TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression

Xian Zhang, Chien Feng Li, Ling Zhang, Ching Yuan Wu, Lixia Han, Guoxiang Jin, Abdol Hossein Rezaeian, Fei Han, Chunfang Liu, Chuan Xu, Xiaohong Xu, Chih Yang Huang, Fuu Jen Tsai, Chang Hai Tsai, Kounosuke Watabe, Hui Kuan Lin

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.

Original languageEnglish (US)
Pages (from-to)803-814
Number of pages12
JournalMolecular Cell
Volume64
Issue number4
DOIs
StatePublished - Nov 17 2016

Keywords

  • K63-linked ubiquitination of p53
  • MCL1/BaK
  • TRAF6 inhibits apoptosis
  • colorectal cancer
  • genotoxic stress
  • p300 recruitment
  • p53 K24 ubiquitination
  • p53 mitochondrial translocation
  • p53 transactivation
  • tumor suppression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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