Elsevier

Cellular Signalling

Volume 24, Issue 5, May 2012, Pages 981-990
Cellular Signalling

Review
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling

https://doi.org/10.1016/j.cellsig.2012.01.008Get rights and content

Abstract

Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Oxidative stress refers to the imbalance due to excess ROS or oxidants over the capability of the cell to mount an effective antioxidant response. Oxidative stress results in macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging. Paradoxically, accumulating evidence indicates that ROS also serve as critical signaling molecules in cell proliferation and survival. While there is a large body of research demonstrating the general effect of oxidative stress on signaling pathways, less is known about the initial and direct regulation of signaling molecules by ROS, or what we term the “oxidative interface.” Cellular ROS sensing and metabolism are tightly regulated by a variety of proteins involved in the redox (reduction/oxidation) mechanism. This review focuses on the molecular mechanisms through which ROS directly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes, such as proliferation and survival (MAP kinases, PI3 kinase, PTEN, and protein tyrosine phosphatases), ROS homeostasis and antioxidant gene regulation (thioredoxin, peroxiredoxin, Ref-1, and Nrf-2), mitochondrial oxidative stress, apoptosis, and aging (p66Shc), iron homeostasis through iron–sulfur cluster proteins (IRE–IRP), and ATM-regulated DNA damage response.

Introduction

Reactive oxygen species (ROS), such as superoxide anion (O2), hydrogen peroxide (H2O2), and hydroxyl radical (HOradical dot), consist of radical and non-radical oxygen species formed by the partial reduction of oxygen. Cellular ROS are generated endogenously as in the process of mitochondrial oxidative phosphorylation, or they may arise from interactions with exogenous sources such as xenobiotic compounds. When ROS overwhelm the cellular antioxidant defense system, whether through an increase in ROS levels or a decrease in the cellular antioxidant capacity, oxidative stress occurs. Oxidative stress results in direct or indirect ROS-mediated damage of nucleic acids, proteins, and lipids, and has been implicated in carcinogenesis [1], neurodegeneration [2], [3], atherosclerosis, diabetes [4], and aging [5]. However, ROS involvement in the pathogenesis of disease states is not confined to macromolecular damage. There is increasing evidence that ROS signaling contributes to disease. For example, ROS have been shown to promote tumor metastasis through gene activation [6]. While there exists ample evidence demonstrating the role of ROS in regulating cellular signaling pathways, the question that is raised is exactly how do ROS initiate cellular signaling? The “oxidative interface” is that boundary between ROS and the signaling molecules they activate; that is, the figurative region that describes how ROS directly activate oxidative stress-responsive pathways. This review seeks to explore the oxidative interface between ROS and a functionally broad selection of cellular signaling pathways regulating a variety of cellular processes (Fig. 1).

In order to understand ROS regulation of signaling pathways, the mechanism of how ROS alters protein function should be briefly addressed. The oxidative interface consists mainly of the redox regulation of redox-reactive cysteine (Cys) residues on proteins by ROS. Oxidation of these residues forms reactive sulfenic acid (single bondSOH) that can form disulfide bonds with nearby cysteines (single bondSsingle bondSsingle bond) or undergo further oxidation to sulfinic (single bondSO2H) or sulfonic (single bondSO3H) acid; if nearby nitrogen is available sulfenic acid may also form a sulfenamide. These oxidative modifications result in changes in structure and/or function of the protein. With the exception of sulfonic acid, and to a lesser degree sulfinic acid, these redox modifications are reversible by reducing systems such as thioredoxin and peroxiredoxin [7] which are necessary given that these modifications function in redox sensing and signaling. For a more detailed overview of redox chemistry refer to Winterbourn [8] and Janssen-Heininger [9].

Section snippets

Regulation of MAPK signaling pathways by ROS

The mitogen-activated protein kinase (MAPK) cascades consist of four major MAPKs; the extracellular signal-related kinases (Erk1/2), the c-Jun N-terminal kinases (JNK), the p38 kinase (p38), and the big MAP kinase 1 (BMK1/Erk5). These kinases are evolutionarily conserved in eukaryotes and play pivotal roles in cellular responses to a wide variety of signals elicited by growth factors, hormones, and cytokines, in addition to genotoxic and oxidative stressors. The function and regulation of the

Regulation of PI3K signaling pathways by ROS

Another signaling pathway that plays a key role in cell proliferation and survival in response to growth factor, hormone, and cytokine stimulation is the phosphoinositide 3-kinase (PI3K) pathway. The PI3K, consisting of the p110 catalytic subunit and the p85 regulatory subunit, is tightly coupled with RTKs activated by various growth factors such as Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF), Nerve Growth Factor (NGF), insulin, and Vascular Endothelial Growth Factor

Nrf2 and Ref1-mediated redox cellular signaling

In order to prevent oxidative stress, the cell must respond to ROS by mounting an antioxidant defense system. Antioxidant enzymes play a major role in reducing ROS levels; therefore, redox regulation of transcription factors is significant in determining gene expression profile and cellular response to oxidative stress. Redox factor-1 (Ref-1) (Fig. 4A), identified as a 37-kDa protein that facilitates Fos-Jun DNA binding activity [53], was shown to be identical to an apurinic/apyrimidinic

Regulation of p66Shc, mitochondrial oxidative stress, and aging

ROS have been implicated in the process of aging. Given that the majority of endogenous ROS are generated in mitochondria [98], there has been much interest in the role that mitochondrial ROS may play in aging. Of note is the Shc adaptor protein family, encoded by the shcA locus in mammalian cells, consisting of the p66Shc, p52Shc, and p46Shc isoforms (Fig. 6) [99], [100], [101]. Expression of p66Shc and p52/p46Shc isoforms is regulated by two different promoters [102] along with alternative

