Jnk1 activity lowers the cellular production of H 2O 2 and modulates the growth arrest response to scavenging of H 2O 2 by catalase

Abstract

Hydrogen peroxide (H 2O 2) can interact with intracellular signaling pathways to regulate cell behavior. The c-Jun NH 2-terminal kinase 1 (JNK1) signal, involved in diverse aspects of cellular functioning, is implicated as a cell sensor of redox stress. The growth-inhibitory effect of both high-level H 2O 2 and H 2O 2-scavenging catalase treatments is accompanied by increased JNK1 activity. To investigate the role of this response in growth regulation, the JNK1 signal was increased by the introduction of ectopic HA-JNK1. HA-JNK1 expression correlated with increases in basal c-Jun phosphorylation in a dose-dependent manner. Transient expression of HA-JNK1 potentiated cell growth arrest by catalase; however, with stable expression a degree of resistance to this response was observed. Resistance was accompanied by a lowered endogenous production of H 2O 2. Transient HA-JNK1 expression also reduced H 2O 2 generation, and this effect was reversed by the JNK inhibitor SP600125. These results indicate that the JNK1 stress response contributes to growth inhibition by catalase treatment via inhibition of cellular H 2O 2 production. Stable amplification of the JNK1 pathway leads to cellular adaptation to its signal, resulting in a diminished reliance upon H 2O 2 for efficient growth.