UC Berkeley

Oncogenic RAS (H-RAS V12 ) induces premature senescence in primary cells by triggering production of reactive oxygen species (ROS), but the molecular role of ROS in senescence remains elusive. We investigated whether inhibition of protein tyrosine phosphatases by ROS contributed to H-RAS V12 -induced senescence. We identified protein tyrosine phosphatase 1B (PTP1B) as a major target of H-RAS V12 -induced ROS. Inactivation of PTP1B was necessary and sufficient to induce premature senescence in H-RAS V12 -expressing IMR90 fibroblasts. We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B. Phosphorylation of AGO2 at Tyr 393 inhibited loading with microRNAs (miRNAs) and thus miRNA-mediated gene silencing, which counteracted the function of H-RAS V12 -induced oncogenic miRNAs. Overall, our data illustrate that premature senescence in H-RAS V12 -transformed primary cells is a consequence of oxidative inactivation of PTP1B and inhibition of miRNA-mediated gene silencing. © 2014 Elsevier Inc. All rights reserved.