2001 Fiscal Year Annual Research Report

造血細胞のシグナル伝達

Research Project

Project/Area Number	10181101
Research Institution	The University of Tokyo
Principal Investigator	宮島篤東京大学, 分子細胞生物学研究所, 教授 (50135232)
Co-Investigator(Kenkyū-buntansha)	吉村昭彦九州大学, 生体防御医学研究所, 教授 (90182815) 田賀哲也熊本大学, 発生医学研究センター, 教授 (40192629) 福永理己郎大阪大学, 医学部, 助教授 (40189965) 金倉譲大阪大学, 医学部, 教授 (20177489) 横田崇金沢大学, 医学系研究科, 教授 (50134622)
Keywords	造血因子 / サイトカイン / シグナル伝達 / 受容体 / キナーゼ / 転写因子 / 細胞増殖 / 細胞分化
Research Abstract	造血細胞の増殖分化に関わるシグナルリングについての本年度の主要な成果は以下のようである。 AGM領域で発生した造血幹細胞胎生肝臓での増幅をin vitroで再現し、長期の造血再構築能が発生段階が進むにつれて低下することを示した(宮島)。gp130欠損マウスマウスのAGM培養では、血球の出現がほぼ完全に抑制され、AGM内の背側大動脈に発現する分子としてendomucin-1を同定し、この分子が細胞接着阻害作用をもつことを見いだした(田賀)。c-Kitを介する細胞遊走シグナルやCa2+influxには、Y567/srcファミリーキナーゼ/p38MAPK経路とY719/PI3kinase経路の二経路が重要であることを明らかにした(金倉)。c-Kitに結合する新規分子Spredをクローニングし,細胞膜に局在し活性化されたRas, Rafと複合体を形成することで、チロシンキナーゼからのRas/MAKキナーゼ経路を選択的に阻害することを明らかにした(吉村)。Stat1とStat3の造血における機能を解析するために、抑制型Stat3トランスジェニックマウス、さらにStat1のKOマウスとの交配により、抑制型Stat3/Stat1 KOマウスを作製し、Stat3は巨核球系前駆細胞の増幅に、Stat1は赤芽球系前駆細胞の増幅に重要であることを示した(小松)。骨髄球特異的転写因子MZF-2に結合する核内因子を探索し,SWI2/SNF2型クロマチン再構成因子であるmDomino/p400を同定し,骨髄球分化に関わる遺伝子発現には,MZF-2とmDominoの相互作用によるクロマチン再構成が関与することを示唆した(福永)。新規Znフィンガータンパク質SalIのノックアウトマウスでは左右の腎臓が完全に欠失していた。胎生11.5日に尿管芽が間葉に進入して後腎の発生は開始するが、ノックアウトマウスではこの段階で発生が障害されており、この遺伝子は後腎発生のもっとも初期に必須であることが判明した。この遺伝子は腎臓未分化細胞である後腎間葉のみならず、神経幹細胞、ES細胞でも発現しており、共通の機構が幹細胞において働いている可能性が示唆された(横田)。

Research Products
(25 results)

All Other

All Publications (25 results)

