RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-κB activation

Reactive oxygen species (ROS) produced by many kinds of stimuli are essential for cellular signaling including cell proliferation. The dysregulation of ROS, therefore, is related to a variety of diseases including cancer. However, it was not clearly elucidated how ROS regulate cell proliferation and tumorigenesis. In this study, we investigated a mechanism by which the oxidation of RhoA GTPase regulates nuclear factor-kappa B (NF-kappa B) and cell proliferation. Hydrogen peroxide activated NF-kappa B and RhoA GTPase, but did not activate RhoA C16/20A mutant, an oxidation-resistant form. Remarkably, the oxidation of RhoA reduced its affinity towards RhoGDI, leading to the dissociation of RhoA-RhoGDI complex. Si-Vav2, a guanine nucleotide exchange factor (GEF), inhibited RhoA activation upon hydrogen peroxide. The oxidized RhoA (oxRhoA)-GTP was readily bound to I kappa B kinase gamma (IKK gamma), whereas oxidized RhoGDI did not bind to IKK gamma. The oxRhoA-GTP bound to IKK gamma activated IKK beta, leading to I kappa B phosphorylation and degradation, consequently NF-kappa B activation. Hydrogen peroxide induced cell proliferation, but RhoA C16/20A mutant suppressed cell proliferation and tumorigenesis. Conclusively, RhoA oxidation at Cys16/20 is critically involved in cell proliferation and tumorigenesis through NF-kappa B activation in response to ROS.