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Mechanism of Functional Switching of C-MYC: Formation of Different Protein Complexes and Expression of Activities in DNA Replication, Transcription and Apoptosis Induction during the Cell Cycle.

Research Project

Project/Area Number 10044226
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

ARIGA Sanae  Hokkaido Univ., Coll. Med. Technol., Prof., 医療技術短期大学部, 教授 (90184283)

Co-Investigator(Kenkyū-buntansha) KITAURA Hirotake  Hokkaido Univ., Grad. School Pharm. Research Associate, 大学院・薬学研究科, 助手 (10281817)
ARIGA Hiroyoshi  Hokkaido Univ., Grad. School Pharm. Sci.., Prof., 大学院・薬学研究科, 教授 (20143505)
GALLI Ivo  ベルン大学病院, 研究員
RUSCONI Sand  フリブール大学, 教授
WANG Teresa  スタンフォード大学, 医学センター, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsC-MYC / MSSP / AMY-1 / MM-1 / ORC1 / transcriptional regulation / spermatogenesis / tumor suppressor / トランスフォーメイション / 癌抑制遺伝子
Research Abstract

C-MYC has been suggested to be involved in cell proliferation, differentiation, transformation and apoptosis. We supposed that C-MYC plays such kaleidoscopic functions in partnership with various proteins. Besides the reported Max family proteins forming dimers with C-MYC via the basic helix-loop-helix leucine-zipper structure (bHLHZip) in the C-terminal region of C-MYC, we have screened proteins which interacts with C-MYC via the myc boxes, well-conserved among the myc family, in the N-terminal region. We applied the yeast two-hybrid system in the screening and have obtained several novel partner proteins including AMY-1 and MM-1 as well as reported proteins, CBF/NF-Y, ORC1, CDC6 and cdk inhibitor p21. MSSP, which we have also identified as a C-MYC binding protein, recognized the myc boxes. These proteins were examined for their functions both in vitro and in vivo and were classified to the categories including factors for transcription (AMY-1, MM-1 and CBF/NF-Y), DNA replication (MSS … More P, ORC1 and CDC6) and cell-cycle movement (p21). As for the transcriptional activity of C-MYC, only AMY-1 acted as a positive regulatory factor while the others, MM-1 and CBF/NF-Y, were negative factors. AMY-1 induced the erythrocyte differentiation of K562 cells. Male transgenic mice of the AMY-1 gene were sterile and the RII domain of AKAP-84, the binding site of the regulatory subunit of A-kinase which is important in spermatogenesis, was cloned as a AMY-1 binding protein. AMY-1 was thus suggested to inhibit the appropriate localization of the A-kinase and to induce apoptosis of spermatogenic cells. In addition, AMY-1 was found to bind to WAVE/AKAP-149, a factor involved in actin polimerization. MM-1 has a character for putatice tumor suppressor. The substitution of the amino acid #157 of MM-1 from alanine to arginine was frequently observed in the cells and tissues of lymphoma, leukemia and tongue cancer. The arginine mutation abrogated the negative effects of MM-1 on C-MYC. ORC1, a remodeling factor of chromatin, bound to C-MYC competitively with SNF5, an MSSP family protein, to release C-MYC from chromatin. Null-mutation of MSSP tended to be lethal during developmental stage. These findings altogether suggest that C-MYC binding proteins play roles at crucial steps of cell maturation, fertilazation in addition to the modulation of versatile functions of C-MYC. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Taira T.: "Cell cycle-dependent switch of up- and down-regulation of human hsp70 gene expression by interaction between c-Myc and CBF/NF-Y"J.Biol.Chem.. 274. 24270-24279 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Niki T.: "MSSP promotes the ras/myc cooperative cell transforming activity by binding to C-MYC"Genes Cells. 5. 127-140 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitaura H.: "Reciprocal regulation via protein-protein interaction between c-Myc and p21cipl/wafl/sdi1 in DNA replication and transcription"J.Biol.Chem.. 275(in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujimoto M.: "Structure and comparison of genomic and complementary DNAs of mouse MSSP, a c-Myc binding protein"Int.J.Onc.. 16. 245-251 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Furusawa M.: "AMY-1 is a trigger for the erythrocyte differentiation of K562 cells"Int.J.Onc.. 16. 339-345 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takayama M.: "ORC1 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc-SNF5/INT1 interaction"Genes Cells. 5(in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Taira, T., Maeda, J., Onishi, T., Kitaura, H., Yoshida, S., Kato, H., Ikeada, M., Tamai, K., Iguchi-Ariga, S. M.M. and Ariga, H.: "AMY- 1, a novel C-MYC binding protein that stimulates transcriptional activity of C-MYC."Genes Cells. 