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Genes to Cells (2007) 12, 1281-1287. doi:10.1111/j.1365-2443.2007.01131.x
© 2007 Blackwell Publishing or its licensors
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A reduction state potentiates the glucocorticoid response through receptor protein stabilization

 Hirochika Kitagawa1, Ikuko Yamaoka1,2, Chihiro Akimoto1, Ikuko Kase1, Yoshihiro Mezaki1, Takafumi Shimizu1 and Shigeaki Kato1,2,*

1 The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
2 ERATO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan


   Abstract
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 Abstract
Introduction
 Results
 Discussion
 Experimental procedures
 References
 
The intracellular redox state regulates all biological processes including gene expression. The glucocorticoid receptor (GR), a hormone-dependent transcription factor, is affected by the redox state. GR translocation from the cytoplasm to the nucleus is regulated by oxidative stress. The molecular mechanism of how the redox state affects GR transcriptional regulation, however, has not been clarified. We identified a deoxidizing agent, cobalt chloride (CoCl2), that potentiates the GR transcriptional effects by stabilizing endogenously expressed GR protein as well as exogenously over-expressed one without affecting GR mRNA level. Consequent GR protein stabilization enhanced co-factor recruitments on the target gene promoters. These results support the existence of a novel redox-dependent mechanism of GR transcriptional regulation mediated by receptor protein stabilization.


   Introduction
Top
 Abstract
 Introduction
Results
 Discussion
 Experimental procedures
 References
 
The intracellular environment results from the coordination of numerous signaling pathways. These pathways control the most basic biological events, including gene transcription. One component of the intracellular environment is the redox state, which is a reflection of the intracellular concentrations of reactive oxygen species. The intracellular redox state plays a key role in all cellular events including the modulation of gene expression. How the redox state affects gene expression is poorly understood (Kim et al. 2002; Rahman et al. 2004, 2006; Pouyssegur & Mechta-Grigoriou 2006).

Transcription regulatory factors mediate chromatin reorganization and histone modification, and are involved in the key steps of gene expression. These factors require several classes of co-regulator/co-regulator complexes (Kishimoto et al. 2006; Rosenfeld et al. 2006). Protein modification of the transcription factors themselves also affects transcription (Kumar et al. 2004). The glucocorticoid receptor (GR), a member of the nuclear receptor gene superfamily, is one transcription factor regulated in this manner (Rhen & Cidlowski 2005; Qiu et al. 2006).

The GR engages in both positive and negative regulation of transcription. Its roles are diverse and include participation in glucose homeostasis and the suppression of inflammation (Smoak & Cidlowski 2004). Hormone binding induces translocation of the GR from the cytosol into the nucleus. In hormone-dependent transactivation, the GR, activated by hormone binding, binds as a homodimer to the consensus glucocorticoid responsive element (GRE) in the target gene promoters. Hormone-induced transrepression of inflammatory genes by the GR is mediated mainly by indirect GR association with the binding sites for AP-1 and NF-{kappa}B (Jonat et al. 1990; Heck et al. 1994; Ogawa et al. 2005). Thus, the intracellular translocation of the GR is a critical step to initiate gene regulation and appears to be modulated through the other intracellular signals (Saklatvala 2002; Rogatsky & Ivashkiv 2006).

In the present study, we tested how redox conditions modulate the function of the hormone-bound GR in hormone-induced gene regulation. H2O2-induced oxidative stress retained hormone-bound GR in the cytosol. In contrast, a reduced condition induced by cobalt chloride (CoCl2) potentiates the function of the hormone-bound GR in transactivation through protein stabilization, but not in transrepression. Thus, the present findings indicate that a reduction state potentiates the response to glucocorticoids through GR protein stabilization.


