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

[ Vol. 7 , Issue. 10 ]


Jonathan T. Kern, Mark Hannink and J. Fred Hess   Pages 972 - 978 ( 7 )


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.


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


Neuroscience Drug Discovery,Merck Research Laboratories, Merck&Co., PO Box 4, West Point, PA 19486 USA.

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