Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2

Sekhar, Konjet R; Yan, Xuexian; Freeman, Michael L.

doi:10.1038/sj.onc.1205905

Cited by 121 publications

(104 citation statements)

References 28 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, it has been demonstrated that dimerization of Keap1 plays a role in the sequestration of Nrf2 in cytoplasm and that electrophiles disrupt Keap1 complex formation (60). Moreover, suppression of protein degradation is postulated to be involved in Nrf2-mediated ARE activation (49,52). Thus, although it is widely accepted that Nrf2 is a transcription factor that plays a central role in the induction of phase 2 proteins, several conflicting models of Nrf2 activation and its subsequent nuclear translocation have been presented to date.…”

Section: Discussionmentioning

confidence: 99%

“…Although the primary mechanism underlying the Nrf2-dependent gene expression of phase 2 proteins has been increasingly understood, the mechanism by which Nrf2 is liberated from the Nrf2-Keap1 complex remains controversial. Nrf2 regulation has been proposed to involve several different mechanisms, including 1) direct attack of the Nrf2-Keap1 complex by electrophiles or ROS (9,15,21,60), 2) indirect actions, such as phosphorylation, which are involved in the dissociation (4,18,27), and 3) modulation of the stability of Nrf2 protein (2,39,49,52). Furthermore, whether these modifications happen to Nrf2 (9,17) or Keap1 (15,60) has also been argued.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

Numazawa

Ishikawa

Yoshida

et al. 2003

American Journal of Physiology-Cell Physiology

305

189

View full text Add to dashboard Cite

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of antioxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang HC, Nguyen T, and Pickett CB. J Biol Chem 277: 42769–42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12- O-tetradecanoylphorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKCι activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-green fluorescent protein (GFP) fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by coexpression of aPKCι, but not by a kinase inactive mutant aPKCι(K274W). The activity of an ARE-driven reporter was increased by coexpression of aPKCι, and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by coexpression of aPKCι(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in the nuclear translocation and ARE transactivation of Nrf2 by oxidative stress.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

Numazawa

Ishikawa

Yoshida

et al. 2003

American Journal of Physiology-Cell Physiology

305

189

View full text Add to dashboard Cite

show abstract

“…The Neh2 domain of Nrf2 is important for Keap1-dependent degradation of Nrf2 in cells under basal homeostatic conditions. Especially, the Neh2 domain, containing lysine residues at 44, 50, 52, 53, 56, 64 and 68, are ubiquitinated by CUL3-dependent E3-ubiquitin ligase (Sekhar et al 2002).…”

Section: Regulation Of the Nrf2 Degradation Pathwaymentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

show abstract

“…Perhaps glial cells have higher levels of other ARE-specific transcription factors such as Nrf1 that can contribute to a portion of the observed phase II enzyme gene induction Jaiswal, 1996, 1998). Alternatively, glia may have reduced Nrf2 degradation via the ubiquitin-proteasome pathway (Nguyen et al, 2002;Sekhar et al, 2002;Stewart et al, 2002).…”

Section: Characterization Of the Nrf2 Inducible Gene Set In Neurons Amentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

View full text Add to dashboard Cite

Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (Ͻ 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, ␥-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

show abstract

Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2

Cited by 121 publications

References 28 publications

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

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

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Contact Info

Product

Resources

About