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Cross-talks between ETS and GFI family of transcription factors in hematopoietic cell differentiation

Research Project

Project/Area Number 17591019
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionHealth Sciences University of Hokkaido (2006)
Sasaki Institute (2005)

Principal Investigator

OIKAWA Tsuneyuki  Medical Genetics, Dept. of Communication Disorders, Professor, 心理科学部, 教授 (80150241)

Co-Investigator(Kenkyū-buntansha) KIHARA Fumiko (NEGISHI Fumiko)  Department of Pharmacology, Teikyo University, Lecturer, 薬学部・臨床薬学, 講師 (40177902)
OHTA Toru  Inst. of Personalized Medicine, Associate Professor, 個体差健康科学研究所, 准教授 (10223835)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordstranscription factors / ETS / Ets-1 / PU.1 / Gfi-1 / GfilB / cross-talk / apoptosis / hematopoiesis / Gfi-1 / bax / アポトーシス / 血球分化
Research Abstract

The protooncogene Ets-1 and growth factor independent-1 (Gfi-1) are implicated in cell growth and differentiation in various types of cells, and their deregulated expression is involved in malignant formation. We found that Ets-1 and Gfi-1 interacted and affected gene expression through their cross-talk. Co-immunoprecipitation analysis and glutathione-S-transferase (GST) pull-down assay revealed that Ets-1 bound directly to Gfi-1 via its Ets domain, and Gfi-1 bound to Ets-1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reports showed that Gfi-1 repressed Ets-l-mediated transcription activation and Ets-1 repressed Gfi-l-mediated transcriptional activation. However, in the bax promoter where the Ets-and Gfrbinding sites (EBS and GBS) are adjacent, Ets-1 and Gfi-1 cooperatively reduced activation. Site-directed mutagenesis on the EBS and GBS of the bax promoter showed that both binding sites were necessary for full repression. Chromatin immunoprecipitation analyses … More confirmed that an Ets-1-Gfi-1 complex formed on the bax promoter even when either EBS or GBS was mutated. Introduction of small interfering RNA against Ets-1 and/or GE-1 enhanced endogenous bax gene expression. Our results suggest that the interaction between ETs-1 and Gfi-1 facilitates their binding to specific sites on the bax promoter and repress bax expression in vivo. PU.1 is a mater regulator for myeloid development and Gfi-1B is a hematopoietic transcription factor essential for growth and differentiation of the erythroid/megakaryocytic lineages. We found that PU.1 interacted with Gfi-1B in vivo by immunoprecipitation assay. GST pull-down assay showed that the binding sites were in the Ets domain of PU.1 and the zinc finger domain of Gfi-1B. Luciferase reporter assays revealed that PU.1 and Gfi-1B antagonized each other's transcriptional activity in a dose dependent manner. Transduction of Gfi-1B in mouse early myeloid progenitor cells showed that expression of Mac-1 was reduced, although this reduction was not too strong to inhibit PU.1-induced myeloid differentiation completely. Furthermore, transduction of PU.1 with Gfi1B in human cord blood hematopoietic progenitors significantly inhibited growth and colony formation of erythroid cells which were strongly enhanced by transduction of Gfi-lb alone. Co-expression of Gfi-1B with a mutant PU.1 deleted at the N-terminus and the 133/134 region of the Ets domain (PU. lANA133/34), which did not bind to GATA-1 but still bound to Gfi-1B, also inhibited GFi-1B-induced erythroid colony formation. Our results suggest that PU.1 inhibit growth and differentiation of erythroid cells by blocking GFi-1B function as well as by blocking GATA-1 function. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (21 results)

All 2007 2006 2005 Other

All Journal Article (20 results) Book (1 results)

  • [Journal Article] Cooperative interaction between ETS1 and GFI1 transcription factors in the repression of Bax gene expression2007

    • Author(s)
      Nakazawa Y, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene 26(in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Negative cross-talk between hematopoietic transcription factors PU.1 and Gfi-1B2007

    • Author(s)
      Manabe N, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene (subumitted)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cooperative interaction between ETSl and GFI1 transcription factors in the repression of Bax gene expression2007

    • Author(s)
      Nakazawa Y, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene 26

      Pages: 3541-3550

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Cooperative interaction between ETS1 and GFI1 transcription factors in the repression of Bax gene expression2007

