Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells

doi:10.1016/j.gene.2004.04.032

Gene

Volume 337, 4 August 2004, Pages 1-13

https://doi.org/10.1016/j.gene.2004.04.032 Get rights and content

Abstract

Cell cycle progression is regulated by a wide variety of external factors, amongst them are growth factors and extracellular matrix factors. During the last decades evidence has been obtained that reactive oxygen species (ROS) may also play an important role in cell cycle progression. ROS may be generated by external and internal factors. In this overview we describe briefly the generation of ROS and their effects on processes that have been demonstrated to play an essential role in cell cycle progression, including such systems as signal transduction cascades, protein ubiquitination and degradation, and the cytoskeleton. These different effects of ROS influence cell cycle progression dependent upon the amount and duration of ROS exposure. Activation of growth factor stimulated signaling cascades by low levels of ROS result in increased cell cycle progression, or, in case of prolonged exposure, to a differentiation like growth arrest. From many studies it seems clear that the cyclin kinase inhibitor protein p21 plays a prominent role, leading to cell cycle arrest at higher but not directly lethal levels of ROS. Dependent upon the nature of p21 induction, the cell cycle arrest may be transient, coupled to repair processes, or permanent. At high concentrations of ROS all of the above processes are activated, in combination with enhanced damage to the building blocks of the cell, leading to apoptosis or even necrosis.

Introduction

Cells are able to duplicate by a process known as the cell cycle. This is one of the most fundamental properties of living organisms, allowing the organisms to reproduce themselves. Cell cycle research has gained enormous attention during the last decades, mainly because this knowledge is of considerable importance in fighting cancer as well as many other diseases. Knowledge on the regulation of cell cycle progression is also important for understanding embryonal development and is essential in many applied sciences. In general, cell cycle progression is regulated by external factors, amongst them are nutrients and growth factors. These external factors exhibit their effects on the cells by an elaborate intracellular signal transduction network, which ultimately results in progression through the cell cycle or alternatively to cell cycle arrest, cell differentiation or apoptosis. The features of the external cell cycle regulators as well as the signal transduction networks they activate have been subject of a wide variety of review articles, in which many details are described (see for instance: Heldin, 1996, Gutkind, 1998, Hulleman and Boonstra, 2001, Hulleman and van Rossum, 2003).

During the last decades it has become clear that in addition to the traditional cell cycle regulators as nutrients, growth factors and hormones, also less traditional factors may have an important impact on cell cycle regulation. Of these latter the reactive oxygen species (ROS) are of special interest. ROS are commonly thought to be toxic, resulting in oxidation of various cell constituents as DNA, lipids and proteins and consequently these oxidations may cause damage to the cellular machinery leading to cell death as the ultimate consequence. ROS have been implicated in an ever-increasing number of diseases and syndromes. These include various forms of non-hormone dependent cancers, atherosclerosis, ischemic reperfusion injury, neurodegenerative diseases, chronic inflammatory diseases, such as rheumatoid and psoriatic arthritis, and some factors underlying the ageing process itself Halliwell and Gutteridge, 1999, Ames et al., 1993b, Shackelford et al., 2000. Whether ROS are the primary agents causing the disease, or formed secondary as a consequence of some metabolic disorder or environmental influence remains debatable and to some extent a matter of perspective. Next to playing a role in pathological conditions, evidence is now accumulating that ROS might also play a role as signaling molecules and as such they may have a role in cell cycle progression. In this contribution we will consider the effects of ROS in cells and describe the effects of ROS on cell cycle progression.

Section snippets

Reactive oxygen species

Free radicals are molecules that contain one or more unpaired electrons in their highest occupied atomic or molecular orbital. Because electrons are more stable when paired in orbitals, radicals are extremely reactive compared with non-radicals. Based on this definition a compound such as hydrogen peroxide can not be considered as a free radical. However since, in the presence of transition metals, H₂O₂ can easily give rise to the highly reactive hydroxyl radical (OH^•), in general one speaks of

Regulation of cell cycle progression

In virtually all cells, the cell cycle is composed of four discrete phases, being the DNA synthesis phase (S phase), the cell division phase (M phase) and the gap phases between these two, the G1 phase between M and S phases and the G2 phase between S and M phases (Fig. 2). Progression through the cell cycle is dependent upon the integration of a large number of intra- and extra-cellular signals that integrate also with intrinsic genetic controls, resulting in several checkpoints in different

ROS and cell cycle progression

ROS cause a wide range of adaptive cellular responses ranging from transient growth arrest to permanent growth arrest, to apoptosis or to necrosis, dependent on the level of ROS. These responses to allow organisms to remove damage caused by ROS or allow organisms to remove damaged cells. In addition however, low levels of ROS have been demonstrated to cause an increase in cell cycle progression, in this latter case ROS have usually an endogenous origin Martindale and Holbrook, 2002, Davies, 2000

Acknowledgements

We would like to thank our (former) co-workers for their contributions. Due to space constraints and the huge body of literature, we have been unable to cite all original papers. We therefore apologize to authors whose work on this subject area may have been omitted.

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ReviewMolecular events associated with reactive oxygen species and cell cycle progression in mammalian cells

Abstract

Introduction

Section snippets

Reactive oxygen species

Regulation of cell cycle progression

ROS and cell cycle progression

Acknowledgements

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Am. J. Respir. Cell Mol. Biol.

Mechanisms of target recognition and destruction in macrophage-mediated tumor cytotoxicity

Fed. Proc.

Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats

J. Clin. Invest.

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogesis

Environ. Health Perspect.

Oxidants, antioxidants, and the degenerative diseases of aging

Proc. Natl. Acad. Sci. U. S. A.

Activation of delta-isoform of protein kinase C is required for oxidant-induced disruption of both the microtubule cytoskeleton and permeability barrier of intestinal epithelia

J. Pharmacol. Exp. Ther.

Hydrogen peroxide activation of multiple mitogen-activated protein kinases in an oligodendrocyte cell line: role of extracellular signal-regulated kinase in hydrogen peroxide-induced cell death

J. Neurochem.

Ascorbic acid-dehydroascorbate induces cell cycle arrest at G2/M DNA damage checkpoint during oxidative stress

Environ. Mol. Mutagen.

Role of cyclins and cyclin-dependent kinases in G1 phase progression

Progression through the G1-phase of the on-going cell cycle

J. Cell. Biochem.

Restriction points in the G1 phase of the mammalian cell cycle

Activation of the c-fos gene by UV and phorbol ester: different signal transduction pathways converge to the same enhancer element

Oncogene

Review
Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells

Ascorbic acid-dehydroascorbate induces cell cycle arrest at G₂/M DNA damage checkpoint during oxidative stress