造血因子の構造と作用の分子生物学的検討と生体内作用

• Project/Area Number: 04247101
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• 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): 高津 聖志 東京大学, 医科学研究所, 教授 (10107055) ; 井川 洋二 東京医科歯科大学, 医学部, 教授 (40085618) ; 長田 重一 (財)大阪バイオサイエンス研究所, 部長 (70114428) ; 平野 俊夫 大阪大学, 医学部, 教授 (40136718) ; 岡山 博人 東京大学, 医学部, 教授 (40111950)
• Project Period (FY): 1992
• Project Status: Completed (Fiscal Year 1992)
• Budget Amount: ¥34,000,000 (Direct Cost: ¥34,000,000); Fiscal Year 1992: ¥34,000,000 (Direct Cost: ¥34,000,000)
• Keywords: 造血因子 / インターロイキン / コロニー刺激因子 / レセプター / 情報伝達 / サイトカイン / 発現クローニング / 分子生物学

Research Abstract

1.新井らはGM-CSFレセプターのβ鎖で初期応答遺伝子の発現と複製に必須な細胞質内領域を同定した。さらに同レセプターは線維芽細胞でも増殖シグナルを伝達することからαβ鎖に相互作用するチロシンキナーゼは血球系に特異的ではないことを示した。またcAMPとPMAに応答するIL-5遺伝子の調節領域を同定し解析した。2.間野らは血球系でGM-CSFレセプターはc-fpsと相互作用する事および低親和性レセプターがヒト戎毛癌細胞株でゴナドトロピン産生を促進することを示した。3.平野らはIL-6レセプターと会合する第三の分子の存在を示しシグナル伝達との関連について検討した。さらにjunB遺伝子のIL-6応答領域を同定し、この領域に結合するDNA結合蛋白質cDNAをクローニングした。4.長田らはG-CSFレセプターと成長ホルモンレセプターとのキメラ分子を作製しレレプターの二量体化がシグナル伝達に必須であることを示した。5.岡山らは線維芽細胞の増殖におけるc-raf-lとMAPキナーゼの関連について検討し、血清刺激に応答するc-raf-lの下流因子の遺伝子を単離した。6.高津らは低親波性IL-5レセプターα鎖cDNAをパニング法を用いてクローニングし高親和性IL-5レセプターをα鎖とGM-CSF及びIL-3レセプターの共通の成分でもあるβ鎖(AIC2B)を用いて再構成した。さらにα鎖の細胞質内ドメインのシグナル伝達への関与を示した。7。赤血球前駆細胞においてF-SFFVgp55はEPOレセプターを通して細胞増殖を活性化する。井川らはF-MCFのenvに由来するF-SFFVgp55とEPOレセプターをCTLL-2細胞に導入した。両者はBAF/3細胞では増殖シグナルを伝達するがCTLL-2では陰性であることからIL-2レセプターβ鎖とEPOレセプターの下流のシグナルは異なる事を示した。7。長田ら、高津らおよび新井らはG-CSF、IL-5、IL-3およびGM-CSFレセプターの染色体遺伝子の構造を解析した。

