title: Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention.
abstract: Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2 modulators to prevent diseases, mitigate disease progression or overcome chemoresistance.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Bryan
authors.initials: B
authors.lastname: Harder
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, U.S.A. Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, U.S.A. dzhang@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001343:Autophagy; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Hrd1; Kelch-like ECH-associated protein 1 (Keap1); chemoprevention/chemoresistance; nuclear factor erytheroid-derived-2-like 2 (Nrf2); reactive oxygen species (ROS); ubiquitin proteasome system (UPS)