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Gene expression and the thiol redox state

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Abstract

The intracellular redox status is a tightly regulated parameter which provides the cell with an optimal ability to counteract the highly oxidizing extracellular environment. Intracellular redox homeostasis is regulated by thiol-containing molecules, such as glutathione and thioredoxin. Essential cellular functions, such as gene expression, are influenced by the balance between pro- and antioxidant conditions. The mechanism by which the transcription of specific eukaryotic genes is redox regulated is complex, however, recent findings suggest that redox-sensitive transcription factors play an essential role in this process. This review is focused on the recent knowledge concerning some eukaryotic transcription factors, whose activation and DNA binding is controlled by the thiol redox status of the cell.

Introduction

In the face of an oxidizing environment, the redox status that exists inside the cell is tightly controlled and remains relatively constant unless cells are exposed to drastic oxidizing conditions. This redox homeostasis is crucial for numerous biological events to occur, such as enzyme activation, DNA synthesis, cell cycle regulation, transcriptional activation of specific genes, and programmed cell death [1]. In addition, redox homeostasis controls the level of reactive oxygen species (ROS) that are constantly formed as side products of biological reactions that use electron transfers, such as oxidative phosphorylation, oxidases (xanthine, NADPH, … ), and reductases activity [2], [3]. Small variations in the basal level of intracellular ROS have been shown to modulate the cell metabolism, gene expression, as well as post-translational modification of proteins [4]. However, when the level of ROS exceeds the antioxidant capacity of the cell, they become toxic leading to oxidative injuries. Oxidative stress can be observed in different pathologic states, such as cancer, atherosclerosis, rheumatoid arthritis, acquired immunodeficiency syndrome (AIDS), Parkinson’s, and Alzheimer’s diseases or when cells are exposed to different oxidative agents (peroxides, glutathione depriving drugs, toxins, radiations, or high doses of inflammatory cytokines).

Cells have developed sophisticated mechanisms in order to maintain redox homeostasis and/or to try cope with the excess of ROS produced during oxidative stress. These protective mechanisms either scavenge and/or detoxify ROS, block their production, or sequester transition metals that are source of free electrons [2], [3]. They include detoxifiant enzymes, vitamins C and E or thiol-containing molecules (glutathione, thioredoxin, redox factor-1 [Ref-1] … ). The major regulator of intracellular redox status is glutathione, a cysteine containing tripeptide with reducing and nucleophilic properties [5], [6]. This tripeptide exists in either a reduced (GSH) or oxidized (GSSG) form and participate in redox reactions through the reversible oxidation of its active thiol. In addition, glutathione acts as a coenzyme of numerous enzymes involved in cell defense (i.e., glutathione peroxidases, glutathione-S-transferases, thioltransferases, formaldehyde dehydrogenase and glyoxalase I, and maleylacetoacetate isomerase). In unstressed cells, the majority (99%) of this redox regulator is in its reduced form and its intracellular concentration is between 0.5 and 10 mM depending on the cell type. Analysis of the intracellular distribution glutathione, and in particular of its reduced and oxidized form, is still problematic. However, recent results using fluorescent probes have revealed that glutathione can redistribute in the nucleus [7]; a phenomenon amplified by the expression of the anti-apoptotic protein Bcl-2 [8]. Glutathione is also present in the endoplasmic reticulum (ER) and mitochondria. In the ER, an elevated concentration of oxidized glutathione favors protein disulfide bonds formation [9].

Intracellular redox state is also modulated by the small pleiotropic polypeptide thioredoxin (TRX), also known as adult T-cell leukemia-derived factor [10], [11]. This ubiquitous protein, which has two redox-active half-cystine residues [12], [13], [14], [15], is particularly important for gene expression as it facilitates protein-nucleic acid interactions [13] by reducing cysteine in the DNA-binding loop of several transcription factors [16], [17], [18], [19].

