受容体からの分化と腫瘍化のシグナル

• Project/Area Number: 12215080
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 金倉 譲 大阪大学, 医学系研究科, 教授 (20177489)
• Co-Investigator(Kenkyū-buntansha): 仲野 徹 大阪大学, 医学系研究科, 教授 (00172370) ; 松村 到 大阪大学, 医学研究科, 助手 (00294083) ; 池田 弘和 大阪大学, 医学系研究科, 助手 (10311755)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥105,000,000 (Direct Cost: ¥105,000,000); Fiscal Year 2004: ¥38,000,000 (Direct Cost: ¥38,000,000); Fiscal Year 2003: ¥21,000,000 (Direct Cost: ¥21,000,000); Fiscal Year 2002: ¥17,000,000 (Direct Cost: ¥17,000,000); Fiscal Year 2001: ¥17,000,000 (Direct Cost: ¥17,000,000); Fiscal Year 2000: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: サイトカイン / アポトーシス / 造血幹細胞 / 転写因子 / 増幅 / 自己複製 / 細胞周期 / 造血器腫瘍 / 受容体 / 増殖 / 造血 / シグナル伝達 / 腫瘍 / Anamorsin / 分化

Research Abstract

サイトカイン受容体下流に存在する新規抗アポトージス分子Anamorsin(AM)についての解析を行った。AM欠損マウスは胎生致死で、肝臓、脾臓の造血組織が萎縮し、著明な貧血を呈した。AM欠損胎児肝において、造血幹/前駆細胞や未熟赤芽球分画の絶対数は減少していなかったが、分化に伴い造血細胞のアポトーシス亢進により、二次造血が障害され造血不全をきたすと考えられた。造血器腫瘍細胞におけるAMの発現について、組織レベルでの蛋白発現を調べると、白血病やリンパ腫の一部に高発現していることが明らかとなった。
また、NotchやHOXB4は造血幹細胞の増幅に関与していることが知られている。Notch 1やHOXB4によりc-mycの転写の亢進が認められ発現が誘導されたことから、c-mycを造血幹細胞に導入し造血幹細胞への効果を検討した。c-mycにより造血幹細胞のコロニー形成能が増加し、放射線照射マウスに移植すると造血再構築能が上昇していた。また、造血幹細胞の自己複製過程においてPBX1はHOXB4の活性を負に制御している。そこで、内因性のHOX/PBX1複合体の活性を変化させ得るPBX1との結合領域部分のHOXタンパクのdecoyペプチドを設計、合成し、ヒト臍帯血造血幹細胞に導入し造血幹細胞の自己複製能や多分化能に及ぼす影響について検討を行なった。その結果、HOXタンパクのdecoyペプチドは、細胞周期制御因子の発現調節を介して造血幹細胞の自己複製を亢進させた。

