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 H?O?-scavenging function, mediates cell signaling through redox-specific protein-protein interactions. Our data illustrate how Prdx1 specifically coordinates p38MAPK-induced signaling through regulating p38MAPK? phosphatases in an H?O? dose-dependent manner. MAPK phosphatases (MKP-1 and/or MKP-5), which are known to dephosphorylate and deactivate the senescence-inducing MAPK p38?, 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 p38MAPK?. Conversely, over-oxidation of Prdx1-Cys52 was enhancing in the Prdx1:MKP-5 complex with increasing amounts of H?O? 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 p38MAPK? activity. Taken together, our data suggest that Prdx1 orchestrates redox signaling in an H?O? dose-dependent manner through the oxidation status of its peroxidatic cysteine Cys52.

SUBMITTER: Turner-Ivey B 

PROVIDER: S-EPMC3936261 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature