1995 Fiscal Year Annual Research Report

造血調節因子とそのレセプターによるシグナル伝達機構

Research Project

Project/Area Number	06277101
Research Institution	The University of Tokyo
Principal Investigator	新井賢一東京大学, 医科学研究所, 教授 (00012782)
Co-Investigator(Kenkyū-buntansha)	宮島篤東京大学, 分子生物学研究所, 教授 (50135232) 富田幹夫埼玉県立ガンセンター, 主任研究員 (80142115) 松島綱治金沢大学, ガン研究所, 教授 (50222427) 長田重一大阪大学, 医学部, 教授 (70114428) 高津聖志東京大学, 医科学研究所, 教授 (10107055)
Keywords	造血幹細胞 / サイトカイン / レセプター / インターロイキン / シグナル伝達 / プロティンキナーゼ / チロシンリン酸化 / 遺伝子破壊マウス
Research Abstract	新井等はhGM-CSFレセプターシグナルの下流でJAKキナーゼの活性化が必須であることをdominant negative JAKを用いて明らかにした。またβ鎖の複数のチロシン残基がリン酸化されことを示し、各々により伝達されるシグナル分子を解析した。高津等はIL-5レセプターα鎖欠損マウスを作製した。このマウスは正常に発育し、巨視的な異常は認められなかったが、IL-5の広東糞線虫感染による好酸球増多が障害されていた。長田等はG-CSFレセプターのアミノ酸置換変異体を用いた解析により、分化誘導およびミエロペルオキシダーゼ発現誘導に必須なチロシン残基(Tyr-703,Tyr-728)を同定した。松島等はヒト、マウスIL-8,MIP1aレセプターに対する特異抗体を作製し、IL-8レセプターはmetamyelocyte以降の成熟好中球、LGLに多く発現し、MIP1aレセプターはCD34_+前駆細胞、T細胞、LGL,単球に主に発現してることを明らかにした。富田等はマウスLIEレセプターをクローニングし、可溶性レセプターが膜貫通領域手前の塩基配列挿入による転写終結が原因であることを明らかにした。宮島等は造血細胞の増殖を強く促進するIL-3などのサイトカインで誘導される初期応答遺伝子の検索を行い、SH2ドメインを持った新規シグナル分子CIS,オンコスタチンM,などを同定した。

Research Products

(24 results)

All Other

All Publications (24 results)

