The rise of antioxidant signaling—The evolution and hormetic actions of Nrf2

doi:10.1016/j.taap.2010.01.011

Toxicology and Applied Pharmacology

Volume 244, Issue 1, 1 April 2010, Pages 4-15

https://doi.org/10.1016/j.taap.2010.01.011 Get rights and content

Abstract

Organisms have evolved sophisticated and redundant mechanisms to manage oxidative and electrophilic challenges that arise from internal metabolism or xenobiotic challenge for survival. NF-E2-related factor 2 (Nrf2) is a transcription factor that has evolved over millennia from primitive origins, with homologues traceable back to invertebrate Caenorhabditis and Drosophila species. The ancestry of Nrf2 clearly has deep-seated roots in hematopoiesis, yet has diversified into a transcription factor that can mediate a multitude of antioxidant signaling and detoxification genes. In higher organisms, a more sophisticated means of tightly regulating Nrf2 activity was introduced via the cysteine-rich kelch-like ECH-associated protein 1 (Keap1), thus suggesting a need to modulate Nrf2 activity. This is evidenced in Keap1^−/− mice, which succumb to juvenile mortality due to hyperkeratosis of the gastrointestinal tract. Although Nrf2 activation protects against acute toxicity and prevents or attenuates several disease states, constitutive activation in some tumors leads to poor clinical outcomes, suggesting Nrf2 has evolved in response to a multitude of selective pressures. The purpose of this review is to examine the origins of Nrf2, while highlighting the versatility and protective abilities elicited upon activation. Various model systems in which Nrf2 is normally beneficial but in which exaggerated pharmacology exacerbates a physiological or pathological condition will be addressed. Although Darwinian principles have selected Nrf2 activity for maximal beneficial effect based on environmental and oxidative challenge, both sub- or super-physiological effects have been noted to be detrimental. The functions of Nrf2 thus suggest a hormetic factor that has evolved empirically over time.

Section snippets

Nrf2 and the evolutionary niche

One of the most critical functions of life is the ability to manage oxidative stress. To address this central issue, even the simplest organisms have evolutionarily selected a diverse network of factors to manage a vast multitude of chemical and environmental insults. However, significant overlap and redundancy have been introduced to avoid a single fatal miscalculation upon initial exposure. There are many different transcription factors adapted to protecting against oxidative stress or

Diversification of function—the cap ‘n’ collar transcription factor family

Nrf2 is highly conserved across species, yet has developed a specialized role that is quite distinct from other CNC transcription factors. In vertebrates, the CNC family is now known to consist of six members: Nrf1, Nrf2, and Nrf3, Breakpoint cluster region/Abelson murine leukemia viral oncogene homolog 1 (Bach) 1 and Bach 2, and p45. The original identification of this family derived from sequence similarity to the DNA response element of nuclear factor-erythroid-derived 2 (NFE2). The NFE2

The Keap1-Nrf2 signaling pathway: multiple checkpoints in antioxidant gene regulation

In humans and in several of the observed mammalian species, Nrf2 activity is primarily regulated via the suppressor protein Keap1. Although Keap1 may be able to sequester Nrf2 in some basic capacity, the main regulatory ability seems to be derived from serving as a Cul3-adapter protein that allows for Nrf2 to be ubiquinated and degraded by the 26S proteosome complex (Kobayashi et al., 2004). Nrf2 has a notably short half-life of approximately 20 min but possibly as long as 3 hrs (Sekhar et al.,

Nrf2 downstream activation—conserved function but generalized regulation

The ARE/EpRE core sequence (TGACXXXGC) has been identified as the key DNA binding element for Nrf2 gene regulation (Itoh et al., 1997). Whereas a general consensus sequence for Nrf2 has been derived from a subset of genes well-known to be Nrf2 target genes, it remains unclear if this consensus will hold true for Nrf2-mediated genes as a whole, or whether there will also be evolution and species differences that will hold true for the responsive element. The core sequence is retained within the

Nrf2—normal physiological functions exaggerated in pathological conditions

As an adaptive transcription factor, Nrf2 has been integrated into several different physiological processes as it diversified away from the hematopoietic system. Whereas many of these alternative functions still involved oxidative stress protection as a central theme, in some cases where the normal cellular homeostasis is no longer relevant, the role of Nrf2 can sometimes be harmful rather than beneficial. These pathologies or events typically involve induction of genes that are regulated by

Conclusions

The above examples represent three physiological conditions in which additional Nrf2 activation leads to exacerbation of a pathological state. It is clear that Nrf2 has diversified and adapted far away from what is believed to be a precursory role in the hematopoietic system in regulating differentiation from early lineages. Indeed, evolutionary hints of such an origin can still be observed in the regulation and handling of iron via upregulation of genes such as SLC40A1 and HO-1. However, Nrf2

Acknowledgments

This work was supported by the NAITO foundation, the Japanese Society for the Promotion of the Sciences (JSPS), and the Global COE project.

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The rise of antioxidant signaling—The evolution and hormetic actions of Nrf2

Abstract

Section snippets

Nrf2 and the evolutionary niche

Diversification of function—the cap ‘n’ collar transcription factor family

The Keap1-Nrf2 signaling pathway: multiple checkpoints in antioxidant gene regulation

Nrf2 downstream activation—conserved function but generalized regulation

Nrf2—normal physiological functions exaggerated in pathological conditions

Conclusions

Acknowledgments

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Cell

Mol. Cell

J. Biol. Chem.

Eur. J. Pharmacol.

FEBS Lett.

Trends Cell Biol.

Gynecol. Oncol.

J. Biol. Chem.

Mol. Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Ethnopharmacol.

Arch. Biochem. Biophys.

Toxicol. Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Mol. Cell

Biochem. Pharmacol.

J. Biol. Chem.

Free Radic. Biol. Med.

Dev. Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Blood

Cell

SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response

Genes Dev.

Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein

Nature

Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice

Cancer Res.

Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing

Mol. Cell. Biol.

Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements

Science

A family of drug transporters: the multidrug resistance-associated proteins

J. Natl. Cancer Inst.

Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

Mol. Cell. Biol.

Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase

Science

Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast

Proc. Natl. Acad. Sci. U. S. A.

Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice

EMBO J.

Nrf1 is critical for redox balance and survival of liver cells during development

Mol. Cell. Biol.

Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression

Am. J. Physiol. Heart Circ. Physiol.

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway

Nat. Med.

Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice

J. Clin. Invest.

Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus

Mol. Cell. Biol.

The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model

Drug Metab. Dispos.