1998 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)	小松則夫自治医科大学, 講師 (50186798) 横田崇東京大学, 医学研究所, 客員教授 (50134622) 吉村昭彦久留米大学, 分子生命科学研究所, 教授 (90182815) 田賀哲也東京医科歯科大学, 難治疾患研究所, 教授 (40192629) 福永理己郎大阪大学, 医学部, 助教授 (40189965)
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	造血幹細胞増殖に重要な機能をもつc-Kitとgp130受容体および造血サイトカインの主要なシグナル伝達経路であるJAK/STATの機能などにつき以下の成果を得た。造血幹細胞発生に重要なOSMのマウス受容体遺伝子のクローニングを通じて機能的なマウスOSM特異的受容体の構造を明らかにした。さらに、OSM受容体のノックアウトマウスの作成を行った(宮島)。gp130とGM-CSF受容体のキメラ分子をES細胞に発現し、多分化能維持にSTAT3が必要であることを示した。さらに、キメラ分子を発現するtransgenic mouseを作成し、造血幹細胞増殖の制御を試みている(横田)。gp130のシグナル伝達に重要なSTAT3のセリンリン酸化するキナーゼの分離を試み、3種の候補を得た(田賀)。一方、c-Kitの細胞内アミノ酸残基の置換による恒常的活性化は特異なダイマー形成によることが示された。また、IL-3,EPOによる増殖にはSTAT5によるcyclin D1の発現が重要であることも明らかにした(金倉)。サイト力インのシグナル伝達を制御するCISのtransgenic mouseはSTAT5欠損マウスに似た表現型を示した。一方、JABのtransgenic mouseではJAK1欠損に近い表現型を示したことから、CIS,JABはそれぞれSTAT5,JAK1の抑制因子として働いていることが明らかになった(吉村)。EPOによるSTAT1,STAT3の活性化には受容体のC末側が必要であること、およびEPOとTPO受容体によるクロストークの存在を示した(小松)。好中球の増殖分化に関与する転写因子MZF-2の機能解析から転写の制御ドメインを同定した。また、MZF-2に生理機能のために、その標的遺伝子の探索とノックアウト作成を進行中である(福永)。

Research Products
(14 results)

All Other

All Publications (14 results)

[Publications] Suzuki,R.et al.: "ICIS3 and JAB have different regulatory roles in interleukin-6 mediateddifferentiation and STAT3 activation in M1 leukemia cells" Oncogene. 17. 2271-2278 (1998)
[Publications] Kirito,K.et al.: "A novel function of Statla and Stat3 in the erythropoletin-induced erythroid differentiation of a human leukemla cell line" Blood.92. 412-417 (1998)
[Publications] Itoh,T.et al.: "Definition of the role of tyrosine residues of the common b subunit regulating multiple signaling pathwavs of granulocvte-macrophage colonv-stimulating factor receptor" Mol.Cell.Biol.18. 742-752 (1998)
[Publications] Matsmura,I.et al.: "Involvement of prolonged ras activation in thrombopoietin-induced megakaryocytic differentiation of a human factor-dependent hematopoletic cell line" Mol.Cell.Biol.18. 4282-4290 (1998)
[Publications] Tsujimura,T.et al.: "Constitutively activating mutation in the catalytic domain of c-kit receptor tyrosine kinase elicits hematopoletic transformation by receptor self-asociation not at the ligand-dependent dimerization site" Blood. 93. 1319-1329 (1999)
[Publications] Matsumura,I.et al.: "Transcriptional regulation of cyclin D1 promoter by STAT5:its involvement in cytokine-dependent growth of hematopoletic cells" EMBO J.in press. (1999)
[Publications] Jiang,W.et al.: "R.PRC1:a human mitotic spindle-associated CDK substrate protein required for cytokinesis" Mol.Cell. 2. 877-885 (1998)
[Publications] X.-J.Wang.et al.: "gp130,the cytokine common signal-transducer of interleukin-6 cytokine family,is down-regulated in T cells in vivo by interleukin-6" Blood. 91. 3308-3314 (1998)
[Publications] Mukouyama,Y.et al.: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." immunity. 8. 105-114 (1998)
[Publications] Tanaka,M.et al.: "Reconstitution of the functional mouse oncostatin M(OSM)receptot:molecular cloning of the mouse OSM receptor b subunit." Blood. 93. 804-815 (1999)
[Publications] Chida,D.et al.: "Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells:functional analvsis of signaling molecules by retrovirus-mediated gene expression." Blood in press. (1999)
[Publications] Yasukawa,H.et al.: "The JAK-Binding Protein JAB Inhibits Janus Tyrosine Kinase Activity Through Binding in the Activation Loop" EMBO J.in press. (1999)
[Publications] Yokouchi,M.et al.: "APS,an adaptor protein containing PH and SH2 domains,is associated with the PDGF receptor and c-Cb1,and inhibits PDGF-induced mitogenesis" Oncogene in press. (1999)
[Publications] Sakamoto,H.et al.: "A Janus kinase inhibitor,JAB,is an interferon-g inducible gene andconfers resistance to interferons" Blood. 92. 1668-1676 (1998)