   Results
Top
 Abstract
 Introduction
 Results
Discussion
 Experimental procedures
 References
 
To test if the redox state regulated GR functions, the effects of oxidative stress induced by H2O2 and reduction with CoCl2 were examined with a luciferase reporter assay. H2O2 is a strong oxidative agent commonly used for the induction of cellular oxidative stress. CoCl2 is a hypoxia mimetic reagent which reduces the oxidative environment in living cells (Zhang et al. 2002). CoCl2 changes cellular conditions such as the NAD+ : NADH ratio and modulates the structure of several proteins. Three types of reporters [Glucocorticoid responsive element (GRE), AP-1 responsive element (AP1-RE) and NF-{kappa}B responsive element (NF{kappa}B-RE)] were utilized with the reporter plasmids. A GR point mutant (C481S), known to remain in the nucleus after oxidative stress, was also used (Okamoto et al. 1999; Tanaka et al. 2000).

As expected, dexamethasone (Dex), a synthetic GR agonist stimulated GR-mediated transactivation through the GRE. It potently repressed transcription through the AP1-RE and NF{kappa}B-RE in the luciferase assay. H2O2 treatment attenuated GR function, while CoCl2 potentiates it. Similar effects were seen on Dex-induced transrepression by the GR, but the effects were not significant (Fig. 1A). However, the Dex-induced function of the GR mutant (C481S) was sensitive to the treatment of CoCl2, but not H2O2. This indicated that H2O2-induced oxidative stress caused the retention of Dex-bound GR in the cytosol (Fig. 1A). Redox state-mediated transcriptional regulation was also confirmed with endogenously expressed GR in A549 cells using the same luciferase assays without GR transfection (Fig. 1B; Wang et al. 2004). Another deoxidizing agent N-acetyl-L-cysteine (NAC) had the same effect as CoCl2 in all assays, confirming the effect of reduction on the GR function (data not shown). Reflecting the GR protein stabilization by CoCl2, the expression of the endogenous GR target genes were up-regulated, although the mRNA level of GR was unaltered (Fig. 1C).


Figure 1
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  		Figure 1  Ligand-dependent transcriptional regulation of the glucocorticoid receptor (GR) is redox state-dependent. (A) Luciferase assays were performed in 293F cells transfected with each of the indicated reporter plasmids (300 ng) and human GR or GR mutant (C481S) expression vectors (50 ng). For AP1-Luc, expression vectors were for c-Jun and c-Fos, and for NF{kappa}B-Luc, expression vectors were for p50 and p65. Vectors were simultaneously transfected (50 ng each). Dexamethasone (10–7 M), H2O2 (0.1 mM) and CoCl2 (0.2 mM) were added 3 h after transfection. (B) Luciferase assays were performed in A549 cells as explained in (A) without transfection of the human GR or GR mutant (C481S). (C) GR target genes were really regulated by redox state in A549 cells. Total RNA was extracted 16 h after indicated stimulations. RT-PCR of GR and its target genes were performed as described in Experimental procedures.

 
Next, we confirmed the cellular localization of the GR in a reduction state by expressing a chimeric human GR protein fused to GFP, in 293F cells. In the absence of ligands, the GR was located mainly in the cytosol and H2O2 treatment induced clear cytosolic localization (Fig. 2A, top panel). Dex treatment induced the nuclear localization of the GR, but H2O2 inhibited GR translocation as previously reported (Okamoto et al. 1999). However, H2O2 treatment failed to block the nuclear translocation of the C481S mutant (Fig. 2A, left panels). These results indicated that the inhibitory action of H2O2 on the transcriptional activity of the GR was correlated with the retention of the GR in the cytosol. In contrast, CoCl2 treatment did not alter the locations of Dex-bound and unbound GR (Fig. 2, right panel). These results suggested that another regulatory mechanism potentiates the function of Dex-bound GR.