Ref-1 [18], [20], [21], [22], [23], [24], previously characterized as the DNA repair enzyme HAP-1, is a protein which, under oxidizing conditions, facilitates the binding of several transcription factors to DNA. The mechanism by which Ref-1 stimulates the DNA-binding activity of transcription factors is thought to occur through the reduction of crucial cysteine residues located in the binding domain of these proteins. Analysis performed by site-directed mutagenesis identified cysteine 65 as the redox active site in the Ref-1 enzyme [21]. In oxidative conditions, cysteine 65 forms a disulfur bond with cysteine 93, a phenomenon that abolishes the stimulatory activity of Ref-1. Active Ref-1 is recycled via its interaction with the hydrogen donor polypeptide TRX [23].

Oxidative stress is a well-known inducer of the transcription of specific genes, however, the mechanism by which oxidants and/or antioxidants modulate the transcription of specific genes is not yet fully understood. Gene activation by oxidative stress was first described in bacteria where regulatory proteins such as oxyR [25] or soxRS [26] were discovered. In eukaryots, a typical example is the heme oxigenase gene that is induced by hydrogen peroxide and ultraviolet irradiation [27], [28]. Other activated genes include those encoding TRX, detoxifiant enzymes (Mn2+-dependent superoxide dismutase, glutathione S-transferase, NAD(P)H:quinone reductase), cytokines, transcription factors, viral proteins, immunoreceptors, and growth factors.

In eukaryots, the mechanism by which oxidative stress and/or variation in the intracellular redox state modulate gene expression appears far more complex than in bacteria. Recent studies have focused on the crucial role played by transcription factors. These proteins bind to the promoter regions of target genes and, by doing so, they allow their transcription by RNA polymerase II. Two major steps in the transcriptional activation of several eukaryotic transcription factors have been described to be influenced by the redox balance. The first step concerns the mechanism of activation of the transcription factor, which allows its redistribution into the nucleus. The second step deals with the binding of the transcription factor to the promoter region located in the 5′ end of the target genes. Indeed, several transcription factors contain in their protein sequence cysteine residues (which are redox sensitive through their thiol group) localized in their DNA binding domain. These cysteines are often essential for the recognition of the binding site through electrostatic interactions with specific DNA bases. Oxidation of these cysteines results in the inhibition the binding of the factor. As described below, the presence in the nucleus of TRX and/or Ref-1 is often required to locally promote a reducing environment that avoid the oxidation of cysteines present in the DNA domain of several transcription factors [13], [18], [20].

It is also possible that oxidized cysteines give rise to inter- or intramolecular disulfide bonds. In this case, cysteine thiols regulate the tridimensional structure of the transcription factor or its binding to a protein cofactor (transcription factor that are active as dimer). Finally, four cysteines and/or histidines, localized at specific sites along the protein sequence, can electrostatically interact with a zinc atom to form a “zinc finger” structure that fits in the large DNA groove. Consequently, because of the sensitivity of thiol group to redox state variations, the activity of several transcription factors can be profoundly modified if their cysteine residues are oxidized or if they are unable to form the appropriate disulfide bond. Moreover, the simple oxidation of the sulfur atom of cysteine by oxygen atoms (-SH oxidized in -SOH or -SO2H) can be critical. Variations in the intracellular redox state mediated by a nonlethal oxidative stress can, therefore, transiently modify the activity of several transcription factors. Depending on the transcription factor and its own mechanism of activation, this modulation can be positive or negative and, therefore, can upregulate or downregulate gene expression.

Recent knowledge concerning the modulation of the activity of several transcription factors by thiol redox state will be reviewed (Fig. 1). Emphasis will be given to three well-defined transcription factors: NF-κB (nuclear factor κB) [29]; AP-1 (activator protein-1) [30], [31], and HSF1 [32], which confer inducible gene expression.