1998 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] Suzuki,R.et al.: "ICIS3 and JAB have different regulatory roles in interleukin-6 mediateddifferentiation and STAT3 activation in M1 leukemia cells" Oncogene. 17. 2271-2278 (1998)

[Publications] Kirito,K.et al.: "A novel function of Statla and Stat3 in the erythropoletin-induced erythroid differentiation of a human leukemla cell line" Blood.92. 412-417 (1998)

[Publications] Itoh,T.et al.: "Definition of the role of tyrosine residues of the common b subunit regulating multiple signaling pathwavs of granulocvte-macrophage colonv-stimulating factor receptor" Mol.Cell.Biol.18. 742-752 (1998)

[Publications] Matsmura,I.et al.: "Involvement of prolonged ras activation in thrombopoietin-induced megakaryocytic differentiation of a human factor-dependent hematopoletic cell line" Mol.Cell.Biol.18. 4282-4290 (1998)

[Publications] Tsujimura,T.et al.: "Constitutively activating mutation in the catalytic domain of c-kit receptor tyrosine kinase elicits hematopoletic transformation by receptor self-asociation not at the ligand-dependent dimerization site" Blood. 93. 1319-1329 (1999)

[Publications] Matsumura,I.et al.: "Transcriptional regulation of cyclin D1 promoter by STAT5:its involvement in cytokine-dependent growth of hematopoletic cells" EMBO J.in press. (1999)

[Publications] Jiang,W.et al.: "R.PRC1:a human mitotic spindle-associated CDK substrate protein required for cytokinesis" Mol.Cell. 2. 877-885 (1998)

[Publications] X.-J.Wang.et al.: "gp130,the cytokine common signal-transducer of interleukin-6 cytokine family,is down-regulated in T cells in vivo by interleukin-6" Blood. 91. 3308-3314 (1998)

[Publications] Mukouyama,Y.et al.: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." immunity. 8. 105-114 (1998)

[Publications] Tanaka,M.et al.: "Reconstitution of the functional mouse oncostatin M(OSM)receptot:molecular cloning of the mouse OSM receptor b subunit." Blood. 93. 804-815 (1999)

[Publications] Chida,D.et al.: "Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells:functional analvsis of signaling molecules by retrovirus-mediated gene expression." Blood in press. (1999)

[Publications] Yasukawa,H.et al.: "The JAK-Binding Protein JAB Inhibits Janus Tyrosine Kinase Activity Through Binding in the Activation Loop" EMBO J.in press. (1999)

[Publications] Yokouchi,M.et al.: "APS,an adaptor protein containing PH and SH2 domains,is associated with the PDGF receptor and c-Cb1,and inhibits PDGF-induced mitogenesis" Oncogene in press. (1999)

[Publications] Sakamoto,H.et al.: "A Janus kinase inhibitor,JAB,is an interferon-g inducible gene andconfers resistance to interferons" Blood. 92. 1668-1676 (1998)

宮島篤東京大学, 分子細胞生物学研究所, 教授 (50135232)