Nrf2

Supporting information

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2) is a member of the basic leucine zipper family of transcription factors. Under normal physiological conditions, Nrf2 has a short half-life of around 20 minutes and is retained in the cytoplasm before being degraded by the concerted actions of Kelch-like ECH-associated protein 1 (Keap1) and Cullin 3. Cullin 3, a ubiquitin E3 ligase ubiquitinates Nrf2, targeting it for proteasomal degradation, in a process facilitated by the adaptor protein actions of Keap1. The Nrf2-Cullin 3-Keap1 interaction has been proposed as a crucial cellular sensor of oxidative stress.

Under conditions of oxidative or electrophilic stress, critical cytosine residues in Keap1 are disrupted, preventing the ubiquitination of Nrf2 by Cullin 3. The resultant accumulation of Nrf2 in the cytoplasm and subsequent translocation into the nucleus leads to heterodimer formation with a small Maf protein. The Nrf2-Maf heterodimer binds to the antioxidant response element (ARE) in the upstream promoter regions of several antioxidant genes. Genes whose expression is upregulated by Nrf2 activity include NAD(P)H:quinone oxidoreductase, heme oxygenase-1, glutathione S-transferases and multidrug resistance proteins (Mrps) amongst others.

Nrf2 pathway activity has shown to be impaired in several pathological states such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and acute respiratory distress syndrome. Additionally, Nrf2 gene disruption has been shown to enhance susceptibility to emphysema after exposure to cigarette smoke. In support of this, Nrf2 gene activation in an animal model of cigarette smoke-induced emphysema has demonstrated beneficial effects, suggesting that Nrf2 is a valid therapeutic target for protecting the lung against the effects of oxidative stress.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
Nuclear Factor (Erythroid-derived 2)-like 2 (Nrf2) Human NFE2L2 NM_006164 Q16236
Mouse Nfe2l2 NM_010902 Q60795
Rat Nfe2l2 NM_031789 O54968

Literature for Nrf2

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