2003 Fiscal Year Annual Research Report

造血細胞の生存と増殖・分化の制御機構に関する研究

Research Project

Project/Area Number	14370302
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)	柴山浩彦大阪大学, 医学系研究科, 助手 (60346202) 水木満佐央大阪大学, 医学系研究科, 講師 (80283761) 松村到大阪大学, 医学系研究科, 助教授 (00294083) 菅原浩之大阪大学, 医学系研究科, 助手 (40362701)
Keywords	KIT / FLT3 / 活性酸素種 / E2F1 / NF-κB / アポトーシス / Anamorsin / Bcl-XL
Research Abstract	1.KIT、FLT3を介する造血細胞の増殖・腫瘍化機構の解析野生型KIT、活性型変異KITによる細胞増殖にはチロシン719を介するPI3-Kの活性化が必須であること、野生型KITによる細胞遊走にはチロシン567と719を介するSrcファミリーチロシンキナーゼの活性化とPI3-Kの活性化が必要であることを明らかにした。更に、活性型変異FLT3は正常リガンドと比較して、細胞増殖を誘導するPim2の発現を強く誘導し、好中球分化を誘導するPU.1、c/EBPαの発現を抑制することを明らかにした。 2.細胞周期制御とアポトーシス感受性の関連についての解析 c-MycやE2F1を過剰発現する細胞では活性酸素種が蓄積し、また、E2F1によって抗アポトーシス分子NF-kBの機能が損なわれ、アポトーシス感受性が高まっていることを明らかにした。 3.新規抗アポトーシス分子Anamorsinの単離とノックアウトマウスの作製と解析 IL-3依存性細胞株Ba/F3からIL-3非依存性の増殖・生存が可能なBa/F3-Adを樹立し、この亜株から発現ライブラリーを作製し、Ba/F3にIL-3非依存性の増殖・生存を可能にする遺伝子の発現クローニングを試みた。この結果、既知のアポトーシス関連分子とのホモロジーを示さない新規の抗アポトーシス分子を単離し、Anamorsinと命名した。 Anamorsin^<+/->マウスは異常を示さなかったが、Anamorsin^<-/->マウスは胎生14日目以降に致死であった。Anamorsin^<-/->マウスは著明な貧血を呈し、胎児肝において赤芽球系の細胞がアポトーシスに陥っていた。マイクロアレイ解析の結果、Anamorsin^<-/->マウスの胎児肝細胞では抗アポトーシス分子Bcl-XLやシグナル伝達分子JAK2の発現が低下していることが明らかとなった。

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] Hashimoto K, et al.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway inconstitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation"Blood. 101. 1094-1102 (2003)
[Publications] Kawasaki A, et al.: "Opposing effects of PML and PML/RARa on STAT3 activity"Blood. 101. 3668-3673 (2003)
[Publications] Mizuki M, et al.: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-Specific Flt3 mutations"Blood. 101. 3164-3173 (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. 44178-44187 (2003)
[Publications] Saeki Y, et al.: "Enhanced production of osteopontin in multiple myeloma : clinical and pathogenicimplications"Br.J.Haematol.. 123. 263-270 (2003)
[Publications] Zhang X, et al.: "Constitutively activated Rho GTPases regulate the growth and morphology of hairy cellleukemia (HCL) cells"Int.J.Hematology. 77. 263-270 (2003)
[Publications] Takakuwa T, et al.: "Establishment and characterization of unique cell lines derived from pyothorax-associated lymphoma which develops in long-standing pyothorax and is stronglyassociated with Epstein-Barr virus infection"Cancer Sci.. 94. 858-863 (2003)
[Publications] Matsumura I, et al.: "Molecular mechanisms of E2F1-and c-Myc-enhanced apoptosis"Rec.Res.Dev.in Mol. & Cell.Biol.. 4. 311-324 (2003)
[Publications] Matsumura I, et al.: "Roles for E2F1 and c-Myc in the regulation of cell growth and survival"Cell Cycle. 2. 333-338 (2003)
[Publications] Mizuki M, et al.: "Constitutive active receptor tyrosine kinase in hematological neoplasia"Rec.Res.Dev.in Mol. & Cell.Biol.. 4. 85-100 (2003)
[Publications] Mizuki M, et al.: "Oncogenic receptor tyrosine kinase in leukemia"Cellular and Molecular Biology. 49. 907-922 (2003)
[Publications] Matsumura I, et al.: "Cell cycle regulation in hematopoietic stem cells"Res.Adv.in Blood. 2. 39-49 (2003)
[Publications] Okawa Y, et al.: "Purification of N-terminally truncated histone H2A-monoubiquitin conjugates fromleukemic cell nuclei : probable proteolytic products of ubiquitinated H2A"Int.J.Biochem.Cell Biol.. 35. 1588-1600 (2003)
[Publications] Yamanishi H, et al.: "Total iron-binding capacity calculated from serum transferrin concentration or serumiron concentration and unsaturated iron-binding capacity"Clin.Chem.. 49. 175-178 (2003)
[Publications] Yamanishi H, et al.: "Modification of the colorimetric assay for serum unsaturated iron-binding capacity"Clin.Chem.. 49. 1023-1025 (2003)
[Publications] Kimura S, et al.: "Enzymatic assay for determination of bicarbonate ion in plasma using urea amidolyase"Clin.Chim.Acta.. 328. 179-184 (2003)
[Publications] Kimura S, et al.: "New enzymatic assay for serum urea nitrogen using urea amidolyase"J.Clin.Lab.Anal.. 17. 52-56 (2003)
[Publications] Kabutomori O, et al.: "Marked decreases of total and immature reticulocytes in myelodysplastic syndromeamong patients with pancytopenia"Acta Haematol.. 109. 212-213 (2003)
[Publications] Kabutomori O, et al.: "Incorrect measurement of leukocyte counts in post-bone marrow transplantation (P-BMT) patients"Ann.Hematol.. 82. 529-530 (2003)
[Publications] Ueda Y, et al.: "New homogeneous HDL-cholesterol assay without the influence of high TG sample using the selective detergent to lipoproteins"J Clin Lab Anal.. 17. 201-208 (2003)
[Publications] Tanaka S, et al.: "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome"Int.J.Mol.Med.. 12. 225-230 (2003)
[Publications] Shibayama H, et al.: "Identification of a cytokine-induced antiapoptotic molecule Anamorsin essential for definitive hematopoiesis"J.Exp.Med.. 199. 581-592 (2004)
[Publications] Ezoe S, et al.: "Roles for CDK inhibtors in hematopoietic system"Cell Cycle. (in press). (2004)

