The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library

Tomohiro Kawaguchi, Shunsuke Kato, Kazunori Otsuka, Gou Watanabe, Toshihiro Kumabe, Teiji Tominaga, Takashi Yoshimoto, Chikashi Ishioka

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Tumor suppressor p53 forms a homo-tetramer through its COOH-terminal oligomerization domain and acts as a sequence-specific transcription factor. We have analysed the interrelation among the transcriptional activities, the structure and the cancer-related mutations in the oligomerization domain by using a comprehensive missense mutation library. Here, we examined the ability of 184 mutant p53s in the domain to form an oligomer by expressing these mutant p53s in yeast, and compared the data with the previous information. We showed that specific residues in the α-helix and the β-strand of the oligomerization domain were critical for both oligomer formation and sequence-specific transactivation, and the activities were closely related. In particular, the α-helix was more sensitive to amino-acid substitutions than the β-strand. We found identity in the interrelation between the two activities, that is, monomer mutants were transcriptionally inactive whereas dimer and tetramer mutants retained their transcriptional activities. In TP53 mutation databases, a small number of mutations have been reported in this domain. Surprisingly, most do not encode p53s defective in functional properties. These results indicate that, although oligomer formation is essential for p53 transactivation function, the inactivation of oligomer formation and therefore the inactivation of transactivation may not be essential for tumor suppression by p53 because they do not lead to oncogenic proteins.

Original languageEnglish
Pages (from-to)6976-6981
Number of pages6
JournalOncogene
Volume24
Issue number46
DOIs
Publication statusPublished - 2005 Oct 20

Keywords

  • Oligomerization
  • Transactivation
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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