The cytoprotective and the dark side of Nrf2

Abstract

where it induces transcription of a number of cytoprotec-tive genes.In their comprehensive review, Baird and Dinkova-Kostova (2011) present different models of regulation, such as the ‘sequester and release model’ for Keap1-Nrf2, the role of cullin 3 during dissociation, the hinge and latch model, sensing of inducers by Nrf2 and the role of phosphorylation. Moreover, a comprehensive overview of cytoprotective Nrf2 target genes and the chemistry of inducers are provided. In a complementary review, Slo-cum and Kensler (2011) focus on genetic mouse mod-els of the Keap 1-Nrf2 pathway and its role in carcino-genesis of the colon, bladder, lung, stomach, skin, liver and breast. Upregulation of Nrf2 signaling provides tumor cells with a survival advantage in adverse environ-ments (Slocum and Kensler 2011). Moreover, Nrf2 also upregulates the expression of the multidrug-resistant protein-3 (MRP3), which exports a variety of cytostatic drugs, including chlorambucil, cisplatin, doxorubicin and etoposide.Further influential articles published in the Archives of Toxicology in recent years focus on nanotoxicity (Kim et al. 2012; Landsiedel et2012 al. ; Nunes et 2012al. ; Trpkovic et 2012al. ; Gebel 2012; Oesch and Landsiedel 2012), the use of stem cells in toxicology (Wobus and Loser 2011; Krug et al. 2013; Seiler et al. 2011), carcino-genesis (Bernstein etal. 2011 ; Golka etal. 2011; Burns and Korach 2012; Pavanello and Lotti 2012; Brambilla et al. 2011), metal toxicology (Chasapis et2012al. ), neu-rotoxicity (Soderlund 2012; Carvalho et al. 2012; Marius-sen 2012), in silico and in vitro methods (Karp and Caspi 2011; Godoy et2013al. ; Mehling et2012 al. ; Geenen et al. 2012) and oxidative stress (Mates et2012 al. ). The editors hope that this choice meets the current needs of our readers, and encourage them to suggest further In 1988, Paul Talalay and colleagues described a pro-tein with highly reactive cysteine residues that protects against chemical carcinogenesis (Talalay et1988) al. This led to the discovery of an elaborate network of highly inducible, cytoprotective proteins that are con-trolled by the Keap1-Nrf2 pathway (Itoh et1999; al. Dinkova-Kostova et2002; Kobayashi et al. 2004 ; al. Wakabayashi et2004; Motohashi and Yamamoto al. 2004; Zhang and Hannink 2003; Balogun etal. 2003 ; McMahon et 2003al. ; Zhang et al. 2004; Kwak et al. 2003). In the following decades, the Keap1-Nrf2-signal-ing axis became one of the most studied topics in toxicol -ogy. Therefore, it comes as no surprise that two of the most discussed invited reviews published in the Archives of Toxicology highlight the importance of this pathway (Baird and Dinkova-Kostova 2011; Slocum and Kensler 2011) (Table1). Nrf2 is bound by Keap1 via two bind-ing sites, the so-called hinge and latch domains. Follow-ing binding, Nrf2 is ubiquitinated and degraded by the proteasome, which controls Nrf2 basal levels. Chemicals or cell stress may disrupt the interaction between Nrf2 and Keap1 leading to inefficient ubiquitination of Nrf2. Instead, Nrf2 accumulates and translocates to the nucleus