Analysis of the transcriptional activation mediated by the intronic κ light chain enhancer and the promoter located in the long terminal repeat (LTR) of human immunodeficiency virus-1 (HIV-1) have revealed a DNA sequence (GGAnnnTCC), denoted κB, recognized by the protein factor NF-κB. Excepted in mature B cells where NF-κB is constitutively active, this factor needs to be activated by different agents and conditions, particularly oxidative stress, to migrate in the nucleus and bind DNA. NF-κB regulates a wide variety of cellular genes, particularly those involved in immune and inflammatory responses [29].

The more frequent form of NF-κB is a heterodimer complex containing the p50 and p65/RelA subunits. These proteins reside in the cytoplasm in a latent form through their association with a family of cytoplasmic inhibitors, the most frequent one being IκB-α. Upon activation, NF-κB-IκB-α complexes are dissociated, thereby allowing free NF-κB dimers to translocate into the nucleus and activate the transcription of genes containing κB regulatory elements. Phosphorylation of IκB-α and its subsequent degradation by the proteasome is involved in this process [29].

NF-κB is activated by an extraordinarily large number of conditions and agents, which usually generate a pro-oxidant state by disrupting the intracellular redox homeostasis [33], [34], [35]. N-acetylcysteine (NAC), elevated level of intracellular glutathione level and extracellular cysteine supply can inhibit the activation of NF-κB by numerous different agents [36]. Moreover, agents that neutralize free radicals such as dithiocarbamate (DTC), pyrrolidine dithiocarbamate (PDTC) [37], as well as a natural antioxidant lipoic acid [38] gave similar results. Expression of small stress proteins that increases the concentration of glutathione in L929 cells also abolishes the NF-κB activation in response to oxidative stress [39]. A glutathione depletion in HIV-1 infected lymphocytes is also thought to be responsible for an indirect stimulation of the virus through NF-κB activation [40]. An interesting study by Schmidt et al. [41], using mouse JB6 cell lines that overexpress catalase, clearly showed that the overexpression of this detoxifiant enzymes inhibited the activation of NF-κB by TNFα or okadaic acid. In contrast, Cu/Zn-dependent superoxide dismutase overexpression stimulated the activation mediated by these agents. We also showed that the TNF-α and H2O2 mediated activation of NF-κB in human T47D carcinoma cells is abolished by the overexpression of seleno-dependent glutathione peroxidase (GSHPx) [42]. This effect was no longer observed when the concentration of selenium, a trace element required for GSHPx activity, was decreased; hence confirming earlier observation that selenium is a key regulator of NF-κB activation [43]. These observations together with the fact that NF-κB activation by TNF-α is inhibited by free radical trapping agents suggests that this activation is not mediated by peroxide but rather by more downstream free radicals. Analysis of IκB-α phosphorylation and degradation revealed that these free radicals act by stimulating the phosphorylation of IκB-α [42]. However, it is not yet known whether these radicals directly stimulate the activity of IκB-α kinase (IKKα or β) or act at upstream of this kinase step. Another interesting target is the proteasome whose activity also appears to be modulated by changes in intracellular redox homeostasis [44].

Despite the observations mentioned above, several reports have suggested that pro-oxidant conditions by themselves are not sufficient to activate NF-κB in all cell types [38], [45]. For example, the pro-oxidant diamide will or will not activate NF-κB according to the cellular type and the type of inducer [38]. It was also found that, depending on the cellular type, TRX can either activate or inhibit NF-κB [16]. Moreover, the DNA-binding of the NF-κB p50 subunit has been reported to be increased by 1,4-dithiothreitol and abolished by N-ethylmaleimide. Recent evidence also suggest that TRX upregulates DNA binding of activated NF-κB in vitro and enhances κB-dependent gene expression in vivo [17], [46]. To conciliate these observations, it has been postulated that oxidative conditions in the cytoplasm favor the activation and transport of NF-κB to the nucleus, and that reducing conditions in nuclei are required in some cellular types to favor the binding of NF-κB to DNA [47]. In the later cell compartment, TRX is thought to act by reducing a critical residue of P50 that was identified as cysteine 62 [16].

