Heat shock factor 1 deficiency via its downstream target gene αB-crystallin (Hspb5) impairs p53 degradation

Xiongjie Jin, Demetrius Moskophidis, Yanzhong Hu, Andrew Phillips, Nahid F. Mivechi

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Heat shock factor Hsf1 regulates the stress-inducibility of heat shock proteins (Hsps) or molecular chaperones. One of the functions attributed to Hsps is their participation in folding and degradation of proteins. We recently showed that hsf1-/- cells accumulate ubiquitinated proteins. However, a direct role for Hsf1 in stability of specific proteins such as p53 has not been elucidated. We present evidence that cells deficient in hsf1 accumulate wild-type p53 protein. We further show that hsf1-/- cells express lower levels of αB-crystallin and cells deficient in αB-crystallin also accumulate p53 protein. Reports indicate that αB-crystallin binds to Fbx4 ubiquitin ligase, and they target cyclin D1 for degradation through a pathway involving the SCF (Skp1-Cul1-F-box) complex. Towards determining a mechanism for p53 degradation involving αB-crystallin and Hsf1, we have found that ectopic expression of Fbx4 in wild-type mouse embryo fibroblasts (MEFs) expressing mutant p53 (p53R175H) leads to increase in its degradation, while MEFs deficient in hsf1 or αBcry are defective in degradation of this p53 protein. In addition, immunoprecipitated p53R175H from wild-type MEFs is able to pull-down both αB-crystallin and Fbx4. Finally, immunoprecipitated wild-type p53 from doxorubicin treated U2OS cells can pull-down endogenous αB-crystallin and Fbx4. These results indicate that hsf1- and αBcry-deficient cells accumulate p53 due to reduced levels of αB-crystallin in these cells. Elevated levels of p53 in hsf1- and αBcry-deficient cells lead to their increased sensitivity to DNA damaging agents. These data reveal a novel mechanism for protein degradation through Hsf1 and αB-crystallin.

Original languageEnglish (US)
Pages (from-to)504-515
Number of pages12
JournalJournal of cellular biochemistry
Volume107
Issue number3
DOIs
StatePublished - Jun 1 2009

Keywords

  • HSF1
  • p53 degradation
  • αB-crystallin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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