Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Sasaki, Hiromi; Sato, Hiroki; Kuriyama-Matsumura, Kazumi; Sato, Kanako; Maebara, Kanako; Wang, Hongyu; Tamba, Michiko; Itoh, Ken; Yamamoto, Masayuki; Bannai, Shiro

doi:10.1074/jbc.m208704200

Cited by 465 publications

(364 citation statements)

References 29 publications

(26 reference statements)

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“…Studies on the role of the GC box in constitutive gene expression, however, are controversial. Similarly to what was observed here with rat GGT promoter 5, deletion of the GC box abrogated EpRE-mediated basal expression of the rat GSH S-transferase Ya [55] and cystine/glutamate exchange transporter [56]; however, deletion of the GC box had no effect on the constitutive expression of hGCLm and mice heme oxygenase-1 (HO-1) [54,57].…”

Section: Discussionsupporting

confidence: 74%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal-and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.

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Section: Discussionsupporting

confidence: 74%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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“…Furthermore, cysteine could be supplied through its uptake from extracellular space by mechanisms involving Nrf2, the transcriptional factor activated in response to oxidative stress or electrophiles such as heme. 28,29 By contrast, the amounts of sulfur-containing amino acids consumed to generate H 2 S seems relatively smaller than that for synthesizing GSH or hypotaurine, as judged from quantitative information collected by metabolome analysis. Because CBS not only limits synthesis of cystathionine from homocysteine but also directly suppresses H 2 S generation from cysteine, the inhibitory effects of CO on the enzyme could dictate largely on the action of H 2 S in the liver, causing a stimulatory effect on bile excretion.…”

Section: Discussionmentioning

confidence: 99%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

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“…For these experiments cells were treated on the second day following seeding with various NO donors: 3-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (SNOG), or 3-morpholinosydnonimine hydrochloride (SIN-1) at concentrations of 10 μM, 50 μM, 100 μM and 500 μM, for 4, 6, 18 or 24 hours. Additional experiments were carried out using three other donors of reactive oxygen species (ROS), since oxidative stress has been shown to upregulate system x c -in other systems [4][5][6][7][8][9]. These ROS were menadione sodium bisulfite [5.4 μM], hydrogen peroxide prepared from a 30% (W/W) solution (final concentration 0.0001%), and xanthine sodium salt/xanthine oxidase (concentrations 10 μM and 2 mU/ml, respectively); the treatment time was 6 h. These concentrations were selected based on earlier reports of toxicity to retinal cells [30].…”

Section: Measurement Of System X C -Activitymentioning

confidence: 99%

“…As GSH is necessary for protection of cells against oxidative damage, system x c -assumes significance as a transport system closely associated with the cellular antioxidant machinery. The relevance of system x c -to cellular antioxidant processes is underscored by its upregulation in multiple cell types exposed to oxidative stress [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

et al. 2006

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Purpose-The cystine-glutamate transporter, system x c -, mediates the Na + -independent exchange of cystine into cells coupled to the efflux of intracellular glutamate. Within cells, cystine is reduced to cysteine, a component of glutathione, thus system x c -plays a critical role in glutathione homeostasis. Studies in brain had initially suggested that system x c -was present primarily in astrocytes and not neurons, but more recent work suggests that certain brain neurons have an active system x c -. In the retina, system x c -has been demonstrated in retinal Müller and RPE cells. Recent immunohistochemical work from our lab suggested that the two protein components of system x c -, xCT and 4F2hc, are present in ganglion cells of the intact retina. The purpose of this investigation was to determine whether system x c -was present in primary ganglion cells isolated from neonatal mouse retinas and, if so, to study its regulation by oxidative stress in a retinal ganglion cell line, RGC-5.Methods-The presence of xCT and 4F2hc in RGC-5 cells was established by RT-PCR, immunoblotting and immunohistochemistry and in primary mouse retinal ganglion cells by immunoblotting and immunohistochemistry; the function of the transporter in RGC-5 cells was established by measuring radiolabeled glutamate uptake in the absence of Na + . To assess regulation of system x c -by oxidative stress in ganglion cells, RGC-5 cells were incubated in the presence or absence of nitric oxide (NO) donors (3-nitroso-N-acetylpenicillamine (SNAP), Snitrosoglutathione (SNOG), or 3-morpholinosydnonimine hydrochloride (SIN-1) and reactive oxygen species (ROS) donors menadione sodium bisulfite, hydrogen peroxide and xanthine sodium salt/xanthine oxidase and system x c -was analyzed using functional assays, RT-PCR and immunoblotting.Results-RGC-5 cells and primary ganglion cells isolated from mouse retina express xCT and 4F2hc as demonstrated by RT-PCR, immunoblotting and immunohistochemistry. RGC-5 cells take up glutamate in the absence of Na + and this uptake was blocked by known inhibitors of system x c -, glutamate, cysteine, and cystine as well as quisqualic acid. Treatment of RGC-5 cells with NO donors and donors of ROS led to an increase in the functional activity of system x c -. Kinetic analysis of SNAP-treated RGC-5 cells compared to control cells showed that the increase was associated with an increase in the maximal velocity of the transporter with no significant change in the substrate affinity. Molecular analyses showed that the upregulation is associated with an increase in the expression of xCT with no detectable change in the expression of 4F2hc. Conclusions-RGC-5 cells and ganglion cells isolated from neonatal mice express the cystine/ glutamate transporter x c -(the light chain xCT and the heavy chain 4F2hc) as is evident from functional and molecular studies. Oxidative stress upregulates this transport system in RGC-5 cells and the process is associated with an increase in xCT mRNA and protein but no change in 4F2hc mRNA or...

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Electrophile Response Element-mediated Induction of the Cystine/Glutamate Exchange Transporter Gene Expression

Cited by 465 publications

References 29 publications

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

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