Another example of a transcription factor modulated by intracellular redox state is activator protein-1 (AP-1) that binds to the so-called TPA response element (TRE) (5′-TGAG/CTCA-3′) [48], [49] present in the promoter region of a wide variety of genes implicated in cell proliferation and tumor promotion. AP-1 is activated by several stimuli including growth factors, protein kinase C (PKC) activators, and modulators of intracellular redox homeostasis [50].

AP-1 is a dimeric factor composed of the c-Jun and c-Fos proteins, products of the c-jun and c-fos proto-oncogenes. Other proteins related to c-Fos and c-Jun (such as JunB, JunD, FosB, Fra1, and Fra2 [51]) are also known, which altogether form the Jun and Fos families of proteins. Interaction between Jun and Fos via a “leucine zipper” domain [30], [31], [52] is required for binding to TRE. Homo- and heterodimers can be formed by the Jun proteins while the Fos proteins cannot form homodimers. Consequently, different AP-1 transcription factors exists that show modulated affinities to TRE and to the various sequences that slightly deviate from it.

Activation of AP-1 is regulated by complex mechanisms. It first requires the synthesis of c-Fos and c-Jun proteins and will generate dimeric AP-1 factors whose composition is different during the activation process [53]. Upon stimulation, a rapid induction of c-jun and c-fos genes is observed, which leads to a transient accumulation of c-Jun and c-Fos proteins. This induction of c-jun and c-fos genes is protein synthesis independent and under the control of different sites in the promoter of these genes. In the case of c-jun, an AP-1-like binding site (TRE) exists in the promoter of this gene, which is recognized by pre-existing c-Jun homodimer; a phenomenon that requires a specific dephosphorylation of pre-existing c-Jun polypeptides. Concerning the c-fos promoter, the transcriptional stimulation of this gene is under the control of SRF (serum response factor), which binds to SRE (serum response element) [54]. This phenomenon is further regulated by the ets family of proto-oncogenes, which confers stimulatory effects on the SRE upon phosphorylation by MAP kinases. Both the binding of SRF to SRE and the DNA binding of oncogenic v-ETS are highly sensitive to intracellular redox [55], [56]. In the case of v-ETS, cysteine 394 appears responsible of the effect [56].

Both c-jun and c-fos genes are induced by agents that promote intracellular ROS accumulation such as TNFα, UV irradiation, hydrogen peroxide and mitogens [57], [58]. The mechanism that regulates AP-1 activation has been suggested to result from thiol redox status perturbation [59]. However, different results have been obtained, suggesting that the mode of action of thiol antioxidants is probably very complex. For example, the oxidative stress–mediated activation of c-jun/c-fos gene expression by abeistos is stimulated by NAC [60], while this compound prevents the induction mediated by hydrogen peroxide [61]. Moreover, overexpression of TRX and other reducing thiol (PDTC, NAC) increases phorbol ester–induced activation of AP-1 [62]. AP-1 is also activated by certain antioxidant compounds [55], such as those of phenolic origin (d-α-tocopherol and butylated hydroxytoluene and butylated hydroxyanisole) [63], [64]. Hence, AP-1 also acts as a secondary antioxidant-responsive transcription factor and TREs are considered as potent ARE (antioxidant response elements) [55].

An intriguing observation concerns the weak ability of AP-1 to bind TREs in cells exposed to hydrogen peroxide, which contrasts with the strong induction of the c-jun and c-fos mRNAs induced by this oxidant [65], [66], [67]. This phenomenon results from the fact that the binding of the Fos-Jun complex to DNA relies on the reduction of a conserved cysteine in the DNA binding domain of the two proteins [21], [22]. Substitution of the cysteine residue (cyst 252 in c-Jun) by serine enhanced the DNA-binding activity of Fos-Jun that was no longer redox regulated. A similar mutation is observed in v-Jun, hence suggesting that the transforming activity of this oncogene may result, at least in part, of a mutated regulatory cysteine residue [22]. The binding of the Fos-Jun complexes to DNA is facilitated by Ref-1 [20], [21]. This polypeptide acts by reducing the critical cysteine of c-Jun; an activity recycled by the hydrogen donor capability of TRX [23].