3. 551-567 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujimoto, M., Iguchi-Ariga, S.M.M. and Ariga, H.: "Characterization of an element positively regulating the transcription of MSSP gene-2 which encodes C-MYC binding proteins."Gene. 214. 113-120 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mori, K., Maeda, Y., Kitaura, H., Taira, T., Iguchi-Atiga, S.M.M. and Atiga, H.: "MM-1, a novel C-MYC associating protein which represses transcriptional activity of C-MYC."J. Biol. Chem.. 273. 29794-29800 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Taira, T., Sawai. M., Ikeda, M., Talnai, K., Iguchi-Ariga, S.M.M. and Ariga, H.: "Cell cycle-dependent switch of up- and down-regulation of human hsp70 gene."J. Biol. Chem.. 274. 24270-24279 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Niki, T., Izumi. S., Saegusa, Y., Taira, T., Takai. T., Iguchi-Ariga, S.M.M. and Ariga, H.: "MSSP promotes the ras/myc cooperative cell transforming activity by binding to C-MYC."Genes Cells. 5. 127-140 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitaura, H., Shinshr, M., Uchikoshi, Y., Ono, T., Tsurimoto. T., Yoshikawa, H., Iguchi-Ariga, S.M.M. and Ariga, H.: "Reciprocal regulation via protein-protein interaction between C-MYC and p21cipl/waf1/sdi1 in DNA ' replication and transcription."J. Biol. Chem.. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujimoto, M., Matsumoto, K., Iguchi-Ariga, S.M.M. and Atiga, H.: "Structure and comparison of genomic and complementary D As of mouse MSSP, a c-Myc binding protein."Int. J. Oncol.. 16. 245-251 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Furusawa, M., Onishi, T., Taira, T., Iguchi-Ariga, S. M.M. and Ariga, H.: "AMY is a trigger for the erythrocyte differentiation of K562 ceils."Int. J. Oncol.. 16. 339-345 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Koike, N., Maita, H., Taira, T., Ariga, H. and Iguchi, Ariga, S.M.M.: "Identification of heterochromotin protein 1 (HP 1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation the transaiptional repression function of HP1."FEBS Lett.. 467. 17-21 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Taira, T.: "Cell cycle-dependent switch of up- and down-regulation of human hsp70 gene expression by interaction between c-Myc and CBF/NF-Y"J. Biol. Chem.. 274. 24270-24279 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Niki, T.: "MSSP promotes the ras/myc cooperative cell transforming activity by binding to C-MYC"Genes Cells. 5. 127-140 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitaura, H.: "Reciprocal regulation via protein-protein interaction between c-Myc and p21cip1/waf1/sdi1 in DNA replication and transcription"J. Biol. Chem.. 275. in press (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujimoto, M.: "Structure and comparison of genomic and complementary DNAs of mouse MSSP, a c-Myc binding protein"Int. J. Onc.. 16. 245-251 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Furusawa, M.: "AMY-1 is a trigger for the erythrocyte differentiation of K562 cells"Int. J. Onc.. 16. 339-345 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayama, M.: "ORC1 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc-SNF5/INT1 interaction"Genes Cells. 5(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mori,K: "MM-1,a novel C-MYC associating protein which represses transcriptional activity of C-MYC" J.Biol.Chem.273. 29794-29800 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ikuta,T.: "Structural analysis of mouse tenascin-X:Evolutionary aspects of reduplication of FNIII repeats in the tenascin gene family" Gene. 217. 1-13 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kimura,K.: "c-Myc gene single-strand binding protein-1,MSSP-1,suppresses transcription of a-smooth muscle actin gene in chicken visceral smooth muscle cells" Nucleic Acids Res.26. 2420-2425 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujimoto,M.: "Characterization of an element positively regulating the transcription of MSSP gene-2 which encodes C-MYC binding proteins." Gene. 214. 113-120 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taira,T.: "AMY-1,a novel C-MYC binding protein that stimulates transcriptional activity of C-MYC" Genes Cells. 3. 551-567 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tsuchiya,T.: "Ku antigen binds to Alu family DNA" J.Biochem.123. 120-127 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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