When NRF2 talks, who's listening?

Abstract

Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl-reactive, small-molecule pharmacologic agents, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor to antioxidant response elements in the promoter regions of target genes. However, it is becoming evident that some of the protective effects may be mediated indirectly through cross talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses. This review highlights recent observations on the molecular interactions and their functional consequences between NRF2 and the arylhydrocarbon receptor (AhR), NF-κB, p53, and Notch1 signaling pathways.

FIG. 1.

Possible means for regulation of cell survival and other cell-fate responses through interactions of NRF2 with additional cell-signaling pathways, including AhR, NF-κB, p53, and Notch1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Regulation of xenobiotic metabolism by AhR and NRF2. Xenobiotics are metabolized by cytochrome P450s (CYPs) into intermediates that are reactive or nonreactive. Reactive intermediates can be metabolized by cytoprotective enzymes into less-toxic and often readily excretable products. When activated by a ligand, AhR in the cytoplasm complexes with ARNT and translocates into the nucleus and induces the transcription of CYPs by binding to the xenobiotic response elements (XREs) in the promoters of target genes. NRF2 bound to KEAP1 in the cytoplasm translocates into the nucleus when the pathway is activated by exogenous or endogenous electrophilic or free radical stresses, and binds to the antioxidant response elements (AREs) to induce transcription of cytoprotective genes.

FIG. 3.

Schematic representation of stages of adipogenesis regulated by AhR and NRF2. Adipogenic stimuli such as dexamethasone and isobutylmethylxanthine induce expression of the early markers CEBPβ and CEBPδ, which leads to induction of PPARγ and CEBPα. NRF2 induces expression of Ahr mRNA by directly binding to the promoter of the Ahr gene. AhR inhibits differentiation stages that follow CEBPβ activation (i.e., CEBPα or PPARγ upregulation).

FIG. 4.

E3 ubiquitin ligase activities of KEAP1 and AHR. KEAP1 binds with CUL3, RBX1, and E2 to facilitate the ubiquitination of NRF2, leading its enhanced degradation by the proteasome. Ligand-bound AhR assembles a CUL4B-based E3 ubiquitin ligase complex to mediate a nongenomic signaling pathway for influencing estrogen and androgen actions. ER, estrogen receptor; AR, androgen receptor.

FIG. 5.

Repression of NRF2 signaling by members of the NF-κB pathway. p65 represses NRF2-dependent transcription at the ARE when phosphorylated on S276 by either competition for coactivator binding proteins or by recruiting HDAC to the ARE, which can deacetylate histone H4 and MafK.

FIG. 6.

The interactions of the NRF2 and NF-κB target proteins HO-1 and iNOS and their products can regulate the activity of each other in macrophages to protect against an overabundance of NO. Excess NO acts as a signal to increase HO-1, which is able to scavenge NO and block the activity of iNOS to prevent further production.

FIG. 7.

p53 modulates a gradient of responses to cellular stress. When the cell is exposed to a high level of stress, p53 acts in a proapoptotic fashion, modulating multiple pathways to secure a full commitment to cell death, whereas with a low level of cellular stress, p53 modifies gene expression to ensure cytoprotection after removal of the stress. The intermediate response is also possible, with p53 retaining the ability to induce cellular senescence through exit of the cell cycle and induction of terminal differentiation with a concurrent cytoprotective response.

FIG. 8.

Possible effects of NRF2–Notch interactions on cell fate.