Disruption of the Keap1-Containing Ubiquitination Complex as an Antioxidant Therapy

Jonathan   T.   Kern; Mark      Hannink; J.      Fred Hess

doi:10.2174/156802607780906825

Abstract

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 Parkinsons 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 Nrf2s nuclear accumulation and the transcription of AREdependent genes to enhance cellular resistance to oxidative insult.

Keywords: Keap1, Nrf2, Cul3, antioxidant, oxidative stress, antioxidant response element

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