[Publications] Kinoshita,T.,etal.: "Suppression of apoptotic death in hematopoietic cell by signalling through the IL-31GM-CSF receptors." EMBO J.14. 266-275 (1995)
[Publications] Watanabe,S.,etal.: "Involvement of the interleukin-2 receptor γ subunit in interleukin-4-dependent activation of mouse hamatopoietic cells and splenic B cells." Eur.J.Immunol,. 25. 126-131 (1995)
[Publications] Muto,A.,etal.: "High affioity cbimeric buman granulocyte-macrophage colony-stimulating factor receptor carrying the ctyoplasmic domain of the β subunit but-not the a subunlt transduces growth promoting signals in Ba/F3 Cells." Biochem-Biophys.Res.Commun.208. 368-375 (1995)
[Publications] Kosugi,H.,et al.: "Structure of the gene encoding the a subunit of the human interleukin-3 receptor" Biochem.Biophys.Res.Commun.360-367 (1995)
[Publications] Nishinakamura,R.,et al.: "Mice deficient for the IL-3/GM-CSF/IL-5 receptor exhibit lung pathology and impaired immune response" Immunity. 2. 211-222 (1995)
[Publications] Watanabe,S.,et al.: "Cranulocyte-macrophage colony stimulation factor dependent replication of polyoma virus replicon-in hematopoietic cells:Analyses of receptor signals for replication and transcription" J.Biol.Chem.270. 9615-9621 (1995)
[Publications] Watanabe,S.,et al.: "Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse IL-3 in mouse proB Cell Iine BA/F3 cell expressing the human GM-CSF receptor" Mol.Biol.Cell.6. 627-636 (1995)
[Publications] Nishijima.I.,etal.: "A.human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitore to all lineages in response to human GM-CSF" Mol.Biol.Cell. 6. 497-508 (1995)
[Publications] Watanabe,S.,et al.: "JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor (GM-CSF)receptor in BA/F3 cells" J.Biol.Chem.(in press).
[Publications] A.Muto,etal.: "The β subunit of human GM-CSF receptor forms a homopdimer and is activated by association with the α subunit" J.Exp.Med.(in press)19GA11:Kosugi,H.,et al.
[Publications] "Gene utrucrures of te α subunits of the human interleukin-3 and granulocyte-macrophagecolony-stimulating factor receptors:Comparison with cytokine receptor superfamily" J.Allergy Clinic.Jmmunol.96. 1115-1125 (1995)
[Publications] Muto,A.,et al.: "Roles of the cytoplasmic domains of the α and β subunits of human granulocyte-macrophage colony-stimulatig factor receptor." J.Allergy Clinic.Jmmunol.96. 1100-1114 (1995)
[Publications] Ito,T.,etal.: "Granulocyte-macrophage colony-stimulating factor provokes different modes of signalling Ieading to ras activation and transcription of c-fos through tyrosine residues of the receptor β subunit" J.Biol,Chem.
[Publications] O'Neal,K.D.,et al.: "CIarification of the role of the Pro-x-PRO sequence in interleukin-5 receptor signal transduction." Mol.Cill.Biol.15. 4657-4658 (1995)
[Publications] Li,T.,et al.: "Oncogenic activation of Bruton's tyrosine Kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain." Immunity. 2. 451-460 (1995)
[Publications] Kikuchi,Y.,et al.: "CD38 Iigation induces Btk activation and enhanced expression of IL-5 receptor α chain." Proc.Natl.Acad.Sci.92. 10879-10883 (1995)
[Publications] Kouro,T.,et al.: "Critical cytoplasmic domain of the IL-5 receptor α chain and its function in IL-5-mediated activation of JAK Kinase and STATS astivation." Int.Immunol. (in press). (1996)
[Publications] Zhang,Y.,et al.: "TNFo as a physiological regulator of hematopoietic progenitor cells:increase of early hematopoietic progenitor cells in TNF-R55-/-mice in vivo and potent inhibition of progenitor cell proliferation by TNFa in vitro." Blood. 86. 2930-2937 (1995)
[Publications] Kuno,K.,et al.: "1Dentification of an lxBα-associated protein Kinase in a human cell line and determination of its phosphorylation sites on lxBα." J.Biol.Chem.270. 27914-27919 (1995)
[Publications] Tomida,M: "lnduction of differentiation of WEHl-3B D+leukemic cells transfected with differentiation-stimulating factor/leukemia" Blood. 85. 217-221 (1995)
[Publications] Ichihara.M.,et al.: "Impaired intcrleukin 3 (IL-3)response of the A/J mouse is caused by a branch point deletion in the IL-3 receptor α subunit gene." EMBO J.14. 939-950 (1995)
[Publications] Yoshimura,A.,et al.: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tyrosine phospharylated interleukin-3 and erythropoictin receptors." EMBO J.14. 2816-2826 (1995)
[Publications] Mui,A.,et al.: "Interleukin-3, granulocyte-macrophage colony stimulating factor, and interleukin-5 cransduce signals through cwo STATS homologues." EMBO J.14. 1166-1175 (1995)
[Publications] Nishinakamura,R.,: "Mice deficient for the IL-3/GM-CSF/IL-5 bc recepor exhibit lung pathology and impaircd immune response,while bIL3 receptor-deficient mice arc nomal." Immunity. 2. 211-222 (1995)

1995 Fiscal Year Annual Research Report

造血調節因子とそのレセプターによるシグナル伝達機構

Principal Investigator

新井 賢一 東京大学, 医科学研究所, 教授 (00012782)

Research Products

[Publications] Kinoshita,T.,etal.: "Suppression of apoptotic death in hematopoietic cell by signalling through the IL-31GM-CSF receptors." EMBO J.14. 266-275 (1995)

[Publications] Watanabe,S.,etal.: "Involvement of the interleukin-2 receptor γ subunit in interleukin-4-dependent activation of mouse hamatopoietic cells and splenic B cells." Eur.J.Immunol,. 25. 126-131 (1995)

[Publications] Muto,A.,etal.: "High affioity cbimeric buman granulocyte-macrophage colony-stimulating factor receptor carrying the ctyoplasmic domain of the β subunit but-not the a subunlt transduces growth promoting signals in Ba/F3 Cells." Biochem-Biophys.Res.Commun.208. 368-375 (1995)

[Publications] Kosugi,H.,et al.: "Structure of the gene encoding the a subunit of the human interleukin-3 receptor" Biochem.Biophys.Res.Commun.360-367 (1995)

