor mRNA and bioactivity were detected in a mouse bone marrow-derived stromal Cell line, termed OZ-11. We propose that Stem Cell Factor is a stromal-derived Factor that synergizes with IL-7 to stimulate the proliferation and differentiation of pro-B Cells to pre-B Cells, which become responsive to IL-7 alone.