Nrf2:INrf2(Keap1) Signaling in Oxidative Stress
By James W. Kaspar, Suresh Niture, Anil K. Jaiswal. Free Radical Biology & Medicine, 2009
1,592 citations recorded by the source corpus.
Nrf2:INrf2(Keap1) are cellular sensors of chemical and radiation induced oxidative and electrophilic stress. Nrf2 is a nuclear transcription factor that controls the expression and coordinated induction of a battery of defensive genes encoding detoxifying enzymes and antioxidant proteins. This is a mechanism of critical importance for cellular protection and cell survival. Nrf2 is retained in the cytoplasm by an inhibitor INrf2. INrf2 functions as an adapter for Cul3/Rbx1 mediated degradation of Nrf2. In response to oxidative/electrophilic stress, Nrf2 is switched on and then off by distinct early and delayed mechanisms. Oxidative/electrophilic modification of INrf2cysteine151 and/or PKC phosphorylation of Nrf2serine40 results in the escape or release of Nrf2 from INrf2. Nrf2 is stabilized and translocates to the nucleus, forms heterodimers with unknown proteins, and binds antioxidant response element (ARE) that leads to coordinated activation of gene expression. It takes less than fifteen minutes from the time of exposure to switch on nuclear import of Nrf2. This is followed by activation of a delayed mechanism that controls switching off of Nrf2 activation of gene expression. GSK3β phosphorylates Fyn at unknown threonine residue(s) leading to nuclear localization of Fyn. Fyn phosphorylates Nrf2tyrosine568 resulting in nuclear export of Nrf2, binding with INrf2 and degradation of Nrf2. The switching on and off of Nrf2 protect cells against free radical damage, prevents apoptosis and promotes cell survival.
Subfields: Health, Toxicology and Mutagenesis, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/46bd2962b019b4cc1b7b5b4d9aa7ddc20eab375b
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Citations in the corpus
- ROS and ROS-Mediated Cellular Signaling (2016, background): “However, under oxidizing conditions, the increased level of intracellular ROS promotes the dissociation of Nrf2 and Keap1, either by the oxidization of key reactive cysteine residues (Cys273, Cys288, and Cys151) that govern Keap1 activity or via the activation of kinases, such as protein kinase C (P”
- Regulation of Nrf2 – An update (2013, background): “Nrf2 is stabilized, translocate to the nucleus, heterodimerize with small Maf or c-Jun protein, and binds with ARE that leads to coordinated activation of cytoprotective gene expression [17, 81].”
- Oxidative Stress and Lipid Peroxidation Products in Cancer Progression and Therapy (2012, background): “Nrf2 protein serves as a sensor of chemical- and radiation-induced oxidative and electrophilic stress [207].”