NFE2L2

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a is_associated_with::transcription factor that in humans is encoded by the NFE2L2 is_associated_with::gene. Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of is_associated_with::antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.

Function
NFE2L2 and other genes, such as is_associated_with::NFE2 and is_associated_with::NFE2L1, encode basic is_associated_with::leucine zipper (bZIP) is_associated_with::transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.

Under normal or unstressed conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.

Nrf2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (is_associated_with::Keap1) and is_associated_with::Cullin 3 which degrade Nrf2 by is_associated_with::ubiquitination. Cullin 3 ubiquitinates its substrate, Nrf2. Keap1 is a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2. When Nrf2 is ubiquitinated, it is transported to the is_associated_with::proteasome, where it is degraded and its components recycled. Under normal conditions Nrf2 has a half-life of only 20 minutes. is_associated_with::Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When Nrf2 is not ubiquitinated, it builds up in the cytoplasm, and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with a small Maf protein and binds to the antioxidant response element (ARE) in the upstream is_associated_with::promoter region of many antioxidative genes, and initiates their transcription.

Target genes
Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:


 * NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive is_associated_with::quinones that can cause is_associated_with::redox cycling and is_associated_with::oxidative stress.
 * is_associated_with::Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (is_associated_with::GCLM) subunits form a heterodimer, which is the rate-limiting step in the synthesis of is_associated_with::glutathione (GSH), a very powerful endogenous is_associated_with::antioxidant. Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.
 * is_associated_with::Sulfiredoxin 1 (is_associated_with::SRXN1) and is_associated_with::Thioredoxin reductase 1 (is_associated_with::TXNRD1) support the reduction and recovery of is_associated_with::peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including is_associated_with::hydrogen peroxide and is_associated_with::peroxynitrite.
 * Heme oxygenase-1 (is_associated_with::HMOX1, HO-1) is an enzyme that catalyzes the breakdown of is_associated_with::heme into the antioxidant is_associated_with::biliverdin, the anti-inflammatory agent is_associated_with::carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including is_associated_with::sepsis, is_associated_with::hypertension, is_associated_with::atherosclerosis, acute lung injury, kidney injury, and pain. In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after is_associated_with::intracerebral hemorrhage.
 * The is_associated_with::glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and is_associated_with::microsomal enzymes that catalyze the conjugation of GSH with endogenous and is_associated_with::xenobiotic is_associated_with::electrophiles.  After detoxification by is_associated_with::GSH conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds.  GSTs are induced by Nrf2 activation and represent an important route of detoxification.
 * The UDP-is_associated_with::glucuronosyltransferase (UGT) family catalyze the conjugation of a is_associated_with::glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for is_associated_with::glucuronidation include is_associated_with::bilirubin and is_associated_with::acetaminophen.  Nrf2 has been shown to induce UGT1A1 and UGT1A6.
 * Multidrug resistance-associated proteins (Mrps) are important is_associated_with::membrane transporters that efflux various compounds from various organs and into is_associated_with::bile or plasma, with subsequent excretion in the feces or urine, respectively.  Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the is_associated_with::pharmacokinetics and toxicity of compounds.

Structure
Nrf2 is a basic leucine zipper (bZip) is_associated_with::transcription factor with a Cap “n” Collar (CNC) structure.

Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins. The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1. The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus. The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (is_associated_with::CREB), which possesses intrinsic is_associated_with::histone acetyltransferase activity. The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.

Tissue distribution
Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.

Clinical drug target
is_associated_with::Tecfidera (is_associated_with::dimethyl fumarate or BG-12), marketed by is_associated_with::Biogen Idec, was approved by the is_associated_with::Food and Drug Administration (FDA) on March 27, 2013 following the conclusion of is_associated_with::Phase 3 clinical trials which demonstrated that the drug reduced relapse rates and increased time to progression of disability in patients with is_associated_with::multiple sclerosis. The mechanism by which Tecfidera exerts its therapeutic effect is unknown. Tecfidera (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a is_associated_with::nicotinic acid receptor is_associated_with::agonist in vitro. Adverse events associated with Tecfidera include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased is_associated_with::lymphocyte counts and elevated liver is_associated_with::aminotransferase levels.

The dithiolethiones are a class of organosulfur compounds, of which is_associated_with::oltipraz, an NRF2 inducer, is the best studied. Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. Oltipraz also generates is_associated_with::superoxide radical, which can be toxic.

is_associated_with::Bardoxolone methyl, a synthetic oleanane triterpenoid compound, is under clinical investigation for the treatment of is_associated_with::pulmonary hypertension.

RTA 408 is a synthetic triterpenoid. Preclinical studies have demonstrated that it possesses antioxidative and anti-inflammatory activities, as well as the potential to improve mitochondrial bioenergetics. A Phase 2 clinical studies is evaluating RTA 408 for the prevention of radiation-induced is_associated_with::dermatitis.

Potential adverse effects of NRF2 activation
Activation of NRF2 may promote the development of is_associated_with::de novo cancerous tumors. as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.

Interactions
NFE2L2 has been shown to interact with:


 * is_associated_with::C-jun,
 * CREBBP,
 * is_associated_with::EIF2AK3,
 * is_associated_with::KEAP1,   and
 * UBC.