Recently visited
Please sign in to see a list of articles you recently visited.
Recently updated
Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
Comments (post)
There are no comments posted here... Yet.
No annotation is available in this section for this article. The content below is taken from a related TF, NFE2L2 (Homo sapiens).

The official symbol for this TF is NFE2L2 (nuclear factor erythroid 2 related factor 2) but this article will refer to it as NRF2, echoing the predominant use of this alias in the literature.

Nrf2 is a basic "cap and collar" leucine zipper transcription factor, which regulates environmental stress response by activating the expression of genes for antioxidants and detoxification enzymes. The Nrf2-directed environmental stress response protects cells against variety of stressors including environmental pollutants such as electrophiles and oxidizing agents, immunotoxicants, and inflammation[1]

Under normal conditions, Nrf2 is bound to Keap1 (Kelch-like erythroid-cell-derived protein with CNC homology [ECH]-associated protein), which anchors it in the cytoplasm and targets it for ubiquitination and proteasome degradation. Upon exposure to stressors, the Nrf2-Keap1 complex dissociates and Nrf2 translocates to the nucleus. This activation involves modification of the Nrf2-Keap1 complex by phosphorylation of Nrf2 and/or covalent binding of inducer molecules to certain cysteine residues in Keap1. Nrf2 heterodimerizes with small Maf proteins (avian musculoaponeurotic fibrosarcoma) in the nucleus and binds to antioxidant response elements (AREs) on target gene promoters[2][1][3].

The list of Nrf2 target genes, which constitute environmental stress response, has been growing since the first transcriptional profile was published by our group in 2001 and it includes pathways for xenobiotic detoxification, antioxidants, anti-inflammatory response, DNA repair, molecular chaperones, and proteasome systems. The degree of expression of these genes involves other transcription factors such as small Mafs and BACHs (brain acyl-CoA hydrolases), which bind to either AREs or Nrf2, or both [1].

Gene-environment interactions that regulate inflammation and oxidative stress play an important role in determining susceptibility to lung diseases. Past research has focused on understanding the role of Nrf2 in the regulation of environmental stress response and oxidative stress. Studies have shown that Nrf2 may be critically involved in various pulmonary diseases such as chronic obstructive pulmonary disease (COPD), sepsis mediated lung injury, asthma, and cancer [4][5][6].

Recent studies have indicated that suboptimal stress response as a result of decline in Nrf2 in the lung and macrophages is associated with increased oxidative stress and inflammation and worsened COPD in patients . Strategies based on targeting Nrf2 using small molecule approach for intervention of these disorders are being developed [7][8][9].

See Kensler, Wakabayashi, and Biswal review (see Papers tab) for informative figures illustrating these processes.

  1. Kensler TW et al. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 47:89-116. (PMID 16968214)
  2. Rushmore TH et al. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J. Biol. Chem., 266(18):11632-9. (PMID 1646813)
  3. Itoh K et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun., 236(2):313-22. (PMID 9240432)
  4. Thimmulappa RK et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Invest., 116(4):984-95. (PMID 16585964)
  5. Rangasamy T et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Invest., 114(9):1248-59. (PMID 15520857)
  1. Rangasamy T et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med., 202(1):47-59. (PMID 15998787)
  2. Suzuki M et al. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol., 39(6):673-82. (PMID 18566336)
  3. Goven D et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax, 63(10):916-24. (PMID 18559366)
  4. Malhotra D et al. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am. J. Respir. Crit. Care Med., 178(6):592-604. (PMID 18556627)
No annotation is available in this section for this article. The content below is taken from a related TF, NFE2L2 (Homo sapiens).
FIGURE 1 Current model for the induction of stress response and cell survival genes via Nrf2 activation
Under basal conditions, Nrf2 is sequestered in the cytoplasm by KEAP1. Keap1 associates with a number of cytosolic proteins, including Cul3, a ubiquitin ligase. Nrf2 under basal conditions, is therefore ubiquitinated and targeted for proteasomal degradation. Under conditions of oxidative stress or upon exposure to Nrf2 activators, oxidation/modification of adjacent sulfhydryl groups in KEAP1 lead to dissociation of Nrf2. Nrf2 can be further activated through phosphorylation by intracellular kinases. Upon release and activation, NRf2 translocates to the nucleus and heterodimerizes with another member of the bZIP family, sMaf, and binds to antioxidant response element (ARE) in the promoter region of target genes. Nrf2 binding to AREs induces the expression of a myriad of genes involved in key stress response and cell survival pathways. Figure was created using Ingenuity Systems software.

This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.