Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications

The chemopreventive agent sulforaphane is an isothiocyanate derived from cruciferous vegetables. Transcriptional activation of antioxidant response element (ARE)-regulated phase II detoxification and antioxidant genes through the induction of transcription factor NF-E2-related factor-2 (Nrf2) is considered as the prime mechanism of its chemopreventive action. Cellular level of Nrf2 is tightly regulated by proteolysis through Cullin3 (Cul3)/Kelch-like ECH-associated protein 1 (Keap1)-dependent polyubiquitination. Sulforaphane is an electrophile that can react with protein thiols to form thionoacyl adducts and is believed to affect the Cys residues in Keapl protein. In addition, sulforaphane might affect the activity of a variety of intracellular kinases to phosphorylate Nrf2 proteins, which dictates the nucleocytoplasmic trafficking of Nrf2 or modulates the Nrf2 protein stability. This review is designed to briefly account for the regulatory mechanism of Nrf2 protein expression by Cul3/Keap1 E3 ligase and for the possible roles of posttranslational modifications of cellular Keap1 or Nrf2 proteins by sulforphane in the regulation of ARE-dependent gene activation.