DJ-1-binding compound B enhances Nrf2 activity through the PI3-kinase-Akt pathway by DJ-1-dependent inactivation of PTEN

Takeshi Niki, Jinro Endo, Kazuko Takahashi-Niki, Tatsuki Yasuda, Asami Okamoto, Yoshiro Saito, Hiroyoshi Ariga, Sanae M.M. Iguchi-Ariga

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

DJ-1 was identified as an oncogene and also as a causative gene for a familial form of Parkinson disease (PD). DJ-1 plays various roles in anti-oxidative stress response. Superfluous oxidation of DJ-1 at cysteine residue 106 (C106), an inactive form of DJ-1, was observed in PD patients. DJ-1-binding compound B, which specifically bound to the C106 region of DJ-1, has been isolated and it has been shown to prevent oxidative stress-induced cell death through maintaining active forms of DJ-1 by inhibiting its superfluous oxidation. The molecular mechanism of the action of compound B, however, has not been fully elucidated. In this study, we found that compound B stimulated transcriptional activity of Nrf2 in H2O2-treated SH-SY5Y cells by inhibiting its degradation through the ubiquitin-proteasome system. Although Keap 1 is a major negative regulator of Nrf2, compound B strongly increased Nrf2 activity in Keap1-mutant A549 cells but not in PTEN-null PC3 and PTEN-knockout SH-SY5Y cells. Furthermore, treatment of cells with inhibitors of the PI3-kinase/Akt pathway inhibited the effect of compound B, and compound B increased the binding of PTEN to DJ-1 and decreased lipid phosphatase activity of PTEN concomitantly with increased oxidation of PTEN, an inactive form of PTEN. These results suggest that compound B enhances transcriptional activity of Nrf2 under an oxidative stress condition in a Keap1-independent manner and that its activity is elicited by activation of the PI3Kinase/Akt pathway with DJ-1-dependent inactivation of PTEN, leading to protection of oxidative stress-induced cell death.

Original languageEnglish
Article number146641
JournalBrain research
Volume1729
DOIs
Publication statusPublished - 2020 Feb 15

Keywords

  • DJ-1
  • DJ-1-binding compound
  • Keap1
  • Nrf2
  • Oxidative stress
  • Parkinson's disease
  • PI3K/Akt

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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