Regulation of the IRE–IRP system and iron homeostasis by ROS

Iron is an essential element that plays crucial roles in cell proliferation and metabolism by serving as a functional constituent of various enzymes including ribonucleotide reductase and cytochrome P450. However, when present in excess, free iron generates ROS via the Fenton reaction [117], [118], [119], placing cells under deleterious oxidative stress. Therefore, tight regulation of iron homeostasis is crucial not only to maintain normal cellular function, but also to prevent iron-mediated

ROS and DNA-damage response

Ataxia–telangiectasia mutated (ATM) and Ataxia–telangiectasia and Rad3-related (ATR) are PI3K-like serine/threonine protein kinases activated under genotoxic stress conditions and phosphorylate various proteins involved in cell proliferation, cell death and survival, and DNA repair [140], [141]. These two signaling proteins were initially thought to be activated by a particular type of DNA damage therefore serving in parallel signaling pathways; however, accumulating evidence suggests that the

Conclusions

The disease states in which ROS signaling and toxicity have been implicated are areas of intensive research in regards to prevention and therapy. Unveiling the molecular mechanisms of disease pathogenesis and progression is therefore essential in providing relevant targets in order to develop innovative therapeutic strategies. In this context it is worthwhile not only to investigate ROS signaling in disease, but also to reveal how ROS instigate cellular signaling under homeostatic conditions.

Acknowledgment

This work was supported in part by NIH grant numbers R01 GM-088392 and R01 GM-095550 from the National Institute of General Medical Sciences to Y. Tsuji.

References (149)

  • M.C. Haigis et al.

    Mol. Cell

    (2010)
  • G. Roos et al.

    Free Radic. Biol. Med.

    (2011)
  • C.C. Winterbourn et al.

    Free Radic. Biol. Med.

    (2008)
  • Y.M. Janssen-Heininger et al.

    Free Radic. Biol. Med.

    (2008)
  • C.R. Weston et al.

    Curr. Opin. Cell Biol.

    (2007)
  • J.W. Ramos

    Int. J. Biochem. Cell Biol.

    (2008)
  • K. Takeda et al.

    J. Biol. Chem.

    (2007)
  • T.G. Choi et al.

    Biochim. Biophys. Acta

    (2011)
  • Z. Li et al.

    Blood

    (2006)
  • H. Kamata et al.

    Cell

    (2005)
  • R.M. Liu et al.

    J. Biol. Chem.

    (2010)
  • C.C. Wentworth et al.

    J. Biol. Chem.

    (2011)
  • T.C. Meng et al.

    Mol. Cell

    (2002)
  • S.R. Lee et al.

    J. Biol. Chem.

    (1998)
  • T.C. Meng et al.

    J. Biol. Chem.

    (2004)
  • I. Weibrecht et al.

    Free Radic. Biol. Med.

    (2007)
  • K. Lee et al.

    Free Radic. Biol. Med.

    (2002)
  • N.R. Leslie et al.

    Cell. Signal.

    (2002)
  • S.R. Lee et al.

    J. Biol. Chem.

    (2002)
  • I. Goren et al.

    J. Mol. Biol.

    (2001)
  • M. Ueno et al.

    J. Biol. Chem.

    (1999)
  • S. Merluzzi et al.

    Mol. Immunol.

    (2008)
  • T. Nguyen et al.

    J. Biol. Chem.

    (2000)
  • A.K. Jaiswal

    Free Radic. Biol. Med.

    (2000)
  • E.L. MacKenzie et al.

    Free Radic. Biol. Med.

    (2008)
  • R.B. Tjalkens et al.

    Arch. Biochem. Biophys.

    (1998)
  • T. Nguyen et al.

    J. Biol. Chem.

    (2009)
  • K. Itoh et al.

    Biochem. Biophys. Res. Commun.

    (1997)
  • M. Ishikawa et al.

    Free Radic. Biol. Med.

    (2005)
  • J.W. Kaspar et al.

    J. Biol. Chem.

    (2010)
  • R.S. Balaban et al.

    Cell

    (2005)
  • G. Pelicci et al.

    Cell

    (1992)
  • D. Trachootham et al.

    Nat. Rev. Drug Discov.

    (2009)
  • J.K. Andersen

    Nat. Med.

    (2004)
  • V. Shukla et al.

    Adv Pharmacol Sci.

    (2011)
  • T.M. Paravicini et al.

    Cardiovasc. Res.

    (2006)
  • K. Ishikawa et al.

    Science

    (2008)
  • M. Raman et al.

    Oncogene

    (2007)
  • A. Cuadrado et al.

    Biochem. J.

    (2010)
  • H. Ichijo et al.

    Science

    (1997)
  • K. Tobiume et al.

    EMBO Rep.

    (2001)
  • M. Saitoh et al.

    EMBO J.

    (1998)
  • G. Fujino et al.

    Mol. Cell. Biol.

    (2007)
  • H. Liu et al.

    Mol. Cell. Biol.

    (2000)
  • K. Tobiume et al.

    J. Cell. Physiol.

    (2002)
  • K. Morita et al.

    EMBO J.

    (2001)
  • A. Matsuzawa et al.

    Nat. Immunol.

    (2005)
  • F. Hofmann et al.

    Physiol. Rev.

    (2006)
  • J.R. Burgoyne et al.

    Science

    (2007)
  • J.P. Brennan et al.

    J. Biol. Chem.

    (1836)
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