2003 Fiscal Year Annual Research Report

E2F1による細胞内ROSの蓄積及び癌抑制機構の解析

Research Project

Project/Area Number	15023231
Research Institution	Osaka University
Principal Investigator	松村到大阪大学, 医学系研究科, 助教授 (00294083)
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) 金倉譲大阪大学, 医学系研究科, 教授 (20177489)
Keywords	E2F1 / ROS / NF-κB / アポトーシス / 細胞周期
Research Abstract	細胞周期推進分子であるc-MycやE2F1を過剰発現させた線維芽細胞が、血清除去によるアポトーシスに高い感受性を示すように、一般に、細胞周期の進行はアポトーシス感受性を亢進させる。また、E2F1ノックアウト(E2F1^<-/->)マウスでは、生後早期に各種の悪性腫癌が発生した。これらの結果から、E2F1は細胞周期推進分子としてのみでなく、アポトーシス誘導分子、癌抑制遺伝子としても機能すると推測された。我々はE2F1が抗アポトーシス分子NF-κBの機能を阻害することを見出しているが、本研究では、E2F1によるアポトーシス制御の分子機構について更に検討し、以下の知見を得た。 E2F1を過剰発現させた細胞では、 1.細胞内にROSが蓄積し、血清除去、抗がん剤処理、放射線照射に対するアポトーシス感受性の亢進が認められた。このアポトーシス感受性の亢進はROSを消去すると回避された。 2.恒常的なDNAダメージが検出された。 3.JNK、p38MAPKなどが恒常的に活性化され、放射線照射によってこの活性化は増強され、コントロールの細胞より遷延化した。 4.E2F1^<-/->の胎児線維芽細胞をv-Srcやv-Ablなどの癌遺伝子でtransformすると、野生型のMEFより各種のアポトーシス刺激に抵抗性を示した。 5.NF-κBに対するSiRNAを導入しNF-κBを消去した細胞では、E2F1を導入してもアポトーシス感受性の亢進が認めちれなかった。この結果から、E2F1によるアポトーシス感受性の亢進にはNF-κBが関わると考えられた。これらの結果から、E2F1は細胞内にROSを蓄積させ、DNAダメージやJNK、p38MAPKの活性化を介して、細胞のアポトーシス感受性を亢進させると考えられた(論文投稿中)。

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/RAR α 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. 263-273 (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-terminaJly truncated histone H2A-monoubiquitin conjugates from leukemic 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

E2F1による細胞内ROSの蓄積及び癌抑制機構の解析

Principal Investigator

松村 到 大阪大学, 医学系研究科, 助教授 (00294083)

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/RAR α 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. 263-273 (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-terminaJly truncated histone H2A-monoubiquitin conjugates from leukemic 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)

松村到大阪大学, 医学系研究科, 助教授 (00294083)