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2004 Fiscal Year Final Research Report Summary

Design and development of tumor suppressor protein p53 variant that cannot form heterooligomers with the wild-type protein

Research Project

Project/Area Number 14380290
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionHOKKAIDO UNIVERSITY (2003-2004)
Kyushu University (2002)

Principal Investigator

SAKAGUCHI Kazuyasu  Hokkaido Univ., Grad.School of Sci., Prof., 大学院・理学研究科, 教授 (00315053)

Co-Investigator(Kenkyū-buntansha) SHIMOHIGASHI Yasuyuki  Kyushu Univ., Fac.of Sci., Prof., 大学院・理学研究院, 教授 (00211293)
CHUMAN Yoshiro  Hokkaido Univ., Grad.School of Sci., Inst., 大学院・理学研究科, 助手 (40372263)
Project Period (FY) 2002 – 2004
Keywordsheterooligomer / combinatorial library / peptide / dominant negative / tumor suppressor protein
Research Abstract

The tumor suppressor protein p53 is a 393 amino acid phosphoprotein that is a transcriptional enhancer in tetrameric form and suppresses cell cycle progression in response to genotoxic stress. The tetramerization domain of p53 is essential for efficient site-specific DNA binding and contributes to p53's ability to activate transcription from natural promoters. The p53 tetramerization domain is located at residues 326-356. More than 50% of human cancer is associated with p53 gene mutation, which is mostly located at sequence specific DNA binding domain. The missense mutant p53 inactivates a wild-type p53 in a dominant-negative manner via hetero-oligomerization.
In this study, we designed and synthesized two peptide libraries of the 40 amino acid p53 tetramerization domain to screen peptides that cannot form hetero-oligomer with the wild-type p53. For the first library, termed p53lib-4, four hydrophobic residues, which are located on the α-helix at the interface of two dimers, were randomized with seven hydrophobic amino acids including Tip, Tyr, Phe, Met, Lew, Ire, and Val. In the second library, p53lib-9, all nine residues that form the hydrophobic core of p53 tetramer were randomized in the same way. Two peptide libraries were screened for non-heterooligomerizing peptides with the wild-type sequence. The screened fraction showed the almost identical CD spectrum, indicating that peptides in the fraction could form a wild-type tetrameric structure. Second library was designed by characterization of the screened peptides on the first screening. The library was subjected for second screening. The results indicated that a peptide fraction isolated by this screening could contain peptides that form homo-tetramers by themselves and do not form hetero-oligomers with wild type. The results demonstrated that the strategy used in this study could be applied to screen peptide that does not form hetero-oligomers.

  • Research Products

    (27 results)

All 2005 2004 2003 2002

All Journal Article (27 results)

  • [Journal Article] Effects of mutation and modification on tetramer formation of tumor suppressor protein p53.2005

    • Author(s)
      Sakaguchi, K.
    • Journal Title

      Peptide Science 2004

      Pages: 17-20

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mechanism of amyloid-like fibrillar aggregation of mutant peptide of p53 tetramerization domain.2005

    • Author(s)
      Asanomi, Y.
    • Journal Title

      Peptide Science 2004

      Pages: 313-316

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] DNA binding of peptide with single helix-hairpin-helix motif.2005

    • Author(s)
      Yamamoto, T.
    • Journal Title

      Peptide Science 2004

      Pages: 517-520

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Stability and folding mechanism for Trp-contaning peptides of p53 tetramerization domain.2005

    • Author(s)
      Kasai, Y.
    • Journal Title

      Peptide Science 2004

      Pages: 419-422

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Charactarization of superstable variant peptide of human p53 tetramerization domain.2005

    • Author(s)
      Nomura, T.
    • Journal Title

      Peptide Science 2004

      Pages: 423-426

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Thr-774 (Transmembrane Segment M5), Val-920 (M8), and Glu-954 (M9) Are Involved in Na^+ Transport, and Gln-923 (M8) Is Essential for Na,K-ATPase Activity.2005

    • Author(s)
      Imagawa, T.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 18736-18744

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Charactarization of superstable variant peptideof human p53 tetramerization domain.2005

    • Author(s)
      Nomura, T.
    • Journal Title

      Peptide Science 2004

      Pages: 423-426

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Thr-774 (Transmembrane Segment M5), Val-920 (M8), and Glu-954 (M9) Are Involved in Na+ Transport, and Gln-923 (M8) Is Essential for Na,K-ATPase Activity.2005

