What genes does Nrf2 activate?
Nrf2 increases the supply of cysteine by directly activating Slc7a11, the gene encoding the xCT subunit of system xc− (141). In addition to GSH synthesis, Nrf2 plays a role in GSH maintenance.
What is Nrf2 and KEAP1?
The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation.
What is KEAP1 mutation?
KEAP1/NRF2-mutant tumors have been shown to depend on nonessential amino acids and to increase pentose phosphate pathway flux and usage of glutamine-, serine- and cysteine-derived metabolites15,16,17,18,19. KEAP1 mutations correlate with poor survival1 and promote metastasis in Keap1-mutant GEMMs20.
What is KEAP1-Nrf2 pathway?
The Keap1-Nrf2 pathway is the body’s primary inducible response to oxidative stress. Since the discovery in 1997 that Nrf2 is responsible for the expression of cytoprotective genes, an intricate molecular mechanism has been revealed through which the stress sensor protein Keap1 tightly regulates Nrf2 activity.
What is the function of Nrf2?
The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure.
What is the Nrf2 gene?
NF-E2–related factor 2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense gene expression in the liver. It is activated in response to oxidative stress and induces the expression of its target genes by binding to the antioxidant response element (ARE).
What is the NRF2 gene?
What is the function of NRF2?
What does Nrf2 stand for?
Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) is a critical transcription factor that regulates the expression of over 1000 genes in the cell under normal and stressed conditions.
Is Keap1 an oncogene?
In human lung ADC, KEAP1 is the third most commonly mutated gene, behind the tumor suppressor TP53 and KRAS oncogene, where it is found mutated in 19% of patients [4,23].
What role does Nrf2 play in the response of cells to potentially toxic substances?
Nuclear factor erythroid 2-related factor 2 (Nrf2), an emerging regulator of cellular resistance to oxidants, serves as one of the key defensive factors against a range of pathological processes such as oxidative damage, carcinogenesis, as well as various harmful chemicals, including metals.
Why is Nrf2 important?
Taken together, Nrf2 is an important mediator of antioxidant signaling during inflammation. Its function is based mainly on induction of the expression of target genes responsible for detoxifying and anti-oxidant effects, although a role of Nrf2 as a transcriptional repressor is also well established.
What can we learn from mutations in KEAP1 and NRF2?
Somatic mutations in KEAP1 and NRF2 provide an insight into the molecular mechanisms by which NRF2 is regulated. Moreover, constitutive NRF2 activation might cause drug resistance in tumours, and an understanding of how the transcription factor is regulated indicates ways in which this could be overcome.
What is the stoichiometry of Nrf2 and Keap1?
Since KEAP1 molecules form homodimers within cells, the stoichiometry of the KEAP1 homodimer and NRF2 is 1:1, and that of a single KEAP1 molecule and NRF2 is 2:1 ( 6) (Figure (Figure1B). 1 B).
What is the keap1-nrf2 system in cancer?
The KEAP1-NRF2 System in Cancer Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells.
How does the nrf2/keap1 signaling pathway regulate amino acid metabolism in cancer?
KEAP1-mutant cells reduced the intracellular glutamate pool by increasing glutamate consumption for GSH synthesis and exporting glutamate via anti-porter xCT in exchange for cysteine [ 75, 118 ]. These studies indicate that the NRF2/KEAP1 signaling pathway could regulate amino acid metabolism in malignant tumors. 3.2.3. Lipid Metabolism