Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer
| Autor: | Agnieszka Jezierska-Drutel, Yefim Manevich, Brittany Turner-Ivey, Emily Kistner-Griffin, Jennifer Schulte, Carola A. Neumann, Yusen Liu |
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| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Cell signaling MAP Kinase Signaling System Phosphatase Breast Neoplasms Protein tyrosine phosphatase Peroxiredoxin 1 Biology p38 Mitogen-Activated Protein Kinases Article Enzyme activator Cell Line Tumor Genetics Humans Molecular Biology Cellular Senescence Dual Specificity Phosphatase 1 Epithelial Cells Hydrogen Peroxide Peroxiredoxins Cell biology Enzyme Activation HEK293 Cells Biochemistry MCF-7 Cells Dual-Specificity Phosphatases Mitogen-Activated Protein Kinase Phosphatases Female Reactive Oxygen Species Oxidation-Reduction Cell aging Cysteine |
| Zdroj: | Oncogene. 32:5302-5314 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2012.624 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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