[Publications] Matsui T. et al.: "K-Ras mediates cytokine-induced formation of adherens junctions during liver development"EMBO J.. 21. 1021-1030 (2002)
[Publications] Takeuchi M. et al.: "Cultivation of AGM-derived hematopoietic stem cells in the fetal liver microenvironment amplifies long-term repopulating activity and enhances homing to the bone marrow"Blood. 99. 1190-1196 (2002)
[Publications] Kinoshita T. et al.: "Oncostatin M suppresses generation of progenitors in fetal liver by inhibiting the hepatic microenvironment"Experimental Hematology. 29. 1091-1097 (2001)
[Publications] Tanaka, M. et al.: "Forkhead family transcription factor FKHRL1 is expressed in human megakaryocytes and regulates cell cycling as a downstream molecule of TPO signaling"J. Biol. Chem.. 276. 15082-15089 (2001)
[Publications] Kirito, K. et al.: "Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation"Blood. 99. 102-110 (2002)
[Publications] Kirito, K. et al.: "A Functional role of Stat3 in in vivo megakaryopoiesis"Blood. (in press). (2002)
[Publications] Kirito, K. et al.: "TPO regulates Bcl-xL gene expression through Stat5 and phosphatidylinositol-3-kinase activation pathways"J. Biol. Chem.. (in press). (2002)
[Publications] Fukurnoto, T. et al.: "The Fused protein kinase regulates Hedgehog-stimulated transcriptional activation in Drosophila Schneider 2 cells"J. Biol. Chem.. 276. 38441-38448 (2001)
[Publications] Kawasaki, A. et al.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells"J. Cell Biol.. 152. 275-287 (2001)
[Publications] Nojima, J. et al.: "Anti-prothrombin antibodies combined with lupus anticoagulant activity is an essential risk factor for venous thrombolism in patients with systemic lupus erythrmatosus"Br. J. Haematol. 114. 647-654 (2001)
[Publications] Ueda, S. et al.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. (in press). (2002)
[Publications] Sonoyama, J. et al.: "Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activities of BCR/ABL in K562 cells"J. Biol. Chem.. (in press). (2002)
[Publications] Mizuki, M. et al.: "Role of receptor tyrosine kinases in hematological malignancies"Res. Adv. Blood. (in press). (2002)
[Publications] Takizawa, T. et al.: "Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3"Cytokine. 13. 272-279 (2001)
[Publications] Nakashima, K. et al.: "BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis"Proc. Natl. Acad. Sci. USA. 98. 5868-5873 (2001)
[Publications] Ochiai, W. et al.: "Astrocyte differentiation of fetal neuroepithelial cells involving cardiotrophin-1-induced activation of stat3"Cytokine. 14. 264-271 (2001)
[Publications] Takizawa, T. et al.: "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain"Dev. Cell. 1. 749-758 (2001)
[Publications] Nishinakanmra, R. et al.: "Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development"Development. 128. 3105-3115 (2001)
[Publications] Wakioka, T. et al.: "Spred, a Sprouty-related suppressor of Ras signaling"Nature. 412. 647-651 (2001)
[Publications] Shouda, T. et al.: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J. Clin. Invest.. 108. 1781-1788 (2001)
[Publications] Hanada, T. et al.: "A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAI3/CIS family proteins through the SOCS-box"J. Biol. Chem.. 276. 40746-40754 (2001)
[Publications] Sasaki, A. et al.: "Identification of a dominant negative form of Sproutys that potentiates FGF-but not EGF-induced ERK activation"J. Biol. Chem.. 276. 36804-36808 (2001)
[Publications] Suzuki, A. et al.: "CIS3/SOCS3/SSI3 Plays a Negative Regulatory Role in STAT3 Activation and Intestinal Inflammation"J. Exp. Med.. 193. 471-482 (2001)
[Publications] Kamizono, S. et al.: "The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2"J. Biol. Chem.. 276. 12530-12538 (2001)
[Publications] Minehata, K. et al.: "Macrophage-colony stimulating factor modulates the development of hematopoiesis by stimulating the differentiation of endothelial cells in the AGM region"Blood. (in press). (2002)

2001 Fiscal Year Annual Research Report

造血細胞のシグナル伝達

Principal Investigator

宮島 篤 東京大学, 分子細胞生物学研究所, 教授 (50135232)

Research Products

[Publications] Matsui T. et al.: "K-Ras mediates cytokine-induced formation of adherens junctions during liver development"EMBO J.. 21. 1021-1030 (2002)

[Publications] Takeuchi M. et al.: "Cultivation of AGM-derived hematopoietic stem cells in the fetal liver microenvironment amplifies long-term repopulating activity and enhances homing to the bone marrow"Blood. 99. 1190-1196 (2002)

[Publications] Kinoshita T. et al.: "Oncostatin M suppresses generation of progenitors in fetal liver by inhibiting the hepatic microenvironment"Experimental Hematology. 29. 1091-1097 (2001)

[Publications] Tanaka, M. et al.: "Forkhead family transcription factor FKHRL1 is expressed in human megakaryocytes and regulates cell cycling as a downstream molecule of TPO signaling"J. Biol. Chem.. 276. 15082-15089 (2001)

[Publications] Kirito, K. et al.: "Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation"Blood. 99. 102-110 (2002)

[Publications] Kirito, K. et al.: "A Functional role of Stat3 in in vivo megakaryopoiesis"Blood. (in press). (2002)

[Publications] Kirito, K. et al.: "TPO regulates Bcl-xL gene expression through Stat5 and phosphatidylinositol-3-kinase activation pathways"J. Biol. Chem.. (in press). (2002)

[Publications] Fukurnoto, T. et al.: "The Fused protein kinase regulates Hedgehog-stimulated transcriptional activation in Drosophila Schneider 2 cells"J. Biol. Chem.. 276. 38441-38448 (2001)

[Publications] Kawasaki, A. et al.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells"J. Cell Biol.. 152. 275-287 (2001)

[Publications] Nojima, J. et al.: "Anti-prothrombin antibodies combined with lupus anticoagulant activity is an essential risk factor for venous thrombolism in patients with systemic lupus erythrmatosus"Br. J. Haematol. 114. 647-654 (2001)

[Publications] Ueda, S. et al.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. (in press). (2002)

[Publications] Sonoyama, J. et al.: "Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activities of BCR/ABL in K562 cells"J. Biol. Chem.. (in press). (2002)

[Publications] Mizuki, M. et al.: "Role of receptor tyrosine kinases in hematological malignancies"Res. Adv. Blood. (in press). (2002)

[Publications] Takizawa, T. et al.: "Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3"Cytokine. 13. 272-279 (2001)

[Publications] Nakashima, K. et al.: "BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis"Proc. Natl. Acad. Sci. USA. 98. 5868-5873 (2001)

[Publications] Ochiai, W. et al.: "Astrocyte differentiation of fetal neuroepithelial cells involving cardiotrophin-1-induced activation of stat3"Cytokine. 14. 264-271 (2001)

[Publications] Takizawa, T. et al.: "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain"Dev. Cell. 1. 749-758 (2001)

[Publications] Nishinakanmra, R. et al.: "Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development"Development. 128. 3105-3115 (2001)

[Publications] Wakioka, T. et al.: "Spred, a Sprouty-related suppressor of Ras signaling"Nature. 412. 647-651 (2001)

[Publications] Shouda, T. et al.: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J. Clin. Invest.. 108. 1781-1788 (2001)

[Publications] Hanada, T. et al.: "A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAI3/CIS family proteins through the SOCS-box"J. Biol. Chem.. 276. 40746-40754 (2001)

[Publications] Sasaki, A. et al.: "Identification of a dominant negative form of Sproutys that potentiates FGF-but not EGF-induced ERK activation"J. Biol. Chem.. 276. 36804-36808 (2001)

[Publications] Suzuki, A. et al.: "CIS3/SOCS3/SSI3 Plays a Negative Regulatory Role in STAT3 Activation and Intestinal Inflammation"J. Exp. Med.. 193. 471-482 (2001)

[Publications] Kamizono, S. et al.: "The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2"J. Biol. Chem.. 276. 12530-12538 (2001)

[Publications] Minehata, K. et al.: "Macrophage-colony stimulating factor modulates the development of hematopoiesis by stimulating the differentiation of endothelial cells in the AGM region"Blood. (in press). (2002)

宮島篤東京大学, 分子細胞生物学研究所, 教授 (50135232)