Figure 2
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  		Figure 2  The ligand induced change in cellular localization of the glucocorticoid receptor (GR) is redox state-dependent. (A) Oxidative stress affects the cellular localization of the GR. 293F cells were transfected with expression vectors of GFP-GR or GFP GR mutant (C481S). Dex (10–7 M) and H2O2 (0.1 mM) were added at the indicated times before fixing. (B) Cobalt chloride (CoCl2) did not affect GR localization. Dex (10–7 M) and CoCl2 (0.2 mM) were added at the indicated times before fixing. After 24 h of transfection, the cells were scanned using a Zeiss confocal laser scanning system 510, and results were assessed with Adobe Photoshop 5.0 (Adobe) (Miyamoto et al. 2007).

 
To explore the molecular mechanism underlying potentiation of the GR by CoCl2, we measured the expression levels of the GR over time. Measurements were made upon Dex addition since several steroid hormone receptors like ERs or AR are destabilized by ligand binding (Dennis & O'Malley 2005; Garside et al. 2006; Ohtake et al. 2007). In the 293F GR expressing stable transformant, the expression level of the GR was down-regulated in a time-dependent manner after Dex treatment (Fig. 3B). Furthermore, Dex-induced down-regulation of the GR was also seen with endogenous GR protein in A549 cells (Fig 3A,C). In the presence of CoCl2, Dex-induced down-regulation of GR protein levels was not detected. This suggested that CoCl2 interfered with Dex-induced destabilization of the GR protein. As a proteasome inhibitor MG132 was also effective in attenuating Dex-induced destabilization, Dex-induced destabilization of the GR protein appeared to be mediated by a ubiquitin-proteasome cascade that was presumably blocked by CoCl2 (Fig. 3B,C).


Figure 3
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  		Figure 3  CoCl2 stabilizes the GR protein and co-factor recruitment. (A) Expression of the glucocorticoid receptor (GR) in indicated cells. Cell extracts were immunoprecipitated with GR antibody and subjected to Western blotting. (B) CoCl2 stabilized the GR protein. Whole cell extract from 293F cells with stable expression of the GR were immunoprecipitated at an indicated time upon stimulation with Dex or Dex + CoCl2 and Western blotted as shown in (A). MG132 (3 µM) was also used for cell stimulation. (C) Endogenous GR protein was also stabilized by CoCl2 in A549 cells. A549 cells were treated and processed in the same way as (B). (D) Co-factor recruitment was also stabilized by CoCl2. A ChIP assay was performed as described in the Experimental procedures.

 
To address if stabilization of the GR protein by CoCl2 reflected the transcriptional potentiation of Dex-bound GR at the promoter level, GR recruitment to its target gene promoters was tested by a ChIP assay. An ATPase chromatin remodeling factor, Brg-1, was utilized as a representative co-factor for the GR as previously reported (Nagaich et al. 2004). The presence of CoCl2 enhanced the recruitment of the GR as well as Brg-1 to three different gene promoters which contained either GRE, AP1-RE or NF{kappa}B-RE (Fig. 3D). Since the protein stability of Brg-1 was unaltered by either Dex or CoCl2 (data not shown), the potentiation of GR function by CoCl2 most likely resulted from increased co-factor recruitment by the stabilized GR protein in the target gene promoters.


   Discussion
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 Abstract
 Introduction
 Results
 Discussion
Experimental procedures
 References
 
During the decade, the regulation of nuclear receptor transcription was extensively analyzed with the development of biochemical approach and the improvement of protein identification methods using mass spectrometry (Yanagisawa et al. 2002; Kitagawa et al. 2003; Takezawa et al. 2007). Various types of transcriptional co-factors have been already identified, most of which are related to chromatin reorganization (Perissi & Rosenfeld 2005; Rosenfeld et al. 2006). Accumulating knowledge suggests that the chromatin reorganization related to the transcriptional regulation occurred in spatiotemporally-specific manner and is supported by a number of specific protein complexes (Ju et al. 2006; Garcia-Bassets et al. 2007). Moreover, specific combinations of the complex components appear to be highly regulated responding to extracellular signals. Redox condition is presumed as such a key determinant, and affects the biological conditions affecting the cell fate. Although it is generally accepted that redox condition modulates the property of transcription factors, it remains to be understood how it regulates the conditions of promoter regions around the target gene promoters of transcription factors, particularly in terms of complex formation (Pouyssegur & Mechta-Grigoriou 2006).

