Disruption of the Keap1-containing ubiquitination complex as an antioxidant therapy.

The transcription of antioxidant response element (ARE)-containing cytoprotective genes has been proposed as a means to combat oxidative stress-related disorders, such as cancer and Parkinson's disease. Transactivation of the ARE requires the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Cellular levels of Nrf2 protein are regulated by the Kelch-like ECH-associated protein 1 (Keap1), a substrate adaptor protein for the ubiquitin ligase machinery and subsequent proteasomal degradation. Recently, detailed studies have elucidated the structure and interactions of the Keap1-containing ubiquitin ligase complex. Here, we propose that small molecule modulation of Keap1 protein:protein interactions may permit Nrf2's nuclear accumulation and the transcription of ARE-dependent genes to enhance cellular resistance to oxidative insult.