HSF1 belongs to a family of heat shock factors whose activation and DNA binding is mediated by stresses that disrupt thiol homeostasis. Stress-induced transcription of heat shock (or stress) genes requires activation of HSF1 that binds to the heat shock promoter element (HSE), characterized as multiple adjacent and inverse iterations of the motif 5′-nGAAn-3′ [32]. Activation of HSF1 is characterized by the conversion of this factor from a monomer to trimer state, a phenomenon induced by heat shock and a large variety of different chemicals or conditions that generate abnormally folded proteins. The mechanism promoting non-native proteins as well as the signal transduction mechanism resulting in HSF1 trimerization is still not well understood, but may be related to the fact that stress such as heat shock promotes intracellular oxidative damage [68]. Several studies have evaluated the effects of thiol-reducing agents on HSF1 activation. It was found that the incubation of cells with dithiothretol (DTT) inhibited the heat-mediated trimerization, phosphorylation, nuclear translocation, and DNA-binding activity of HSF1 [69]. This agent, however, failed to modulate the DNA-binding activity of activated HSF1 when it was added to cell extracts. DTT also inhibits the nephrotoxic cysteine conjugates (NCC) [70] or iodoacetamide (IDAM) [71] activated transcription of hsp70 gene. The covalent binding of NCC-derived reactive metabolites leads to a cascade of events including nonprotein thiols depletion, while IDAM induces protein alkylation through glutathione depletion and oxidative stress generation. Experiments were also performed to test the effect induced by glutathione depletion, which causes oxidation of protein thiols, protein denaturation, and aggregation [72]. It was observed that glutathione depletion increased HSF1 activation induced by hyperthermia [73], alkylating agents [71], and 12-prostaglandin J2 [74]. Other studies showed that thiol oxidation–induced production of non-native protein disulfides mediated by the diazenecarbonyl derivative diamide, induces HSF1 DNA binding and hsp70 gene transcription [75]. Recently, a study has carefully analyzed the effect induced by 13 different stress response inducers, including heat shock [76]. It was shown that all these agents or conditions trigger oxidation of thiols containing molecules, particularly glutathione, leading to the formation of GSSG, glutathione-protein mixed disulfides and protein-protein disulfides, under conditions that they induce trimerization of HSF1 and its binding to DNA. These observations, together with the fact that HSF1 binding activity is attenuated under anoxic condition, suggest the involvement of a redox-dependent step during the early transduction pathway that leads to HSF1 activation. Two subsequent steps can be identified: (i) disruption of intracellular thiol-disulfite redox homeostasis, which leads to the formation of disulfide linked aggregates of cellular proteins; and (ii) the recognition of denatured proteins by pre-existing protein chaperones, a phenomenon that triggers HSF1 trimerization. This latter step does not appears to require HSF1 oxidation [76].

HSF1 DNA-binding ability in vitro has been reported to be decreased by hydrogen peroxide, diamide, or alkylating agents such as iodoacetic acid. In contrast, hydrogen peroxide in vivo activates HSF1, but only after a long delay compared to heat shock [77]. This leads to the hypothesis that HSF1 is dually regulated by oxidants. On one hand, hydrogen peroxide favors the nuclear translocation of HSF1, while in the other, it alters HSF1 DNA-binding activity, most likely by oxidizing critical cysteine residues. Of interest, kinetic experiments have revealed that hydrogen peroxide upregulates TRX before HSF1 activation could be detected. Hence, it can be hypothesized that reducing conditions generated by TRX upregulation are required to trigger HSF1 DNA-binding activity during oxidative stress [77].

