Oxidative stress, redox regulation and diseases of cellular differentiation

doi:10.1016/j.bbagen.2014.11.010

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1850, Issue 8, August 2015, Pages 1607-1621

https://doi.org/10.1016/j.bbagen.2014.11.010 Get rights and content

Highlights

•
Redox homeostasis mediates cell pathways that determine life and death events.
•
Aberrant redox homeostasis causes pathologies linked with differentiation.
•
ROS intersects with GSH based enzyme pathways to influence cell differentiation.
•
Redox targeted differentiation therapy provides a drug discovery platform.

Abstract

Background

Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers.

Scope of review

We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects.

Primary conclusions

Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development.

General Significance

The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

Section snippets

Oxygen

Earth’s atmosphere presently contains 78% nitrogen and 21% oxygen. Life has evolved within this biosphere such that higher eukaryotes derive much of their energy requirements through oxidative metabolism, to date the most efficient means of generating ATP and sustaining life. During the Precambrian epoch, oxygen was present at trace levels, but at given points in an evolving geology, increased and decreased, reaching a maximum of 35% during the Carboniferous period. Obviously, life has adapted

Sources of ROS/free radicals

Although molecular oxygen has two unpaired electrons in different orbitals, it is not per se a free radical, which by definition contain a single unpaired electron. The term ROS refers to a number of chemically reactive molecules derived from O₂, while RNS are derivative of nitrogen and oxygen, particularly nitric oxide (NO). In general the half-lives of RNS are longer than ROS [2], [3]. Three of the most common and biologically important ROS are O₂⁻ (superoxide anions), H₂O₂ (hydrogen

Cellular antioxidant systems

Excessive or uncontrolled production of ROS can cause damage to nucleic acids, proteins and lipids and this is closely associated with human disease pathogenesis. Here, the salient point is that ROS need not be harmful to normal cellular functions as long as redox homeostasis is iteratively regulated; indeed, ROS/RNS are important signaling messengers for proliferation, differentiation, apoptosis and other critical events during development. Growth in multicellular organisms depends on

Human pathologies influenced by ROS and differentiation pathways

There is a growing body of literature supporting crucial roles for ROS in the pathogenesis of many diseases, including those related to cell differentiation (e.g. cancer due to loss of differentiation, bone loss-associated disorders due to osteoclast differentiation or type 2 diabetes due to beta-cell dedifferentiation) (Table 2). Accumulation of ROS together with depletion of reducing molecules shifts the cellular redox environment to a more oxidized state. ROS-mediated redox regulation may be

Redox active drugs used for differentiation/redox therapy

Despite many encouraging results obtained both in vivo and in vitro, the only existing successful clinical application of differentiation therapy is ATRA for acute promyelocytic leukemia. ATRA is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoic acid, plays an important role in mediating the growth and

Conclusion

Conflict of interest

All authors state that they have no conflicts of interest.

Acknowledgements

This work was supported by grants from the National Institutes of Health (CA08660, CA117259, NCRR P20RR024485 − COBRE in Oxidants, Redox Balance and Stress Signaling) and support from the South Carolina SmartState program and was conducted in a facility constructed with the support from the National Institutes of Health, Grant Number C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. Supported in part by the Drug Metabolism and Clinical

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^☆: This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

¹: These authors contribute equally.

View full text

ReviewOxidative stress, redox regulation and diseases of cellular differentiation☆

Highlights

Abstract

Background

Scope of review

Primary conclusions

General Significance

Section snippets

Oxygen

Sources of ROS/free radicals

Cellular antioxidant systems

Human pathologies influenced by ROS and differentiation pathways

Redox active drugs used for differentiation/redox therapy

Conclusion

Conflict of interest

Acknowledgements

Ageing Res. Rev.

Free Radic. Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Pathol. Res. Pract.

Int. J. Dev. Neurosci.

Biochim. Biophys. Acta

Exp. Gerontol.

Mol. Cell

Immunity

J. Biol. Chem.

Biochim. Biophys. Acta

Free Radic. Biol. Med.

Adv. Cancer Res.

Mutat. Res.

Biochem. Pharmacol.

Biochim. Biophys. Acta

J. Biol. Chem.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

J. Biol. Chem.

Methods Enzymol.

Free Radic. Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Leuk. Res.

J. Biol. Chem.

Blood

Cancer Lett.

Blood

Exp. Cell Res.

J. Biol. Chem.

Bone

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

J. Biol. Chem.

Adv. Nutr.

Redox control of the survival of healthy and diseased cells

Antioxid. Redox Signal.

Free radicals and metal ions in health and disease

Proc. Nutr. Soc.

Redox regulation of cell survival

Antioxid. Redox Signal.

Cellular mechanisms and physiological consequences of redox-dependent signalling

Nat. Rev. Mol. Cell Biol.

Redox regulation of OxyR requires specific disulfide bond formation involving a rapid kinetic reaction path

Nat. Struct. Mol. Biol.

Requirement for generation of H2O2 for platelet-derived growth factor signal transduction

Science

Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms

Oncogene

Endogenous nitric oxide synthesis: biological functions and pathophysiology

Free Radic. Res.

Review
Oxidative stress, redox regulation and diseases of cellular differentiation☆