Phytoagents for Cancer Management: Regulation of Nucleic Acid Oxidation, ROS, and Related Mechanisms

Figure 4

Inducible antioxidant defense regulated by Nrf2/Keap1 and the antioxidant response element. Under normal physiological conditions, the transcription factor Nrf2 is sequestered in the cytosol by Keap1. Keap1 recruits ubiquitin ligase E3 which then ubiquitinates Nrf2 and directs it to the proteasome degradation pathway. The increased level of ROS promotes the dissociation of Nrf2 and Keap1, either via activation of kinases that phosphorylate Nrf2 or by oxidization of key cysteine residues that govern Keap1 activity. The dissociated Nrf2 is then translocated into the nucleus and binds to the antioxidant response element (ARE). ARE-regulated genes are then transcriptionally activated, including a panel of antioxidant enzymes or proteins, such as glutathione synthetase (GSS), glutathione reductase (GR), glutathione peroxidase (GPx), thioredoxin (TRX), thioredoxin reductase (TRR), and peroxiredoxin (PRX). These inducible antioxidant enzymes then provide further ROS clearance capacity and antioxidant defense mechanism to exert a cytoprotective effect.