title: Hydrogen peroxide sensing, signaling and regulation of transcription factors.
abstract: The regulatory mechanisms by which hydrogen peroxide (H2O2) 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 H2O2 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 H2O2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H2O2, being activated by different concentrations and times of exposure to H2O2. The specific regulation of local H2O2 concentrations is also crucial and results from H2O2 localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H2O2 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 H2O2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H2O2 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.
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: H Susana
authors.initials: HS
authors.lastname: Marinho
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Real
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Luísa
authors.initials: L
authors.lastname: Cyrne
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal ; Instituto Gulbenkian de Ciência, Oeiras, Portugal ; Escola Superior de Tecnologia da Saúde de Lisboa, IPL, Lisboa, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Soares
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Antunes
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D002451:Cell Compartmentation; D003545:Cysteine / Q000378:metabolism; D005656:Fungal Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D055550:Protein Stability; D020871:RNA Stability; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D001426:Bacterial Proteins; D005656:Fungal Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C122138:peroxide repressor proteins; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D003545:Cysteine
keywords: AD, activation domain; Cytosol-nuclear traffic; DNA binding and transactivation; ER, endoplasmic reticulum; GPx, glutathione peroxidases; Localized H2O2 concentrations; NES, nuclear exporting signal; NLS, nuclear localization signal; PHD, prolyl hydroxylase; Prxs, peroxiredoxins; Rate constants; Redox signaling; TF, transcription factor; Thiol reactivity; Ub, Ubiquitin