    • Author(s)
      Nakazawa Y, Oikawa T. et al.
    • Journal Title

      Oncogene 26 (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b2006

    • Author(s)
      Suzuki M, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene 25

      Pages: 2477-2488

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Site-specific DNA methylation by a complex of PU.l and Dnmt3a/b2006

    • Author(s)
      Suzuki M, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene 25

      Pages: 2477-2488

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b2006

    • Author(s)
      Suzuki M, Oikawa T. et al.
    • Journal Title

      Oncogene 25

      Pages: 2477-2488

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ets family of transcription factors in normal hematopoiesis and in leukemogenesis2005

    • Author(s)
      Oikawa T, Kihara-Negishi F. et al.
    • Journal Title

      Molecular Genetics of Cancer Book

      Pages: 119-148

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Classification of neural differentiation-associated genes in P19 embryonic carcinoma cells2005

    • Author(s)
      Teramoto S, Oikawa T, et al.
    • Journal Title

      Oncol. Rep. 14

      Pages: 1231-1238

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Impaired repressor activity and biological functions of PU. 1 in MEL cells induced by mutations in the acetylation motif2005

    • Author(s)
      Kihara=Negishi F, Oikawa T. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 335

      Pages: 477-484

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ets family of transcription factors in normal hematopoiesis and in leukemogenesis (Review)2005

    • Author(s)
      Oikawa T, Kihara-Negishi F. et al.
    • Journal Title

      In "Molecular Genetics of Cancer".(ed by Sinnet D.)( Research Signpost, India)

      Pages: 119-148

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Classification of neural differentiation-associated genes in P19 embryonic carcinoma cells2005

    • Author(s)
      Teramoto S, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncol. Rep. 14

      Pages: 1231-1238

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Impaired repressor activity and biological functions of PU.1 in MEL cells induced by mutations in the acetylation motif2005

    • Author(s)
      Kihara=NeEgishi F, Oikawa T. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 335

      Pages: 477-484

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ets transcription factors : Possible targets for cancer therapy (Japanese Review)2005

    • Author(s)
      Oikawa T.
    • Journal Title

      In "Basic and Clinical approaches for molecular target therapy"(ed. by Tsuruo T. et al.)(Shinoharashinnsha Ltd. Tokyo)

      Pages: 41-53

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ets family of transcription factros in normal hematopoiesis and in leukemogenesis.2005

    • Author(s)
      Oikawa T, Yamada T, Kihara-Negishi F, Sakurai T.
    • Journal Title

      Molecular Genetics of Cancer Research Signpost

      Pages: 119-148

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Classification of neural differentiation-associated genes in P19 embryonal carcinoma cells by their expression patterns induced after cell aggregation and/or retinoic acid treatment.2005

    • Author(s)
      Teramoto S, Kihara-Negishi F, Sakurai T, Yamada T, Oikawa Y.
    • Journal Title

      Oncol.Rep. 14

      Pages: 1231-1238

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b.2005

    • Author(s)
      Suzuki M, Yamada T, Kihara-Negishi F, Tenen DG, Hozumi N, Oikawa T.
    • Journal Title

      Oncogene

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Impaired repressor activity and biological functions of PU.1 in MEL cells induced by mutations in the acethylation motifs within the ETS domain.2005

    • Author(s)
      Kihara-Negishi F, Suzuki M, Yamada T, Sakurai T, Oikawa T.
    • Journal Title

      Biochem.Biophys.Res.Com. 335

      Pages: 477-484

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Negative cross-talk between hematopoietic transcription factors PU.1 and GFi-lB

    • Author(s)
      Manabe N, Kihara-Negishi F, Oikawa T. et al.
    • Journal Title

      Oncogene, submitted

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Negative cross-talk between the hematopoietic transcription factors PU.1 and Gfi-1B

    • Author(s)
      Manabe N, Oikawa T. et al.
    • Journal Title

      Oncogene (submitted)

    • Related Report
      2006 Annual Research Report
  • [Book] 分子標的療法の基礎と臨床(分担 : ETS転写因子を標的としたがんの治療(p.41-53)2005

    • Author(s)
      及川恒之(分担執筆)
    • Total Pages
      281
    • Publisher
      篠原出版新社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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