The stabilization mechanism of mutant-type p53 by impaired ubiquitination: The loss of wild-type p53 function and the hsp90 association

Yoichi Nagata, Tadashi Anan, Tetsuo Yoshida, Tamio Mizukami, Yoichi Taya, Toshiyoshi Fujiwara, Hirohisa Kato, Hideyuki Saya, Mitsuyoshi Nakao

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Mutant-type p53 (mt p53) is largely accumulated in cancer cells due to its increased stability. To elucidate the mechanism of mt p53 stabilization, we analysed the turnover of p53 mutated at codon 248 whose alteration is most frequently found in human cancers. Proteasome inhibition induced the accumulation of ubiquitinated mt p53, indicating that the ubiquitinated forms were essentially unstable and degraded by the proteasome. The presence of a small amount of the ubiquitinated mt p53 relative to the abundant non-ubiquitinated form suggested that the mt p53 ubiquitination was a rate-limiting process in the slow turnover. Two phenomena destabilizing mt p53 via the ubiquitin-proteasome degradation were proved to be independent. First, the coexpression of wild-type p53 (wt p53) promoted mt p53 destabilization as feedback regulation. Second, geldanamycin also induced mt p53 destabilization through the dissociation of the protein from hsp90 but not through the restoration of wt p53 function. Neither the mutant-specific conformation nor the N-terminal phosphorylation seemed to contribute directly to the mt p53 stabilization. Further, a two-dimensional gel electrophoresis revealed that most of the post-translationally modified mt p53 was equally subjected to ubiquitination and subsequent proteasomal degradation. These findings are that mt p53 stabilization depends on the ubiquitination due to both the loss of wt p53 function and the hsp90 association.

Original languageEnglish
Pages (from-to)6037-6049
Number of pages13
JournalOncogene
Volume18
Issue number44
DOIs
Publication statusPublished - Oct 28 1999

Keywords

  • Conformation
  • Phosphorylation
  • Ubiquitin-proteasome
  • hsp90
  • mdm2
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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