Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors

Abstract

A progressive rise of oxidative stress due to the altered reduction–oxidation (redox) homeostasis appears to be one of the hallmarks of the processes that regulate gene transcription in physiology and pathophysiology. Reactive oxygen (ROS) and nitrogen (RNS) species serve as signaling messengers for the evolution and perpetuation of the inflammatory process that is often associated with the condition of oxidative stress, which involves genetic regulation. Changes in the pattern of gene expression through ROS/RNS-sensitive regulatory transcription factors are crucial components of the machinery that determines cellular responses to oxidative/redox conditions. Transcription factors that are directly influenced by reactive species and pro-inflammatory signals include nuclear factor-κB (NF-κB) and hypoxia-inducible factor-1α (HIF-1α). Here, I describe the basic components of the intracellular oxidative/redox control machinery and its crucial regulation of oxygen- and redox-sensitive transcription factors such as NF-κB and HIF-1α.

Introduction

Molecular oxygen is an important environmental and developmental signal that regulates cellular energetics, growth and differentiation [1], [2], [3], [4]. Despite its central role in nearly all higher life processes, the molecular mechanisms for sensing oxygen levels and the pathways involved in transducing this information remain largely obscure [1], [3]. Oxygen, a gaseous element with colorless, odorless and tasteless appearance, is the most abundant element on planet earth, making up about 20% by volume of the atmosphere at sea level, about 50% of the material of the earth's surface and about 90% of water. Biologically, oxygen is necessary for sustaining the life processes of nearly all living organisms and, chemically, for most forms of combustion. It readily forms compounds with nearly all other known elements, except the inert gases, and it is used in blast furnaces, steel manufacture, chemical synthesis, in resuscitation and for many other industrial purposes. Oxygen, then, is an essential molecule for all aerobic life forms; however, oxygen plays univalent roles: while oxygen is indispensable for the cell to obtain the essential chemical energy as a form of ATP, it is often transformed into highly reactive forms, radical oxygen species (ROS), which are often toxic for the cell [1], [3], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. In order to defend themselves from the cytotoxic actions of ROS and other free radicals, cells have acquired multiplicity in endogenous antioxidant systems during the long evolutionary periods. These defense mechanisms include reduction–oxidation (redox) enzymatic systems such as glutaredoxin and thioredoxin [1], [2], [3], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. Studies having the nature of cell biology and molecular biochemistry have revealed that these molecules are also involved in cell signaling [1], [2], [3], [6], [15], [16], [17], [28], [33], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54]. The term ‘oxidative regulation’ has thus been proposed to indicate the active role of oxide-reductive modifications of proteins in regulating their functions. Oxide-reductive reactions of bio-molecules, mostly proteins, formerly considered as ‘oxidative stress,’ are now considered as ‘signals’ and contain biological information that is necessary for maintaining cellular homeostasis [1], [2], [3], [6], [24], [28], [35], [39], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73].

Altering gene expression is the most fundamental and effective way for a cell to respond to extracellular signals and/or changes in its environment, in both the short term and long term. In the short term, transcription factors are involved in mediating responses to growth factors and a variety of other extracellular signals In contrast, the long-term control of gene expression induced by growth factors and the changes in gene expression, which occur during development, are generally (with few exceptions) irreversible [1], [6], [17], [19], [21], [24], [28], [35], [50], [60], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105]. During development, the expression of specific sets of genes is regulated spatially (by position/morpho-genetic gradients) and temporally. Regulation of the signaling responses is governed at the genetic level by transcription factors that bind to control regions of target genes and alter their expression. Transcription factors are endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process, while in the cytoplasm, the transcription factor is incapable of promoting transcription. A signaling event, such as a change of the state of phosphorylation, occurs, which results in protein subunit translocation into the nucleus. Transcription is a process in which one DNA strand is used as a template to synthesize a complementary RNA. Signal transduction, therefore, involves complex interactions of multiple cellular pathways [1], [2]. In particular, interest in reduction–oxidation/oxygen (redox{y})-sensitive transcription factors has gained an overwhelming backlog of interest momentum over the years ever since the onset of the burgeoning field of free radical research and oxidative stress. The reason for this is that redox(y)-sensitive transcription factors are often associated with the development and progression of many human disease states; therefore, their ultimate regulation bears potential therapeutic intervention for possible clinical applications [9], [11], [12], [17], [22], [25], [37], [38], [42], [47], [54], [58], [69], [91], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120]. In this review, I will focus on elaborating a comprehensive overview of the current understanding of redox/oxidative mechanisms mediating the regulation of key transcription factors, particularly nuclear factor-κB (NF-κB) and hypoxia-inducible factor-1α (HIF-1α), which regulate a plethora of cellular functions that span the range from anoxia and hypoxia to extreme hyperoxia and oxidative stress, both in physiologic and pathophysiologic conditions.