Research Products

• [Publications] Nakayama,N.et al.: "Use of mammalian cell expression cloning syst-ems to identify genes for cytokines,receptors" Current Opin.Biotechnology. 3. 497-505 (1992)
• [Publications] Watanabe,S.et al: "Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth promoting signals in mouse NIH3T3 cells." Mol.Cell.Biol.13. (1993)
• [Publications] Koyano,N.et al.: "Reconstition of the functional GM-CSF promoter:evidence for distinct activation mechanisms that mediate the response to phorbol ester..." International Immunology. 5. (1993)
• [Publications] Arai,N.et al.: "Activation of lymphokine genes in T cells:role of cis-acting DNA elements that respond to T cell activation signals" Pharmacology and Therapeutics. 55. 303-318 (1992)
• [Publications] Garret,K.P.et al: "The C-terminus of rat RAP30 is similar in sequence to region 4 of bacterial sigma factos and is required for function." J.Biol.Chem.267. (1992)
• [Publications] Miyajima,A.et al: "Cytokine receptors and signal transduction." Annu.Rev.Immunology. 10. 295-331 (1992)
• [Publications] Muramatsu,M.: "Protein kinase C mutants in the auto-inhibitory region exhibit two distinct properties." FEBS Lett. 311. 75-79 (1992)
• [Publications] Arai,K.: "New era of biochemistry:cytokine signal network and its inplication for biomedical research" Blackwell Scientific Publications. 119-130 (1992)
• [Publications] Wang,H.M.: "Structure of mouse IL-3 binding protein(ACI2A):Amino acid residues critical for IL-3 binding" J.Biol.Chem.267. 979-983 (1992)
• [Publications] Masuda,A.et al: "Signal transduction cadcade shared by epidermal growth factor and platelet-derived growth factor is a major pathway for oncogenic trasformation in NRK cells." New Biologist,. 4. 489-503 (1992)
• [Publications] Kume,K.et al: "Oncogenic signal-induced ability to enter S phase in the absence of anchorage is the mechanism for the growth of transformed NRK cells in soft agar." New Biologist. 4. 504-511 (1992)
• [Publications] Kimura,T.et al: "Structure and expression of a human oxytocin receptor." Nature. 356. 526-529 (1992)
• [Publications] Tatsuka,M.et al: "Elongation factor-la gene determines susceptibility to transformation." Nature. 359. 333-336 (1992)
• [Publications] Kizaka-Kondoh,S.et al: "Raf-l protein kinase is an integral component of the oncogenic signal cascade shared by epidermal growth factor and platelet-derived growth factor." Mol.Cell.Biol.12. 5078-5086 (1992)
• [Publications] Tanaka,K.et al: "A new cdc gene required for S phase entry of Schizosaccharomyces pombe encodes a protein similar to the cdc10+and SWI4 gene products." EMBO J.11(13). 4923-4932 (1992)
• [Publications] Benton,B.K.et al: "A Schizosaccharomyces pombe gene that promotes sexual differentiation encodes a helix-loop-helix protein with homology to MyoD." EMBO J.12. 135-143 (1993)
• [Publications] Kasukabe,T.et al: "Characterization of growth inhibitory factors for mouse monocytic leukemia cells." Leukemia Research. 16. 139-144 (1992)
• [Publications] Oritani,K.et al: "Retinoic acid inhibits interleukin 6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line,Y6." Blood. 80. 2298-2305 (1992)
• [Publications] Kaisho,T.et al: "Human bone marrow stromal cell lines from myeloma and rheumatoid arthritis which can support murine preB cell growth." J.Immunol. 149. 4088-4095 (1992)
• [Publications] Nakajima,K.et al: "Identification of a novel interleukin 6 responsive element composed of an Ets-binding site and a CRE-like site in the JunB promoter" Mol.Cell.Biol.(1993)
• [Publications] Hirano,T.: "Interleukin 6 and autoimmunity and plasma cell neoplasias." Res.Immunol.143. 759-763 (1992)
• [Publications] Matsuda,T.et al: "Interleukin 6 receptor and signal transduction." Adv.Biochem.Biol.Membrane.(1993)
• [Publications] Y.Seto et al.: "Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor." J.Immunol.148. 259-266 (1992)
• [Publications] R.Watanabe-Fukunaga et al.: "The cDNA structure,expression and chromosomal assignment of the mouse Fas antigen." J.Immunol.148. 1274-1279 (1992)
