Thioredoxin and protein kinases in redox signaling

Reactive oxygen species (ROS) play critical roles for the determination of cell fate by eliciting a wide variety of cellular responses, such as proliferation, differentiation and apoptosis. Many intracellular signaling pathways involved in such ROS-induced cellular responses are regulated by the intracellular redox state, which depends on the balance between the levels of oxidizing and reducing equivalents. Recently, increasing attention has been paid to the roles of thioredoxin (Trx) as a signaling intermediate beyond its intrinsic antioxidant activity. Especially, Trx participates in the control of the mitogen-activated protein kinase (MAPK) cascades through the redox state-dependent association and dissociation with apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of the cascades. This review highlights the current understanding of prototypical molecular mechanisms by which the redox signal is converted into the signaling through ROS-responsive protein kinases, with a special focus on the ASK1-Trx system. Understanding of such mechanisms may provide the basis for therapeutic interventions in redox-related diseases including various types of cancer. (c) 2006 Elsevier Ltd. All rights reserved.