title: Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer.
abstract: Recent studies suggest that Peroxiredoxin 1 (Prdx1), in addition to its known H₂O₂-scavenging function, mediates cell signaling through redox-specific protein-protein interactions. Our data illustrate how Prdx1 specifically coordinates p38MAPK-induced signaling through regulating p38MAPKα phosphatases in an H₂O₂ dose-dependent manner. MAPK phosphatases (MKP-1 and/or MKP-5), which are known to dephosphorylate and deactivate the senescence-inducing MAPK p38α, belong to a group of redox-sensitive phosphatases (protein tyrosine phosphatases) characterized by a low pKa cysteine in their active sites. We found that Prdx1 bound to both MKP-1 and MKP-5, but dissociated from MKP-1 when the Prdx1 peroxidatic cysteine Cys52 was over-oxidized to sulfonic acid, which in turn resulted in MKP-1 oxidation-induced oligomerization and inactivity toward p38MAPKα. Conversely, over-oxidation of Prdx1-Cys52 was enhancing in the Prdx1:MKP-5 complex with increasing amounts of H₂O₂ concentrations and correlated with a protection from oxidation-induced oligomerization and inactivation of MKP-5 so that activation toward p38MAPK was maintained. Further examination of this Prdx1-specific mechanism in a model of reactive oxygen species-induced senescence of human breast epithelial cells revealed the specific activation of MKP-5, resulting in decreased p38MAPKα activity. Taken together, our data suggest that Prdx1 orchestrates redox signaling in an H₂O₂ dose-dependent manner through the oxidation status of its peroxidatic cysteine Cys52.
authors: Department of Pathology, Medical University of South Carolina, Charleston, SC, USA.
authors: B
authors: B
authors: Turner-Ivey
authors: Y
authors: Y
authors: Manevich
authors: J
authors: J
authors: Schulte
authors: E
authors: E
authors: Kistner-Griffin
authors: A
authors: A
authors: Jezierska-Drutel
authors: Y
authors: Y
authors: Liu
authors: C A
authors: CA
authors: Neumann
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D048051:p38 Mitogen-Activated Protein Kinases; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases