1999 Fiscal Year Annual Research Report

血球分化の分子機構と臨床的解析

Research Project

Project/Area Number	09470233
Research Institution	Jich Medical School
Principal Investigator	小松則夫自治医科大学, 医学部, 講師 (50186798)
Co-Investigator(Kenkyū-buntansha)	柏井良文自治医科大学, 医学部, 助手 (10271222) 内田美栄自治医科大学, 医学部, 助手 (80316520) 桐戸敬太自治医科大学, 医学部, 助手 (90306150)
Keywords	エリスロポエチン / transgenic mice / 赤芽球分化 / 巨核球分化 / UT-7 / GATA-1 / STAT3 / STAT1
Research Abstract	急性巨核芽球性白血病患者の骨髄血から、インターロイキン-3、顆粒球・マクロファージコロニー刺激因子、エリスロポエチン(EPO)に増殖依存性を示す細胞株の樹立に成功し、UT-7と命名した。さらにUT-7からEPOにのみ増殖依存性を示す亜株UT-7/EPO、EPO刺激により赤血球系へ、TPO刺激により巨核球系へと2方向への分化能を有するきわめてユニークな細胞株UT-7/GMを樹立した。これらの細胞株を用いて、昨年までにUT-7およびその亜株を用いて、EPOがSTAT1αとSTAT3を活性化すること、これらのSTATの活性化がEPOによる赤芽球分化を抑制することを明らかにした。さらにEPO受容体の細胞内領域のBox2からC末端にSTAT1αとSTAT3の活性化に重要な領域が存在すること、これらの活性化にはc-FesとLynチロシンキナーゼが重要な役割を演じていることを明らかにした。本年度はさらにSTAT3がTPOによる巨核球分化に対しても抑制的に機能することを見い出した。そこでSTAT3のin vivoにおける役割を解析する目的で、赤芽球・巨核球に特異的に発現するGATA-1のプロモーターにSTAT3 dominant negagtive型を連結させたconstructを用いてtransgenic miceを作製した。その結果、マウスは正常に生まれ、恒常的造血には異常はなかったが、抗癌剤投与後の骨髄抑制からの赤血球・血小板の回復に著しい遅延が認められた。このことからSTAT3はin vivoにおける赤芽球・巨核球系前駆細胞の増幅に重要な役割を果たしていることがわかった。

Research Products

(10 results)

All Other

All Publications (10 results)

[Publications] Shimizu, R.: "A dominant negative effect of a truncated erythropoietin receptor on erythropoietin-induced erythroid differentiation"Exp Hematol. 27. 229-233 (1999)
[Publications] Madoiwa, S.: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation"Blood. 94. 475-482 (1999)
[Publications] Komatsu, N.: "Process from production to destruction of erythrocytes and causes of anemia"Asian Med J. 42. 114-121 (1999)
[Publications] Kusano E: "Human recombinant erythoropoietin inhibits interleukin-1beta-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth-muscle cells"Nephrol Dial Transplant. 14. 597-603 (1999)
[Publications] Tominaga, S.: "Presence and expression of a novel variant form of ST2 geneproduct in human leukemic cell line UT-7/GM"Biochem Biophs Res Commun. 264. 14-18 (1999)
[Publications] Iwahana, H.: "Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells"Eur J Biochem. 264. 397-406 (1999)
[Publications] Akimoto, T.: "The effect of erythropoietin on interleukin-1beta mediated increase in nitric oxide synthesis in vascular smooth muscle cells"J Hypertens. 17(in press). 1249-1256 (1999)
[Publications] Kuroiwa, K.: "Construction of ELISA system to quantify human ST2 protein in sera of patients. Hybridoma"Hybridoma. (in press).
[Publications] Kashii, Y.: "A member of forkhead family transcription factor FKHRL1 is one of the downstream molecule of phosphatidylinositol 3-kinaze-Akt activation pathway in erythropoietin signal transduction"Blood. (in press).
[Publications] Uchida, M.: "A functional role of mitogen-activated protein kinaze, Erk1 and Erk2, in the differentiation of a human leukemia cell line UT-7/GM:"Int Haematol. (in press).

1999 Fiscal Year Annual Research Report

血球分化の分子機構と臨床的解析

Principal Investigator

小松 則夫 自治医科大学, 医学部, 講師 (50186798)

Research Products

[Publications] Shimizu, R.: "A dominant negative effect of a truncated erythropoietin receptor on erythropoietin-induced erythroid differentiation"Exp Hematol. 27. 229-233 (1999)

[Publications] Madoiwa, S.: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation"Blood. 94. 475-482 (1999)

[Publications] Komatsu, N.: "Process from production to destruction of erythrocytes and causes of anemia"Asian Med J. 42. 114-121 (1999)

[Publications] Kusano E: "Human recombinant erythoropoietin inhibits interleukin-1beta-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth-muscle cells"Nephrol Dial Transplant. 14. 597-603 (1999)

[Publications] Tominaga, S.: "Presence and expression of a novel variant form of ST2 geneproduct in human leukemic cell line UT-7/GM"Biochem Biophs Res Commun. 264. 14-18 (1999)

[Publications] Iwahana, H.: "Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells"Eur J Biochem. 264. 397-406 (1999)

[Publications] Akimoto, T.: "The effect of erythropoietin on interleukin-1beta mediated increase in nitric oxide synthesis in vascular smooth muscle cells"J Hypertens. 17(in press). 1249-1256 (1999)

[Publications] Kuroiwa, K.: "Construction of ELISA system to quantify human ST2 protein in sera of patients. Hybridoma"Hybridoma. (in press).

[Publications] Kashii, Y.: "A member of forkhead family transcription factor FKHRL1 is one of the downstream molecule of phosphatidylinositol 3-kinaze-Akt activation pathway in erythropoietin signal transduction"Blood. (in press).

[Publications] Uchida, M.: "A functional role of mitogen-activated protein kinaze, Erk1 and Erk2, in the differentiation of a human leukemia cell line UT-7/GM:"Int Haematol. (in press).

小松則夫自治医科大学, 医学部, 講師 (50186798)