Unique Pattern of Component Gene Disruption in the NRF2 Inhibitor KEAP1/CUL3/RBX1 E3-Ubiquitin Ligase Complex in Serous Ovarian Cancer
KEAP1/CUL3/RBX1 E3-ligase protein complex. In the absence of ROS (a), NRF2 is regulated by the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex which targets NRF2 for proteasomal degradation and inhibits expression of NRF2-controlled genes. The oxidative metabolism of estrogen through the catechol pathway induces the generation of reactive oxygen species (ROS, b). These oxidative species induce conformational changes in KEAP1, which disrupt the activity of the inhibitory complex. As a consequence, NRF2 is stabilized and translocates to the nucleus, where it induces expression of cytoprotective genes containing NRF2-regulatory sequence motifs (e.g., antioxidant response elements, AREs). When the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is compromised by genetic alteration in any of its component genes (c), NRF2 is stabilized and accumulated and transported to the nucleus. Under these conditions, the activation of cytoprotective genes becomes constitutive, which has been associated with tumor promotion.