mRNA display selection of an optimized MDM2-binding peptide that potently inhibits MDM2-p53 interaction

Hirokazu Shiheido, Hideaki Takashima, Nobuhide Doi, Hiroshi Yanagawa

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

p53 is a tumor suppressor protein that prevents tumorigenesis through cell cycle arrest or apoptosis of cells in response to cellular stress such as DNA damage. Because the oncoprotein MDM2 interacts with p53 and inhibits its activity, MDM2-p53 interaction has been a major target for the development of anticancer drugs. While previous studies have used phage display to identify peptides (such as DI) that inhibit the MDM2-p53 interaction, these peptides were not sufficiently optimized because the size of the phage-displayed random peptide libraries did not cover all of the possible sequences. In this study, we performed selection of MDM2-binding peptides from large random peptide libraries in two stages using mRNA display. We identified an optimal peptide named MIP that inhibited the MDM2-p53 and MDMX-p53 interactions 29- and 13-fold more effectively than DI, respectively. Expression of MIP fused to the thioredoxin scaffold protein in living cells by adenovirus caused stabilization of p53 through its interaction with MDM2, resulting in activation of the p53 pathway. Furthermore, expression of MIP also inhibited tumor cell proliferation in a p53-dependent manner more potently than DI. These results show that two-stage, mRNA-displayed peptide selection is useful for the rapid identification of potent peptides that target oncoproteins.

Original languageEnglish
Article numbere17898
JournalPLoS One
Volume6
Issue number3
DOIs
Publication statusPublished - 2011

Fingerprint

Display devices
peptides
Messenger RNA
Peptides
peptide libraries
Peptide Library
Bacteriophages
Oncogene Proteins
bacteriophages
Cells
scaffolding proteins
Tumor Suppressor Proteins
Thioredoxins
antineoplastic agents
Cell proliferation
Adenoviridae
Cell Cycle Checkpoints
Scaffolds
DNA damage
carcinogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

mRNA display selection of an optimized MDM2-binding peptide that potently inhibits MDM2-p53 interaction. / Shiheido, Hirokazu; Takashima, Hideaki; Doi, Nobuhide; Yanagawa, Hiroshi.

In: PLoS One, Vol. 6, No. 3, e17898, 2011.

Research output: Contribution to journalArticle

Shiheido, Hirokazu ; Takashima, Hideaki ; Doi, Nobuhide ; Yanagawa, Hiroshi. / mRNA display selection of an optimized MDM2-binding peptide that potently inhibits MDM2-p53 interaction. In: PLoS One. 2011 ; Vol. 6, No. 3.
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