• [Publications] R.Watanabe-Fukunaga et al.: "Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates spoptosis." Nature. 356. 314-317 (1992)
• [Publications] G.Fuh et al.: "Rational Design of Potent Antagonists to the Human Growth Hormone Receptor." Science. 256. 1677-1680 (1992)
• [Publications] E.Ishzaka-Ikeda et al.: "Signal transduction mediated by the growth hormone receptor and its chimeric molecules with the G-CSF receptor." Proc.Natl.Acad.Sci.USA. 90. 123-127 (1993)
• [Publications] M.Adachi et al.: "Aberrant transcription caused by an insertion of an early transposable element in intron of the Fas antigen gene of lpr mice." Proc.Natl.Acad.Sci.USA.
• [Publications] Yamamura,Y.et al.: "Distinet downstream signaling mechanisms between erythropoietin receptor and interleukin 2 receptor." The EMBO J.11. 4909-4915 (1992)
• [Publications] Sazuka,T.et al.: "Expression of DRG during murine embryonic development." Biochemical and biophysical Research Communications. 189. 371-377 (1992)
• [Publications] Sazuka,T.et al.: "DRG:a novel developmentally regulated GTP-bindinf protein." Biochemical and Biophysical Research Communications. 189. 363-370 (1992)
• [Publications] Murata,Y.et al: "Molecular cloning and characterization of the human interleukin 5 receptor." Journal of Experimental Medicine.175. 341-351 (1992)
• [Publications] Takatsu,K.et al: "Interleukin-5" Current Opinion of Immunology. 4. 299-305 (1992)
• [Publications] Takaki,S.et al: "Reconstitution of the functional receptors for murine and human interleukin 5" Journal of Experimental Medicine. 176. (1993)
• [Publications] Hitoshi,Y.et al: "Interleukin 5 receptor positive B cells,fut not eosinophils,are functionally and numerically influenced in the mice carrynig the X-linked immune defect." International Immunology. 6. (1993)
• [Publications] Hitosh,Y.et al: "Delayed progressin of a murine retro-rirus-induced acquired immunodeficiency syndrome,MAIDSin X-linked immunodeficient mice." Journal of Experimental Medicine.176. (1993)
• [Publications] Katoh,S.et al: "Characterization of CD5 B cell maintained in IL-5 trasgenic mice:pdyreactive autoautibody production and immunoglobrilin production and immunoglobrilin gene usage." DNA and Genes. (1993)
• [Publications] Mano,H.et al.: "¨Expression of a novel form of Tec kinase in hematopoietic cells and mapping of the gene to chromosome 5 near Kit¨" Oncogene. (1993)
• [Publications] Hanazono,Y.et al.: "¨c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3¨" EMBO J.(1993)
• [Publications] Hanazono,Y.et al.: "¨Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells¨" Blood. (1993)
• [Publications] Hanazono,Y.et al.: "¨Treatment of acute nonlymphocytic leukemia by combination of recombinant human granulocyte colony-stimulating factor and cytotoxic agents:A report of six cases¨" Int.J.Hematol.55. 243-248 (1992)
• [Publications] Sugimoto,K.et al.: "¨Frequent mutations in the p53 gene in human myeloid leukemia celll lines¨" Blood. 79. 2378-2383 (1992)
• [Publications] Sugimoto,K.et al.: "¨Mutations of the p53 gene in myelodysplastic syndromes and MDS-derived leukemia¨" Blood. (1993)
• [Publications] Sasaki,K.et al.: "¨Identification of a soluble GM-CSF binding protein in the supernatant of a human choriocarcinoma cell line¨" Biochem.Biophys.Res.commun.183. 252-257 (1992)
• [Publications] Sasaki,K.et al.: "¨Coordinate expression of the α and β chains of human granulocyte-macrophage colony-stimulating factor receptor confers lignad-induced morphological transformation in mouse fibroblsts¨" J.Biol.Chem.
• [Publications] Chiba,S.et al.: "¨GM-CSF signalling in haematopoietic and non-haematopoietic cells¨" Molerular Biology of Haematopoiesis. 2. (1992)
• [Publications] Hirano,T.: "Concise Reviews in Clinical and Experimental Hematologyの一章を分担" AlphaMed Press, 12 (1992)
• [Publications] Hirano,T.: "IL-6:Physiopathology and Clinical Potentialsの一章を分担" Raven Press, 10 (1992)