1996 Fiscal Year Annual Research Report

P53欠失マウスにおける造血因子およびTGFβを介したシグナル伝達

Research Project

Project/Area Number	08457079
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	国立衛生試験所
Principal Investigator	井上達国立衛生試験所, 安全性生物試験研究センター・毒性部, 部長 (50100110)
Co-Investigator(Kenkyū-buntansha)	梅村隆志国立衛生試験所, 安全性生物試験研究センター・毒性部, 主任研究官 (50185071) 高木篤也国立衛生試験所, 安全性生物試験研究センター・毒性部, 主任研究官 (00179417) 平林容子国立衛生試験所, 安全性生物試験研究センター・毒性部, 主任研究官 (30291115) 佐々木秀樹横浜市立大学, 医学部, 助教授 (50106316)
Keywords	P53欠失マウス / サイトカイン / TGFβ / 骨髄造血前駆細胞
Research Abstract	本研究は培養造血幹細胞および高増殖性造血幹細胞(HPP-CFU)のサイトカイン依存性の増殖制御に対するTGFbとP53の関与を明らかにすることを目的としており、以下に実績の概略を示す。 TGFbは上皮系細胞においてサイクリン依存性キナーゼ(Cdk)の抑制因子の一つp15をup-regulateする事により、また、野生型p53はCdkの抑制因子のうちp21の転写を亢進させることにより、それぞれ細胞回転を抑制する事が知られている。これらp53とTGF-bのシグナルの連関の有無は、p53遺伝子欠失(KO)マウスを用いることで解析出来るものと考え、p53KOマウス骨髄造血前駆細胞のTGF-bに対する反応性を検討した。まず野生型マウスの骨髄造血前駆細胞では、高増殖性前駆細胞(HPP-CFC:5FU投与後骨髄細胞のSCF+mIL-3添加培養14日目に肉眼観察できる大型コロニー(径0.5mm以上)形成前駆細胞)で、TGF-βの濃度依存性に抑制が認められた(1ng/ml添加でほぼ100%)。また分化型コロニー形成細胞では、rmMPO刺激によるコロニー(CFU-Mk)形成が抑制されたが、従前の報告とは異なりrhEPO,rmGM-CSF,rmIL-3刺激依存性コロニー形成にはいずれも抑制効果がみられなかった。以上に対しp53KOマウス骨髄細胞由来HPP-CFCでは、TGF-bを添加してもコロニー形成に対する抑制効果は少なかった(1ng/ml添加で34%)。しかしCFU-Mkは野生型の対照同様に抑制された。このことは、造血前駆細胞の分化に応じて細胞内シグナル伝達の経路が変わる可能性を示唆する結果と考えた。

Research Products
(12 results)

All Other

All Publications (12 results)

[Publications] Inoue T: "Lifetime treatment of mice with AZT produces myelodysplasia." Leukemia. (in press).
[Publications] Trosko JE: "Oxidative stress,signal transduction and intercellular communication in radiation carcinogenesis." Proceedings of International Symposium on "Biological Effects of Radiation Injury". (in press).
[Publications] Hirabayashi Y: "The p53-deficient hemopoietic stem cells : Their resistance to radiatioin-papooses,but lasted transiently." Leukemia. (in press).
[Publications] Yoshida K: "Radiatioin-induced myeloid leukemia in mice under calorie restriction." Leukemia. (in press).
[Publications] Yoshida K: "Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice." Pro Natl Acad Sci,USA. 94. 2515-2519 (1997)
[Publications] Sasaki H: "A fraction unresponsive to growth inhibition by TGF-β among the high-proliferative potential progenitor cells in bone marrow of p53-deficient mice." Leukemia. 11. 239-244 (1997)
[Publications] Nishimura Y: "In vivo analysis of Fas antigen-mediated apoptosis : Effects of agonistic anti-mouse Fas monoclonal antibody on thymus,spleen,and liver." Int Immunol. 19(in press). (1997)
[Publications] Kabaya K: "Effects of recombinant human granulocyte colony-stimulating factor on the growth potential of two murine myeloid leukemias." Leuk Res. 20. 27-35 (1996)
[Publications] Nomura M: "In vivo induction of cytotoxic T lymphocytes specific for a single epitope introduced into an unrelated molecule." J Immunol Methods. 193. 41-49 (1996)
[Publications] Itoh T: "Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling." J Biol Chem. 271. 7578-7592 (1996)
[Publications] Muto A: "The beta subunit of human granulocyte-macrophage colony-stimulating factor receptor forms a homodimer and is activated via association with the alpha subunit." J Exp Med. 183. 1911-1916 (1996)
[Publications] Frith CH: "In : Stromberg PC,Ward JM,and Frith CH (eds.) Proliferaive Lesions in the Mouse Hematopoietic syetem,Springer Verlag,NY." Proliferative lesions of the hematopoietic syetem in mice.(in press),

1996 Fiscal Year Annual Research Report

P53欠失マウスにおける造血因子およびTGFβを介したシグナル伝達

Principal Investigator

井上 達 国立衛生試験所, 安全性生物試験研究センター・毒性部, 部長 (50100110)

Research Products

[Publications] Inoue T: "Lifetime treatment of mice with AZT produces myelodysplasia." Leukemia. (in press).

[Publications] Trosko JE: "Oxidative stress,signal transduction and intercellular communication in radiation carcinogenesis." Proceedings of International Symposium on "Biological Effects of Radiation Injury". (in press).

[Publications] Hirabayashi Y: "The p53-deficient hemopoietic stem cells : Their resistance to radiatioin-papooses,but lasted transiently." Leukemia. (in press).

[Publications] Yoshida K: "Radiatioin-induced myeloid leukemia in mice under calorie restriction." Leukemia. (in press).

[Publications] Yoshida K: "Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice." Pro Natl Acad Sci,USA. 94. 2515-2519 (1997)

[Publications] Sasaki H: "A fraction unresponsive to growth inhibition by TGF-β among the high-proliferative potential progenitor cells in bone marrow of p53-deficient mice." Leukemia. 11. 239-244 (1997)

[Publications] Nishimura Y: "In vivo analysis of Fas antigen-mediated apoptosis : Effects of agonistic anti-mouse Fas monoclonal antibody on thymus,spleen,and liver." Int Immunol. 19(in press). (1997)

[Publications] Kabaya K: "Effects of recombinant human granulocyte colony-stimulating factor on the growth potential of two murine myeloid leukemias." Leuk Res. 20. 27-35 (1996)

[Publications] Nomura M: "In vivo induction of cytotoxic T lymphocytes specific for a single epitope introduced into an unrelated molecule." J Immunol Methods. 193. 41-49 (1996)

[Publications] Itoh T: "Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling." J Biol Chem. 271. 7578-7592 (1996)

[Publications] Muto A: "The beta subunit of human granulocyte-macrophage colony-stimulating factor receptor forms a homodimer and is activated via association with the alpha subunit." J Exp Med. 183. 1911-1916 (1996)

[Publications] Frith CH: "In : Stromberg PC,Ward JM,and Frith CH (eds.) Proliferaive Lesions in the Mouse Hematopoietic syetem,Springer Verlag,NY." Proliferative lesions of the hematopoietic syetem in mice.(in press),

井上達国立衛生試験所, 安全性生物試験研究センター・毒性部, 部長 (50100110)