Elsevier

Seminars in Cancer Biology

Volume 16, Issue 6, December 2006, Pages 427-435
Seminars in Cancer Biology

Review
Thioredoxin and protein kinases in redox signaling

https://doi.org/10.1016/j.semcancer.2006.09.003Get rights and content

Abstract

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.

Introduction

Cells that constitute aerobic organisms are continuously exposed to reactive oxygen species (ROS) generated by aerobic metabolism. ROS such as superoxide anion radical, singlet oxygen, hydrogen peroxide (H2O2) and highly reactive hydroxyl radicals are generated by electron transport through the mitochondrial respiratory chain, NADPH cytochrome P450 reductase in the endoplasmic reticulum (ER), hypoxanthine/xanthine oxidase, NADPH oxidase, lipoxygenase and cyclooxygenase and by various cytotoxic stresses including γ-ray and ultraviolet (UV) light irradiation. ROS play critical roles for the determination of cell fate by eliciting a wide variety of cellular responses, such as proliferation, differentiation and apoptosis, depending on cell types, cellular contexts and amounts and duration of ROS generation [1], [2]. In many cases, low concentrations of ROS promote cell survival and proliferation. For instance, the activity of nuclear transcription factors such as nuclear factor κB (NF-κB) and activator protein-1 (AP-1), which are essential for cell growth and differentiation, are promoted by ROS [3].

Many intracellular signaling pathways involved in ROS-induced cellular responses are regulated by the intracellular redox state, which depends on the balance between the levels of oxidizing and reducing equivalents. Excessively generated ROS is generally counteracted by ubiquitously expressed antioxidant proteins represented by thioredoxin (Trx), glutaredoxin and glutathione. Once the generation of ROS exceeds the capacity of the antioxidant proteins, cells suffer so-called “oxidative stress”, which causes cells to severe dysfunctions or death. Oxidative stress therefore is extensively involved in pathogenesis of a wide range of sporadic and inherited diseases such as inflammation, ischemic tissue damage and neurodegenerative disorders. Oxidative stress also induces DNA damage that leads to cancer promotion and progression through genomic instability. On the other hand, ROS-induced apoptosis is thought to be one of the defense mechanisms against such oxidative stress-induced carcinogenesis. Intracellular redox balance thus is a critical determinant of cell fate and cellular functions (Fig. 1).

Various intracellular signaling molecules sense physiological fluctuations and imbalances of redox state and evoke the appropriate signals for cellular responses. Although Trx (unless indicated, cytosolic thioredoxin 1 is referred to as Trx in this review) contributes to balance the intracellular redox state as a general protein disulfide reductant [4], increasing attention has been paid to the roles of Trx as a signaling intermediate that senses the redox state and transmits its information to signaling molecules such as protein kinases [5], [6], [7]. In this review, we discuss the possible roles of Trx in redox signaling, especially in which the redox signal is converted into the signaling through ROS-responsive protein kinases.

Section snippets

ROS and MAPK cascade

Mitogen-activated protein kinase (MAPK) cascades are evolutionarily well conserved in all eukaryotic cells and are among the most extensively studied intracellular signaling systems [8], [9]. MAPKs phosphorylate specific serines and threonines of target proteins, and then induce a variety of cellular processes such as gene expression, mitosis and apoptosis. Each MAPK cascade typically includes central three-tiered core signaling modules comprising a MAPK kinase kinase (MAP3K), MAPK kinase

Regulation of PI3K-Akt through the interaction between Trx and PTEN

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known as a tumor suppressor and a phosphatidylinositol(3,4,5)trisphosphate [PtdIns(3,4,5)P3]3-phosphatase that regulates many cellular processes through direct antagonism of phosphatidylinositol 3-kinase (PI3K) signaling. ROS has been shown to inactivate PTEN by causing intramolecular disulfide bond formation including the essential cysteine residue in the active site of PTEN. Following the inactivation of PTEN, cellular

Conclusions and perspective

The redox state regulates multiple cellular signaling pathways in concert with extra- and intracellular stimuli. To maintain the physiological redox state, Trx contributes to balance the intracellular redox state as a general protein disulfide reductant. Recent progress in the understanding of Trx function, on the other hand, has focused on the regulatory roles of Trx as an intermediate of ROS-mediated signaling. The ASK1–Trx system is the prototypical model of such regulatory roles of Trx; Trx

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