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.
Kern
Jonathan T
JT
Neuroscience Drug Discovery, Merck Research Laboratories, Merck and Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jonathan_kern@merck.com
Hannink
Mark
M
Hess
J Fred
JF
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008958:Models, Molecular; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020218:Response Elements / Q000235:genetics*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D043743:Ubiquitin-Protein Ligase Complexes