1994 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)	松島綱治金沢大学, がんセンター, 教授 (50222427) 冨田幹夫埼玉県立がんセンター, 主任研究員 (80142115) 溝口秀昭東京女子医科大学, 教授 (70049021) 長田重一大阪バイオサイエンス研究所, 部長 (70114428) 高津聖志東京大学, 医科学研究所, 教授 (10107055)
Keywords	サイトカイン / レセプター / シグナル伝達 / 造血幹細胞 / 細胞増殖・分化 / トランスジェニックマウス / チロシンキナーゼ / 転写調節
Research Abstract	1.新井等はGM-CSF,IL-3,IL-5のレセプターに共通のβ鎖の遺伝子破壊マウスを作製した。このマウスは好酸球の異常が見られたが大きな造血障害はなく、そのかわり肺胞蛋白症が認められた。GM-CSF遺伝子破壊マウスでも造血異常はなく、肺胞蛋白症を生じる。このことによりGM-CSF,IL-3が恒常的造血には必須ではないことが明らかとなった。またhGM-CSFレセプターα,β両鎖を発現するトランスジェニックマウスを作製した。その結果、機能的hGM-CSFレセプターからのシグナルはほとんど全ての血液前駆細胞の増殖を引き起こしうる明らかとなった。 2.高津等はIL-5刺激後、Vav,Shc,PI-3 kinase,HS1などのチロシンリン酸化およびBtk,JAK2などのチロシンキナーゼの活性化が起こることを明らかにし、IL-5レセプターの下流においてMAPキナーゼ経路、PI-3キナーゼシグナル伝達系やJAKキナーゼ経路などの複数のシグナル経路が連動していることを証明した。 3.長田等はG-CSFによって好中球で特異的に誘導されるミエロペルオキシダーゼ(MPO)遺伝子の発現を制御するcis-elementを転写開始点の約1kb上流に同定した。 4.杉山等は急性骨髄生白血病(AML)細胞が機能的なIL-6レセプターを有していることを明らかにし、AML発症進展にIL-6が関与している可能性を示唆した。 5.溝口等は血小板産生に関するIL-11の関与を検討し、純化したヒト巨核球にはIL-11mRNAが認められずIL-11によるオートクリン機構の存在が否定的であることを示した。 6.富田等はWEHI-3B細胞にLIFレセプターを発現させることによりLIFおよびoncostatin Mによって分化誘導を起こすことを示した。 7.松島等はIL-8がマウス造血細胞(Lin-Scal-c-kit+)に働きかけ、IL-3とSCFで分化誘導された前駆細胞の生存増殖を昂進することを示した。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Nishinakamura,R.: "Mice deficient for the IL-3/GM-CSF/IL-5 receptor exhibitlung pathology and impaired immune response" Immunity. (印刷中).
[Publications] Kinoshita,T.: "Suppression of apoptotic death in hematopoieric cells by signalling through the IL-3/GM-CSF receptors" EMBO J.14. 266-275 (1995)
[Publications] Kinoshita,T.: "Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells" Oncogene. (印刷中).
[Publications] Koyano-Nakagawa,N.: "Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the Interleukin-3 promoter" Mol.Cell.Biol.14. 5099-5107 (1994)
[Publications] Nakagawa,Y.: "Structure of the gene encoding the α Snbunit of human GM-CSF Recaptor:Implications for the Evolution of Cytokine Receptor Superfamily" J.Biol.Chem.269. 10905-10912 (1994)
[Publications] Muto,A.: "High affinity chimeric human GM-CSF receptor arrymg the cytoplasmic domain of the β snsimit but not α subunit trangluces growth promcting signal in BAF3" J.Biol.Chem.(印刷中).
[Publications] Takatsu,K.: "Interleukin-5 and its receptor system in the immune system and inflammation." Adv.Immunol.57. 145-190 (1994)
[Publications] Takaki,S.: "Critical cytoplasmic domain of the IL-5Rd chain and its function in IL-5-mediated grouth signal transduction" Mol.Cell.Biol.12. 7404-7413 (1994)
[Publications] Satoh,S.: "IL-5 receptor-mediated tyrosine phosphory lation of SH2/SH3-containing proteins and regulations of Bruton's tyrosine and JAK2 kinases." J.Exp.Med.180. 2101-2111 (1994)
[Publications] Takagi,M.: "Multi-colony stimulating activity of IL-5 on hematopoietic progenitorsdron the transzenic mouse that express IL-5reuptor α subunit enstitutively" J.Exp.Med.(印刷中).
[Publications] Nagata,S: "Fas and Fas ligand adeathfacton and its recaptor" Adv.Immunol.57. 129-144 (1994)
[Publications] Nagata,S: "The Fas death factor" Science. (印刷中).
[Publications] Inoue,K.: "Expression of the IL-6,IL-6 receptor and gp130 genes in acute leukemia" Blood. 84. 2872-2880 (1994)
[Publications] Tomida,M: "Induction of differentiation of WEHI-3B D^+ leukemic cells trausfecad with D-factor/LIF receptor cDNA" Blood. 85. 217-221 (1995)
[Publications] Okamoto,S.-i: "The interleukin-8 AP-1 and kB-like Sites are Genetic end targets of FK506-sensitive patway accompanied by Calcium Mobilization" J.Biol.Chem.269. 8582-8589 (1994)
[Publications] Mukaida,N.: "A Novel mechauism of Glucocorticoid-mediatidgene repression:NF-kB is target for glucocorticoid-mediuted IL-8 gene repression" J.Biol.Chem.269. 13289-13295 (1994)
[Publications] Wada,T.: "Prevention of proteinuria in a cute immune complex-mediated gloveruloraphvitis by an antibody a gainst IL-8" J.Exp.Med.180. 1135-1140 (1994)
[Publications] Ishikawa,Y.: "Establishment of lipopolysacchavide-dependent NF-kB activation in a cell free system" J.Biol.Chem.(印刷中).

