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転写因子PEBP2と白血病発症の機序

Research Project

Project/Area Number 06280214
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionKyoto University

Principal Investigator

伊藤 嘉明  京都大学, ウイルス研究所, 教授 (80004612)

Co-Investigator(Kenkyū-buntansha) 菅野 智彦  京都大学, ウイルス研究所, 助手 (10273525)
丸山 光生  京都大学, ウイルス研究所, 助手 (00212225)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 1996: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1995: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1994: ¥15,000,000 (Direct Cost: ¥15,000,000)
KeywordsPEBP2 / 染色体転座 / 白血病 / 遺伝子破壊 / difinitive hematopoiesis / Ets-1 / 転写因子 / contextdependent / α及びβサブユニット / 転写活性化ドメイン / Ets / AML1 / ETO(MTG8) / β / SMMHC / t(8;21) / inv(16) / 核移行シグナル / MTG8(ETO)キメラたんぱく / MYHIIキメラたんぱく / T細胞特異的遺伝子発現 / PEBP2αC
Research Abstract

染色体転座によって起こるPEBP2のαおよびβサブユニットの構造変化が白血病原性の基になっている。そして構造異常を起こしたPEBP2は正常のPEBP2結合領域に結合する。このことは正常のPEBP2が生理的条件下でターゲットとしている遺伝子の発現制御が転座の結果脱制御を受けることを意味する。この観点から必ず正常のPEBP2の基本的性質を明かにすること、及びそれがターゲットとしている遺伝子の同定が急務である。我々は先ず野田哲生(癌研)、佐竹正延(東北大・加齢研)との共同研究でAML1/PEBP2αB(PEBP2のαサブユニットをコードする遺伝子)とPEBP2β(βサブユニットをコードする遺伝子)の破壊実験を行なった。その結果、両方の対立遺伝子を失ったそれぞれのマウスは全く同一の表現型を示し、α、βサブユニットがin vivoで確かに一緒に機能していることが証明された。そしてPEBP2は2段階で起こる造血のプロセスのうち、primitive hematopiesisには全く関与せず、difinitive hematopoiesis(成人における造血)の最も初期のプロセスに必須で、遺伝子破壊マウスでは血液細胞はどの種類も生成されなかった。
続いてPEBP2とEts-1の共同作用を解析し、AML1の2ケ所がEts-1の2ケ所と独立に相互作用し、Ets-1のDNA結合ドメインを"open"することによりこれら2種の蛋白がDNA結合のための共同作用を行なうことを明かにした。

Report

(3 results)
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Ito,K.: "c-Jun stimulates origin-dependent DNA unwinding by polyomavirus large T antigen." EMBO J.15. 5636-5646 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ito,Y & Bae,S.C.: "The Runt domain transcription factor,PEBP2/CBF,and its involvement in human leukemia." Progress in Gene Expression. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Ito,Y.: "Structural alterations of a transcription factor PEBP2/CBF linked to 4 different types of leukemia." J.Cancer Res.Alin.Oncol.122. 266-274 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kagoshima,H.: "Functional dissection of the α and β subunits of transcription factor PEBP2 and the Redox susceptibility of its DNA binding activity." J.Biol.Chem.271. 33074-33082 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ahn,M.-Y.: "Comparison of the human genomic structure of the Runt domain-encoding PRBP2/CBFα gene family." Gene. 168. 279-280 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ito, Y.: "Structural alterations of a transcription factor PEBP2/CBF linked to 4 different types of leukemia." J. Cancer Res. Clin. Oncol.(in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Ahn, M. -Y.: "Comparison of the human genomic structure of the Runt domain-encoding PEBP2/CEFα gene family." Gene. (in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Takahashi, A.: "Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2." Blood. 86. 607-616 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Bae, S. C.: "Cloning, mapping and expression of PEBP2αC, a third gene encoding the mammalian Runt domain." Gene. 159. 245-248 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Lu, J.: "Subcellular localization of the α and β subunits of the acute myeloid leukemia-linked transcription factor PEBP2/CBF." Mol. Cell. Biol.15. 1651-1661 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Satake, M.: "Expression of the Runt domain-coding PEBP2α genes in T cell during thymic development." Mol. Cell. Biol.15. 1662-1670 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Watanabe, S.: "Granulocyte macrophage-colony stimulating factor-dependent replication of polyoma virus replicon in hematopoietic cells." J. Biol. Chemi.270. 9615-9621 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takahashi,A.: "Positive and negative regulation of granulocyte-macrophage colony-stimulating factor(FM-CSF) promoter activity by AML1-related transcription factor,PEBP2." Blood. (in press). (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Sakakura,C: "Growth inhibition and induction of differentiation of t(8;21)acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisense oligonucletide." Proc.Natl.Acad.Sci.USA. 91. 11723-11727 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Bae,S.-C.: "PEBP2αB/mouse AML1 consists of multiple isoforms that possess differential transactivation potentials." Mol.Cell.Biol.14. 3242-3252 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kanda,T.: "Stimulation of polyomavirus DNA replication by wild-type p53 through the DNA binding site." Mol.Cell.Biol.14. 2651-2663 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Inuzuka,M: "The viral and cellular Rel oncoproteions induce the differentiation of P19 embryonal carcinoma cells." Oncogene. 9. 133-140 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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