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  • Like tBHQ and DEM treatment of Keap MEFs


    Like tBHQ and DEM, treatment of Keap1+/+ MEFs with SFN increased the abundance of Hmox1 and Nqo1 mRNA, and this was blunted by LY294002 and MK-2206 (Figure 2C). However, unlike the situation with tBHQ and DEM, treatment of Keap1−/− MEFs with SFN did not increase further the elevated basal levels of Hmox1 or Nqo1 mRNA in the mutant fibroblasts; similar results have been observed by workers in the laboratory of Antonio Cuadrado. This implies that certain inducing agents inhibit Keap1 but not GSK-3.
    Concluding comments and future directions This article provides an overview of the mechanisms by which Nrf2 is repressed by CRLKeap1 and by GSK-3. We have also presented evidence that tBHQ and DEM can induce Hmox1 and Nqo1 through a Keap1-independent mechanism, and that the GSK-3 inhibitor CT99021 can also stimulate Keap1-independent induction of Hmox1 and Nqo1. We speculate that inducing agents may modify Cys-46, Cys-53 and Cys-106 in DJ-1, and/or Cys-71 and Cys-124 in PTEN, and in so doing cause inhibition of GSK-3 by increasing PIP3-based PDK1 signaling that results in activation of PKB/Akt, thereby preventing formation of the DSGIS-containing phosphodegron in Nrf2 (Figure 3). The possibility that the positive regulation of Nrf2 by PI3K via GSK-3 might be mediated, at least in part, by kinases other that PKB/Akt, such as p70S6K, p90RSK and certain PKC isoforms 14, 16, warrants investigation. As both soft electrophiles and growth stimuli increase Nrf2 activity, it might be anticipated that the two Pefloxacin of activator result in co-induction of antioxidant/detoxication and anabolic metabolism genes. However, genetic experiments suggest that antagonism of repression of Nrf2 by Keap1 results in induction of a distinct battery of genes from that resulting from antagonism of the PIP3 3-phosphatase activity of PTEN. Specifically, disruption of both Keap1 and Pten in mouse hepatocytes results in the marked transactivation of metabolic genes such as G6pdx, Mthfd2 and Pgd, whereas disruption of either Keap1 or Pten alone does not induce these metabolic genes: knockout of Keap1 alone increased modestly the expression of Me1 and Tkt whilst increasing significantly the expression of Gpx2 and Nqo1, whereas knockout of Pten alone increased very modestly the expression of Me1 and Tkt but did not increase the expression of Gpx2 or Nqo1∗∗21, 68. The molecular basis for this selectivity in induction of Nrf2-target genes upon inhibition of Keap1 and/or PTEN requires further study. An important area that needs to be addressed in future concerns the priming of Nrf2 for phosphorylation by GSK-3. In particular, GSK-3 substrates usually have to be phosphorylated (i.e. primed) by another protein kinase before GSK-3 is able to phosphorylate them [69∗]. Further work is required to identify protein kinases that prime Nrf2 for phosphorylation by GSK-3.
    Acknowledgements We thank Professor Masayuki Yamamoto for providing the MEFs used in this study, and for his advice. We also thank Professor Antonio Cuadrado for invaluable discussions and for sharing with us data about the inability of sulforaphane to stimulate Keap1-independent gene expression. We gratefully acknowledge the Medical Research Council for their financial support (MR/N009851/1).
    Introduction Glycogen synthase kinase-3 (GSK-3) is identified in 1980 as a protein kinase that inactivates glycogen synthase. However, in the 1990s, GSK-3 was revealed to regulate a number of cellular functions such as cell proliferation, stem cell renewal, apoptosis and development, by stimulation with insulin, growth factors, hormones and other mediators [1], [2]. Because of its multi-functionality, GSK-3 also plays important roles in the onset and progression of human diseases. Therefore, this kinase could be a good target for new drug development. Indeed, many GSK-3 inhibitors were synthesized and some of them have been examined in clinical trials [3], [4], [5], [6]. This review summarizes the roles of GSK-3 in physiological pathways and human diseases and discusses the possibility of new drug development targeting this kinase, based on recent information about the inhibitors and activators of GSK-3 tested not only in preclinical but also clinical studies.