[Publications] Nishinakamura,R.,et al.: "Mice deficient for the IL-3/GM-CSF/IL-5 receptor exhibit lung pathology and impaired immune response" Immunity. 2. 211-222 (1995)

[Publications] Watanabe,S.,et al.: "Cranulocyte-macrophage colony stimulation factor dependent replication of polyoma virus replicon-in hematopoietic cells:Analyses of receptor signals for replication and transcription" J.Biol.Chem.270. 9615-9621 (1995)

[Publications] Watanabe,S.,et al.: "Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse IL-3 in mouse proB Cell Iine BA/F3 cell expressing the human GM-CSF receptor" Mol.Biol.Cell.6. 627-636 (1995)

[Publications] Nishijima.I.,etal.: "A.human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitore to all lineages in response to human GM-CSF" Mol.Biol.Cell. 6. 497-508 (1995)

[Publications] Watanabe,S.,et al.: "JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor (GM-CSF)receptor in BA/F3 cells" J.Biol.Chem.(in press).

[Publications] A.Muto,etal.: "The β subunit of human GM-CSF receptor forms a homopdimer and is activated by association with the α subunit" J.Exp.Med.(in press)19GA11:Kosugi,H.,et al.

[Publications] "Gene utrucrures of te α subunits of the human interleukin-3 and granulocyte-macrophagecolony-stimulating factor receptors:Comparison with cytokine receptor superfamily" J.Allergy Clinic.Jmmunol.96. 1115-1125 (1995)

[Publications] Muto,A.,et al.: "Roles of the cytoplasmic domains of the α and β subunits of human granulocyte-macrophage colony-stimulatig factor receptor." J.Allergy Clinic.Jmmunol.96. 1100-1114 (1995)

[Publications] Ito,T.,etal.: "Granulocyte-macrophage colony-stimulating factor provokes different modes of signalling Ieading to ras activation and transcription of c-fos through tyrosine residues of the receptor β subunit" J.Biol,Chem.

[Publications] O'Neal,K.D.,et al.: "CIarification of the role of the Pro-x-PRO sequence in interleukin-5 receptor signal transduction." Mol.Cill.Biol.15. 4657-4658 (1995)

[Publications] Li,T.,et al.: "Oncogenic activation of Bruton's tyrosine Kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain." Immunity. 2. 451-460 (1995)

[Publications] Kikuchi,Y.,et al.: "CD38 Iigation induces Btk activation and enhanced expression of IL-5 receptor α chain." Proc.Natl.Acad.Sci.92. 10879-10883 (1995)

[Publications] Kouro,T.,et al.: "Critical cytoplasmic domain of the IL-5 receptor α chain and its function in IL-5-mediated activation of JAK Kinase and STATS astivation." Int.Immunol. (in press). (1996)

[Publications] Zhang,Y.,et al.: "TNFo as a physiological regulator of hematopoietic progenitor cells:increase of early hematopoietic progenitor cells in TNF-R55-/-mice in vivo and potent inhibition of progenitor cell proliferation by TNFa in vitro." Blood. 86. 2930-2937 (1995)

[Publications] Kuno,K.,et al.: "1Dentification of an lxBα-associated protein Kinase in a human cell line and determination of its phosphorylation sites on lxBα." J.Biol.Chem.270. 27914-27919 (1995)

[Publications] Tomida,M: "lnduction of differentiation of WEHl-3B D+leukemic cells transfected with differentiation-stimulating factor/leukemia" Blood. 85. 217-221 (1995)

[Publications] Ichihara.M.,et al.: "Impaired intcrleukin 3 (IL-3)response of the A/J mouse is caused by a branch point deletion in the IL-3 receptor α subunit gene." EMBO J.14. 939-950 (1995)

[Publications] Yoshimura,A.,et al.: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tyrosine phospharylated interleukin-3 and erythropoictin receptors." EMBO J.14. 2816-2826 (1995)

[Publications] Mui,A.,et al.: "Interleukin-3, granulocyte-macrophage colony stimulating factor, and interleukin-5 cransduce signals through cwo STATS homologues." EMBO J.14. 1166-1175 (1995)

[Publications] Nishinakamura,R.,: "Mice deficient for the IL-3/GM-CSF/IL-5 bc recepor exhibit lung pathology and impaircd immune response,while bIL3 receptor-deficient mice arc nomal." Immunity. 2. 211-222 (1995)

新井賢一東京大学, 医科学研究所, 教授 (00012782)