    • Author(s)
      Imagawa, T.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 18736-18744

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Destabilization and oligomer formation of p53 tetramer mutant associated with human lung carcinoma.2004

    • Author(s)
      Higashimoto, Y.
    • Journal Title

      Peptide Science 2003

      Pages: 17-20

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Localization profiles of circadian neuropeptide PDF in brain of the cricket Gryllus Bimaculatus.2004

    • Author(s)
      Honda, T.
    • Journal Title

      Peptide Science 2003

      Pages: 81-84

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Specific affinity labeling of Cys60 in the _opioid receptor by Npys-containing dynorphin A analog.2004

    • Author(s)
      Isozaki, K.
    • Journal Title

      Peptide Science 2003

      Pages: 273-276

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hetero-oligomer formation of peptides derived from tetramerization domain in tumor suppressor protein p53.2004

    • Author(s)
      Sakaguchi, K.
    • Journal Title

      Peptide Science 2003

      Pages: 307-310

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Binding specificity of HhH motif peptide that recognizes DNA structure.2004

    • Author(s)
      Yamamoto, T.
    • Journal Title

      Peptide Science 2003

      Pages: 311-314

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mutant p53 peptide forms amyloid under physiological condition.2004

    • Author(s)
      Asanomi, Y.
    • Journal Title

      Peptide Science 2003

      Pages: 379-382

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Specific affinity labeling of Cys60 in the δ opioid receptor by Npys-containing dynorphin A analog.2004

    • Author(s)
      Isozaki, K.
    • Journal Title

      Peptide Science 2003

      Pages: 273-276

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Specific affinity of delta opioid receptors via thiol-disulfide exchange reaction.2003

    • Author(s)
      Fukahori, H.
    • Journal Title

      Peptide Science 2002

      Pages: 257-260

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Phosphorylation site-specific monoclonal antibody recognizing Ser(P)-Gln sequence.2003

    • Author(s)
      Sakaguchi, K.
    • Journal Title

      Peptide Science 2002

      Pages: 439-442

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Localization profiles of the precursor protein of circadian rhythm pacemaker hormone PDF in Gryllus brain.2003

    • Author(s)
      Honda, T.
    • Journal Title

      Peptide Science 2002

      Pages: 433-436

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Phosphorylation site-specific monoclonal antibody recognizing Ser(P)-Gin sequence.2003

    • Author(s)
      Sakaguchi, K.
    • Journal Title

      Peptide Science 2002

      Pages: 439-442

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effect of phosphorylation on the structure and fold of transactivation domain of p532002

    • Author(s)
      Kar, S.
    • Journal Title

      J.Biol.Chem. 277

      Pages: 15579-15585

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Structural Requirements of Nociceptin Antagonist Ac-RYYRIK-NH2 for Receptor Binding.2002

    • Author(s)
      Kawano M.
    • Journal Title

      J.Peptide Sci. 8

      Pages: 561-569

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Structural characterization of Phe residues in the p53 tetramerization domain.2002

    • Author(s)
      Sakaguchi, K.
    • Journal Title

      Peptide Science 2001

      Pages: 135-138

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Characteristic intra- and intermolecular interactions of dipeptide-chymotrypsin complex as specific structural essentials for enzyme2002

    • Author(s)
      Komada, A.
    • Journal Title

      Peptide Science 2001

      Pages: 179-182

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Structure-activity studies on the nociceptin peptidic antagonist Ac-RYYRIK-NH2.2002

    • Author(s)
      Kawano, M.
    • Journal Title

      Peptide Science 2001

      Pages: 185-188

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Localization profiles of the precursor protein of circadian rhythm pacemaker hormone PDF in Gryllus brain.2002

    • Author(s)
      Honda, T.
    • Journal Title

      Peptide Science 2002

      Pages: 15579-15585

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Effect of phosphorylation on the structure and fold of transactivation domain of p53.2002

    • Author(s)
      Kat, S.
    • Journal Title

      J.Biol.Chem. 277

      Pages: 15579-15585

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Characteristic intra-and intermolecular interactions of dipeptide-chymotrypsin complex as specific structural essentials for enzyme inhibition.2002

    • Author(s)
      Komada, A.
    • Journal Title

      Peptide Science 2001

      Pages: 179-182

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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