title: Selenium in the redox regulation of the Nrf2 and the Wnt pathway.
abstract: Selenium deficiency is known to increase cancer risk by so far unclear mechanisms. Selenium exerts its biological effects via selenocysteine as an integral part of selenoproteins. Certain selenoproteins have redox properties, thereby providing a tool to regulate hydroperoxide-mediated signaling. Selenium deficiency does not only reduce synthesis of selenoproteins but also affects the expression of other proteins and even pathways. A moderate Se deficiency activates the Nrf2 and the Wnt pathways. The link between both pathways appears to be GSK3β which in the active state prepares Nrf2 as well as β-catenin, the key player in Wnt signaling, for ubiquitination and proteasomal degradation, thus silencing their transcriptional activity. Upon stimulation by Wnt signals, GSK3β becomes inactivated and transcription factors are stabilized. Many intermediate steps in both pathways can be modulated by hydroperoxides, making them predestined to be regulated by selenoproteins. Oxidation sensors are (i) Keap1 which keeps Nrf2 in the cytosol unless it is modified by hydroperoxides/electrophiles and (ii) nucleoredoxin (Nrx) which is associated with disheveled (Dvl). NOX1-derived H2O2 oxidizes Nrx leading to the liberation of Dvl and the activation of Wnt signaling. Selenium deficiency can support oxidation of both sensors and activate both pathways. The consequences are dual: while the Keap1/Nrf2 system is generally believed to protect against oxidative stress, diverse xenobiotics, inflammation, and carcinogenesis, the Wnt response is considered rather a risky one in these respects. However, not only healthy cells but also malignant ones benefit from intact Keap1/Nrf2 signaling, making a dysregulated hydroperoxide signaling a plausible explanation for the increased cancer risk in selenium deficiency.
authors.affiliation: Department Biochemistry of Micronutrients, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. flohe@dife.de
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohé
authors.forename: Anna Patricia
authors.initials: AP
authors.lastname: Kipp
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D055550:Protein Stability; D012643:Selenium / Q000502:physiology*; D051140:Selenoproteins / Q000502:physiology; D060449:Wnt Signaling Pathway
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051140:Selenoproteins; D012643:Selenium
keywords: GSK3ß; Keap1; Nrf2; Nucleoredoxin; Phase II enzymes; Selenium deficiency; Wnt