TY - JOUR
T1 - DJ-1-binding compound B enhances Nrf2 activity through the PI3-kinase-Akt pathway by DJ-1-dependent inactivation of PTEN
AU - Niki, Takeshi
AU - Endo, Jinro
AU - Takahashi-Niki, Kazuko
AU - Yasuda, Tatsuki
AU - Okamoto, Asami
AU - Saito, Yoshiro
AU - Ariga, Hiroyoshi
AU - Iguchi-Ariga, Sanae M.M.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - 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.
AB - 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.
KW - DJ-1
KW - DJ-1-binding compound
KW - Keap1
KW - Nrf2
KW - Oxidative stress
KW - Parkinson's disease
KW - PI3K/Akt
UR - http://www.scopus.com/inward/record.url?scp=85077934561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077934561&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2019.146641
DO - 10.1016/j.brainres.2019.146641
M3 - Article
C2 - 31891690
AN - SCOPUS:85077934561
VL - 1729
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0006-8993
M1 - 146641
ER -