DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

Abstract

oxidative stress ͉ PARK7 ͉ NQO1 ͉ Keap1 ͉ neurodegeneration

DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD

“…This suggests that DJ-1 does not function downstream of caspase-8 activation or its effector caspases and their substrates. It has been reported that DJ-1 inhibits apoptosis by regulating different transcription factors to modulate gene expression (Clements et al, 2006;Bretaud et al, 2007;Fan et al, 2008a;Vasseur et al, 2009;Foti et al, 2010). However, we observed that DJ-1 did not affect DR mRNA or protein levels in H1299 cells (Figure 3).…”

“…The levels of TRAIL receptors, including death receptors and decoy receptors, are closely related to apoptosis induced by TRAIL. Because DJ-1 can function in the nucleus to regulate transcription (Clements et al, 2006;Bretaud et al, 2007;Fan et al, 2008a;Foti et al, 2010), it is possible that DJ-1 regulates the TRAIL signaling pathway by influencing the expression of TRAIL receptors at the transcriptional level. We transfected H1299 cells with siNC or siDJ-1 and examined the mRNA levels of the four TRAIL receptors using reverse transcriptase-PCR.…”

“…DJ-1 itself can scavenge reactive oxygen species through a cysteine residue at C106, shifting its pI from 6.2 to 5.8 (Canet-Aviles et al, 2004;Andres-Mateos et al, 2007). DJ-1 also modifies the transcription of antioxidant enzymes by stabilizing the primary regulator of antioxidant responses, nuclear factor erythroid 2-related factor (Clements et al, 2006). DJ-1 suppresses the c-Jun N-terminal kinase (JNK) signaling pathway through its interaction with mitogen-activated protein kinase kinase kinase 1 to repress cell death (Mo et al, 2008).…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…This ameliorates the ROS accumulation of Aβ peptides (Eftekharzadeh et al 2010). Nrf2 has been stabilised by the building up of dysfunctional DJ-1, which prevents the association of Keap1 with Nrf2 and leads to the proteasomal degradation (Clements et al 2006). Collectively, the activation of Nrf2 could be a therapeutic target for AD, which will ameliorate this disease.…”

DJ-1 binds to mitochondrial complex I and maintains its activity

“…DJ-1 was first identified by our group as a novel oncogene product [1] and was later found to be a causative gene product of a familial form of PD, PARK7 [2]. DJ-1 plays roles in transcriptional regulation [3][4][5][6][7][8] and anti-oxidative stress reaction [9][10][11][12], and loss of its function is thought to affect the onset of PD. DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively).…”