As a tumor suppressor frequently inactivated in human cancers, p53 plays a central role in the cellular response to agents or conditions that damage DNA by activating the transcription of several essential genes controlling cell cycle arrest or apoptosis [78]. p53 DNA binding and transcriptional activities are controlled by thiol redox state. Indeed, four out of the nine cysteines present in p53 DNA-binding domain are essential for the activity of this factor [79], [80]. Thiol oxidation is thought to change the structural organization of p53; a phenomenon that abolishes its interaction with its specific DNA target sequence, but not its nonspecific interaction with DNA [81]. A recent report by Wu and Momand [82] revealed that PDTC, a thiol compound widely used to study the activation of redox-sensitive transcription factors, can act as a pro-oxidant that increases p53 cysteine residue oxidation in vivo. This phenomenon correlated with a decreased ability of p53 to perform its downstream functions. Of interest, p53 activity is stimulated by Ref-1 [83]. Moreover, indirect experiments in which the gene encoding thioredoxin reductase was inactivated suggest that p53 is also under the control of TRX [84]. Different cations have also been described to regulate p53 activity through their interaction with thiol containing residues [85], [86]. For example, zinc stabilizes p53 by interacting with three different cysteines [86]. In contrast, the binding to copper induces an aberrant conformation of p53 and inhibits its binding to DNA [80], [87]. It has also been reported that sulfur-containing antioxidants, such as NAC and dimercaptopropanol, induce apoptosis in several transformed cells but not in their untransformed counterparts [88]. This phenomenon relies on an elevated expression of p53 in transformed cells, which is a consequence of an increased rate of translation of p53 mRNA. Hence, a thiol-specific redox sensor probably controls p53 expression in vivo.

Several other transcription factors display a DNA-binding activity that is abolished by oxidation of critical cysteine residues in their DNA-binding domain. They include: NF-1 (nuclear factor 1) [89], USF (upstream stimulatory factor) [90], E2F [91], IIIC [92], κU [93], Egr-1 [94], vETS [95], the bovine papillomavirus type 1 E2 protein [96], Sp1 [97], PB2/CBF [98], and glucocorticoid [99] and oestrogen [100] receptors. The DNA-binding activity of several of these factors is facilitated by specific proteins, probably TRX, as shown in the case of oestrogen receptor [99] or Ref-1. HoxB5, a member of the Hox family of proteins involved in embryonic development, is an interesting example of a transcription factor whose DNA-binding activity is upregulated by oxidative stress. Oxidative conditions trigger the dimerization of HoxB5, a structural reorganization required for the cooperative binding of this factor to tandem DNA target sites. This redox regulation requires the presence of one cysteine residue (cyst 232) in the highly conserved homeobox encoded DNA-bindingdomain [101].

Section snippets

Conclusion

Several studies have provided decisive hints concerning the regulation of gene expression by intracellular thiols. Redox-sensitive transcription factors have been discovered whose effects on gene expression depend on the balance between pro-oxidant and antioxidant conditions within the cell. Thiols may play a role in the signaling pathway that activate the transcription factor (i.e., HSF1) or may regulate its activation and ability to migrate in the nucleus (i.e., NF-κB). Redox regulation of

Acknowledgements

This work was supported by the following grants: 9186 and 5204 from the Association pour la Recherche sur le Cancer and the Région Rhône-Alpes.

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    A.-P. Arrigo has studied chemistry and biology and obtained his Ph.D. from the University of Geneva (Switzerland). His research field concerns the expression and function of heat shock proteins. He also participated in the discovery of the proteasome. Since 1990, he is professor of Molecular and Cellular Genetics at the Claude Bernard University (Lyon, France) where he heads a CNRS research team devoted to the understanding of how cells respond to environmental insults, particularly heat shock and oxidative stress.

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