1994 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] Nishinakamura,R.: "Mice deficient for the IL-3/GM-CSF/IL-5 receptor exhibitlung pathology and impaired immune response" Immunity. (印刷中).

[Publications] Kinoshita,T.: "Suppression of apoptotic death in hematopoieric cells by signalling through the IL-3/GM-CSF receptors" EMBO J.14. 266-275 (1995)

[Publications] Kinoshita,T.: "Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells" Oncogene. (印刷中).

[Publications] Koyano-Nakagawa,N.: "Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the Interleukin-3 promoter" Mol.Cell.Biol.14. 5099-5107 (1994)

[Publications] Nakagawa,Y.: "Structure of the gene encoding the α Snbunit of human GM-CSF Recaptor:Implications for the Evolution of Cytokine Receptor Superfamily" J.Biol.Chem.269. 10905-10912 (1994)

[Publications] Muto,A.: "High affinity chimeric human GM-CSF receptor arrymg the cytoplasmic domain of the β snsimit but not α subunit trangluces growth promcting signal in BAF3" J.Biol.Chem.(印刷中).

[Publications] Takatsu,K.: "Interleukin-5 and its receptor system in the immune system and inflammation." Adv.Immunol.57. 145-190 (1994)

[Publications] Takaki,S.: "Critical cytoplasmic domain of the IL-5Rd chain and its function in IL-5-mediated grouth signal transduction" Mol.Cell.Biol.12. 7404-7413 (1994)

[Publications] Satoh,S.: "IL-5 receptor-mediated tyrosine phosphory lation of SH2/SH3-containing proteins and regulations of Bruton's tyrosine and JAK2 kinases." J.Exp.Med.180. 2101-2111 (1994)

[Publications] Takagi,M.: "Multi-colony stimulating activity of IL-5 on hematopoietic progenitorsdron the transzenic mouse that express IL-5reuptor α subunit enstitutively" J.Exp.Med.(印刷中).

[Publications] Nagata,S: "Fas and Fas ligand adeathfacton and its recaptor" Adv.Immunol.57. 129-144 (1994)

[Publications] Nagata,S: "The Fas death factor" Science. (印刷中).

[Publications] Inoue,K.: "Expression of the IL-6,IL-6 receptor and gp130 genes in acute leukemia" Blood. 84. 2872-2880 (1994)

[Publications] Tomida,M: "Induction of differentiation of WEHI-3B D^+ leukemic cells trausfecad with D-factor/LIF receptor cDNA" Blood. 85. 217-221 (1995)

[Publications] Okamoto,S.-i: "The interleukin-8 AP-1 and kB-like Sites are Genetic end targets of FK506-sensitive patway accompanied by Calcium Mobilization" J.Biol.Chem.269. 8582-8589 (1994)

[Publications] Mukaida,N.: "A Novel mechauism of Glucocorticoid-mediatidgene repression:NF-kB is target for glucocorticoid-mediuted IL-8 gene repression" J.Biol.Chem.269. 13289-13295 (1994)

[Publications] Wada,T.: "Prevention of proteinuria in a cute immune complex-mediated gloveruloraphvitis by an antibody a gainst IL-8" J.Exp.Med.180. 1135-1140 (1994)

[Publications] Ishikawa,Y.: "Establishment of lipopolysacchavide-dependent NF-kB activation in a cell free system" J.Biol.Chem.(印刷中).

新井賢一東京大学, 医科学研究所, 教授 (00012782)