2003 Fiscal Year Annual Research Report

造血細胞の生存と増殖・分化の制御機構に関する研究

Principal Investigator

金倉 譲 大阪大学, 医学系研究科, 教授 (20177489)

Research Products

[Publications] Hashimoto K, et al.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway inconstitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation"Blood. 101. 1094-1102 (2003)

[Publications] Kawasaki A, et al.: "Opposing effects of PML and PML/RARa on STAT3 activity"Blood. 101. 3668-3673 (2003)

[Publications] Mizuki M, et al.: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-Specific Flt3 mutations"Blood. 101. 3164-3173 (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. 44178-44187 (2003)

[Publications] Saeki Y, et al.: "Enhanced production of osteopontin in multiple myeloma : clinical and pathogenicimplications"Br.J.Haematol.. 123. 263-270 (2003)

[Publications] Zhang X, et al.: "Constitutively activated Rho GTPases regulate the growth and morphology of hairy cellleukemia (HCL) cells"Int.J.Hematology. 77. 263-270 (2003)

[Publications] Takakuwa T, et al.: "Establishment and characterization of unique cell lines derived from pyothorax-associated lymphoma which develops in long-standing pyothorax and is stronglyassociated with Epstein-Barr virus infection"Cancer Sci.. 94. 858-863 (2003)

[Publications] Matsumura I, et al.: "Molecular mechanisms of E2F1-and c-Myc-enhanced apoptosis"Rec.Res.Dev.in Mol. & Cell.Biol.. 4. 311-324 (2003)

[Publications] Matsumura I, et al.: "Roles for E2F1 and c-Myc in the regulation of cell growth and survival"Cell Cycle. 2. 333-338 (2003)

[Publications] Mizuki M, et al.: "Constitutive active receptor tyrosine kinase in hematological neoplasia"Rec.Res.Dev.in Mol. & Cell.Biol.. 4. 85-100 (2003)

[Publications] Mizuki M, et al.: "Oncogenic receptor tyrosine kinase in leukemia"Cellular and Molecular Biology. 49. 907-922 (2003)

[Publications] Matsumura I, et al.: "Cell cycle regulation in hematopoietic stem cells"Res.Adv.in Blood. 2. 39-49 (2003)

[Publications] Okawa Y, et al.: "Purification of N-terminally truncated histone H2A-monoubiquitin conjugates fromleukemic cell nuclei : probable proteolytic products of ubiquitinated H2A"Int.J.Biochem.Cell Biol.. 35. 1588-1600 (2003)

[Publications] Yamanishi H, et al.: "Total iron-binding capacity calculated from serum transferrin concentration or serumiron concentration and unsaturated iron-binding capacity"Clin.Chem.. 49. 175-178 (2003)

[Publications] Yamanishi H, et al.: "Modification of the colorimetric assay for serum unsaturated iron-binding capacity"Clin.Chem.. 49. 1023-1025 (2003)

[Publications] Kimura S, et al.: "Enzymatic assay for determination of bicarbonate ion in plasma using urea amidolyase"Clin.Chim.Acta.. 328. 179-184 (2003)

[Publications] Kimura S, et al.: "New enzymatic assay for serum urea nitrogen using urea amidolyase"J.Clin.Lab.Anal.. 17. 52-56 (2003)

[Publications] Kabutomori O, et al.: "Marked decreases of total and immature reticulocytes in myelodysplastic syndromeamong patients with pancytopenia"Acta Haematol.. 109. 212-213 (2003)

[Publications] Kabutomori O, et al.: "Incorrect measurement of leukocyte counts in post-bone marrow transplantation (P-BMT) patients"Ann.Hematol.. 82. 529-530 (2003)

[Publications] Ueda Y, et al.: "New homogeneous HDL-cholesterol assay without the influence of high TG sample using the selective detergent to lipoproteins"J Clin Lab Anal.. 17. 201-208 (2003)

[Publications] Tanaka S, et al.: "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome"Int.J.Mol.Med.. 12. 225-230 (2003)

[Publications] Shibayama H, et al.: "Identification of a cytokine-induced antiapoptotic molecule Anamorsin essential for definitive hematopoiesis"J.Exp.Med.. 199. 581-592 (2004)

[Publications] Ezoe S, et al.: "Roles for CDK inhibtors in hematopoietic system"Cell Cycle. (in press). (2004)

金倉譲大阪大学, 医学系研究科, 教授 (20177489)