Regulation of Nrf2 – An update
By Suresh Niture, Raju Khatri, Anil K. Jaiswal. Free Radical Biology & Medicine, 2013
854 citations recorded by the source corpus.
Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes which encode detoxifying enzymes, drug transporters (MRPs), anti-apoptotic proteins and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase mediated degradation of Nrf2. Chemicals including antioxidants, tocopherols including α-tocopherol (vitamin E), phytochemicals and radiations antagonize the Nrf2:INrf2 interaction and leads to the stabilization and activation of Nrf2. The signaling events involve pre-induction, induction and post-induction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinase(s) in a pre-induction response which phosphorylates specific residues on Nrf2 negative-regulators, INrf2, Fyn and Bach1, leading to their nuclear export, ubiquitination and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2cysteine151 followed by PKC phosphorylation of Nrf2serine40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus resulting in a coordinated activation of gene expression. This is followed by a post-induction response that controls the ‘switching off’ of Nrf2-activated gene expression. GSK3β under the control of AKT and PI3K, phosphorylates Fyn leading to Fyn nuclear localization. Fyn phosphorylates Nrf2Y568 resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provides protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance.
Subfields: Molecular Biology, Sociology and Political Science
View Paper: https://www.semanticscholar.org/paper/5a65f6c693769d76d48e38a66be43447a2fd1e7a
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Citations in the corpus
- The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state (2015, background): “Studies [75, 77] showed that under physiological conditions SkQ1 (10(6′-plastoquinonyl) decyl-triphenyl-phosphonium) is a positive mediator of transcriptional activity of Nrf2 and Nrf2-controlled genes encoding antioxidant enzymes, which enhances the antioxidant potential of leukocytes in normoxia.”
- Engineering plants for heavy metal stress tolerance (2018, positive): “The toxic effect of HMs in plant genome severely affects the process of DNA replication and chromosomes as well as inducing chromosomal aberrations and abnormalities (Niture et al. 2014).”
- Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity (2018, background): “Nrf2 is predominantly regulated by its binding to the inhibitor, Keap1, which targets Nrf2 for ubiquitination and degradation, thus maintaining low cellular levels of Nrf2.”