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      Hydrogen peroxide sensing, signaling and regulation of transcription factors

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          Abstract

          The regulatory mechanisms by which hydrogen peroxide (H 2O 2) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed. The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians. Multiple H 2O 2 sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm–nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes. We also discuss how H 2O 2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H 2O 2, being activated by different concentrations and times of exposure to H 2O 2. The specific regulation of local H 2O 2 concentrations is also crucial and results from H 2O 2 localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H 2O 2 reactivity with sensor molecules. Rate constants of 140 M −1 s −1 and ≥1.3 × 10 3 M −1 s −1 were estimated, respectively, for the reaction of H 2O 2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H 2O 2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.

          Highlights

          • Complexity of redox regulation increases along the phylogenetic tree.
          • Complex regulatory networks allow for a high degree of H 2O 2 biological plasticity.
          • H 2O 2 modulates gene expression at all steps from transcription to protein synthesis.
          • Fast response (s) is mediated by sensors with high H 2O 2 reactivity.
          • Low reactivity H 2O 2 sensors may mediate slow (h) or localized H 2O 2 responses.

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          Most cited references 376

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          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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            The canonical Notch signaling pathway: unfolding the activation mechanism.

            Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
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              HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

               M Ivan,  Theresa Kim,  A Salic (2001)
              HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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                Author and article information

                Affiliations
                [a ]Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
                [b ]Instituto Gulbenkian de Ciência, Oeiras, Portugal
                [c ]Escola Superior de Tecnologia da Saúde de Lisboa, IPL, Lisboa, Portugal
                Author notes
                []Corresponding author. fantunes@ 123456fc.ul.pt
                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                23 February 2014
                23 February 2014
                2014
                : 2
                : 535-562
                3953959 S2213-2317(14)00045-7 10.1016/j.redox.2014.02.006
                © 2014 The Authors
                Categories
                Review Article

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