Research Products

• [Journal Article] Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1. (2005)
  • Author(s): Ishiko E, et al.
  • Journal Title: J.Biol.Chem. 280(6) Pages: 4929-4939
• [Journal Article] Distinct role for c-kit receptor tyrosine kinase and SgIGSF adhesion molecule in attachment of mast cells to fibroblasts. (2005)
  • Author(s): Koma, Y, et al.
  • Journal Title: Lab. Invest. 85(3) Pages: 426-435
• [Journal Article] GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopoietic cell line through the inhibition of STAT3 activity. (2005)
  • Author(s): Ezoe S, et al.
  • Journal Title: J.Biol.Chem. (In press)
• [Journal Article] Identification of a cytokine-induced anti-apoptotic molecule Anamorsin essential for definitive hematopoiesis (2004)
  • Author(s): Shibayama, H., et al.
  • Journal Title: J.Exp.Med. 199(4) Pages: 581-592
• [Journal Article] Roles of c-myc in self-renewal of hematopoietic stein cells. (2004)
  • Author(s): Satoh, Y., et al.
  • Journal Title: J.Biol.Chem. 279(24) Pages: 24986-24993
• [Journal Article] NF κB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species. (2004)
  • Author(s): Nakata S, et al.
  • Journal Title: J.Biol.Chem. 279(53) Pages: 55578-55586
• [Publications] Hashimoto, K., et al.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation."Blood. 101(3). 1094-1102 (2003)
• [Publications] Kawasaki, A., et al.: "Opposing effects of PML and PML/RAR α on STAT3 activities."Blood. 101(9). 3668-3673 (2003)
• [Publications] Kataoka, Y., et al.: "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts."J.Biol.Chem.. 278(45). 44178-44184 (2003)
• [Publications] Mizuki M, et al.: "Oncogenic receptor tyrosine kinase in leukemia."Cell Mol Biol. 49(6). 907-922 (2003)
• [Publications] Matsumura, I., et al.: "E2F1 and c-Myc in cell growth and death."Cell Cycle. 2(4). 333-338 (2003)
• [Publications] Shibayama, H., et al.: "Identification of a cytokine-induced anti-apoptotic molecule Anamorsin essential for definitive hematopoiesis."J.Exp.Med.. 199(4). 581-592 (2004)
• [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.. 277(10). 8076-8082 (2002)
• [Publications] Nishimura, J-I., et al.: "Long-term support of human hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria"Blood. 99(8). 2748-2751 (2002)
• [Publications] Ueda, S., et al.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis"Blood. 99(9). 3342-3349 (2002)
• [Publications] Tanaka, H., et al.: "E2F-1 and c-Myc potentiate apoptosis through inhibition of NFkB activity that facilitates MnSOD-mediated ROS elimination"Mol.Cell. 9(5). 1017-1029 (2002)
• [Publications] Ezoe, S., et al.: "GATA-2/estrogen receptor chimera regulates cytokine-dependent growth of hematopoietic cells through accumulation of p21WAF1 and p27Kip1 proteins"Blood. 100(10). 3512-3520 (2002)
• [Publications] Hashimoto, K., et al.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation"Blood. 101(3). 1094-1102 (2003)
• [Publications] Nishimura, J., et al.: "Paroxysmal Nocturnal Hemoglobinuria and Related Disorders"Springer-Verlag. 235-246 (2003)
• [Publications] Kawasaki, A., et al.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells"J.Cell Biol.. 152(2). 275-287 (2001)
• [Publications] Nishimura, J-I., et al.: "Efficient retrovirus-mediated PIG-A gene transfer and stable restoration of GPI-anchored expression in cells with the PNH phenotype"Blood. 97(10). 3004-3010 (2001)
• [Publications] Ueda, S., et al.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis"Blood. (in press).
• [Publications] Nishimura, J-I., et al.: "Long-term support of human hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria"Blood. (in press).
• [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).
• [Publications] Matumura, I., Kanakura, Y.: "Molecular control of megakaryocytopoiesis and thrombopoiesis"Int.J.Hematol. (in press).
• [Publications] Matsumura,I., et al.: "Increased D-type cyclin expression together with decreased cdc2 activity confers megakaryocytic differentiation of a human thrombopoietin-dependent hematopoietic cell line."J.Biol.Chem.. 275(8). 5553-5559 (2000)
• [Publications] Tanaka,H., et al.: "GATA-1 blocks interleukin-6 induced macrophage differentiation and apoptosis through the sustaine expression of cyclin D1 and bcl-2 in a murine myeloid cell line M1."Blood. 95(4). 1264-1273 (2000)
• [Publications] Daino,H., et al..: "Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells : possible involvement of Stat3 degradation by proteasome pathway"Blood. 95(8). 2577-2585 (2000)
• [Publications] Odajima,J., et al.: "Full oncogenic activities of v-Src are mediated by cooperation of multiple signaling pathways ; ras as an essential mediator for cell survival."J.Biol.Chem.. 275(31). 24096-24105 (2000)
• [Publications] Matsumura,I., et al.: "Biological significance of GATA-1 activities in ras-mediated megakaryocytic differentiation of hematopoietic cell lines."Blood. 96(7). 2440-2450 (2000)
• [Publications] Kawasaki,A., et al.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells."J.Cell Biol.. 152(2). 275-287 (2001)