Three types of redox state-dependent transcriptional regulation have been described so far. One is a direct oxidation/reduction of cysteines on the transcription factor itself (e.g. AP-1). The second is a change of the factor's subcellular localization as in the case of NF-{kappa}B. The last are alterations of the redox buffers (e.g. NAD+/NADH exchange) which change the properties of transcriptional repressors such as CtBP or SirT1 (Zhang et al. 2002; Liu et al. 2005). In this study using the GR, we found a novel mechanism of redox-dependent transcriptional regulation (Tanaka et al. 2000). In this model, blockade of GR protein degradation by the deoxiding agent CoCl2 increased co-factor recruitment and consequently potentiates the GR transactivation property. We used a representative GR interacting co-factor Brg-1, an ATP-dependent chromatin remodeling factor, as an example of co-factor recruitment in our experiments. We also presume that various types of co-factor complexes may be associated with GR at different timing after redox stimulus. A detailed time course analysis is essential to completely understand this form of redox-dependent transcriptional regulation. Moreover, further extensive biochemical analysis is needed to fully describe how the regulation of protein stabilization affects the transcriptional regulation of various nuclear receptors in different biological situations (Lonard & O'Malley 2006; Ohtake et al. 2007).

Regarding the redox–dependent regulation of GR transcriptional function, another regulatory mechanism has already been reported in a certain cell line (Leonard et al. 2005). However, such up-regulation of GR mRNA levels by hypoxia was not observed in the tested cell lines in the present study. Such regulatory mechanisms by hypoxia as well as reduction state may be diverse and may appear in cell context-dependent manner.

It is well known that some nuclear receptors including the GR have an anti-inflammatory effect resulting from the repression of AP-1 or NF-{kappa}B mediated transcription in ligand-dependent manner (Smoak & Cidlowski 2004; Valledor & Ricote 2004). The mechanism for this form of transrepression is largely unknown (Ogawa et al. 2005; Reily et al. 2006). Additionally, increasing co-factor (Brg-1) recruitment on target gene promoters by receptor protein stabilization was not sufficient to potentate the transrepressional property of the GR in the reduced state (see Figs 1 and 3B). These results suggest that distinct co-regulators or protein modifications may affect these transrepressional mechanisms (Kodama et al. 2003). To investigate this further, we are establishing a biochemical purification system for analyzing GR transcriptional regulation under various conditions.


   Experimental procedures
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 Abstract
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 Results
 Discussion
 Experimental procedures
References
 
Reagents and plasmids

Plasmids
The full-length human GR was inserted into the pNTAP expression vector using the InterPlayTM Mammalian TAP system (Stratagene, Cedar Creek, TX). It was also inserted into the pEGFP-C2 vector (BD Bioscience, San Jose, CA). Human GR mutants (Cys 481 for Ser) for both vectors were made with the QuikChange site-directed mutagenesis kit (Stratagene). pGRE-Luc was purchased from BD Bioscience. pAP1-Luc and pNF-{kappa}B-Luc were purchased from Stratagene. Expression vectors with c-Jun, c-Fos, p50 and p65 were cloned from a 293T cDNA library and inserted into the pcDNA3 vector (Invitrogen, Carlsbad, CA).

Antibodies
Anti-human GR antibody (PA1–512) was purchased from Affinity BioReagents (ABR, Golden, CO). Anti-Brg-1 Antibody (H-88) and ß-actin (I-19) was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).

Reagents
Dexamethasone was purchased from Sigma (St. Louis, MO). H2O2 and CoCl2 were purchased from Wako Chemicals, and MG132 was purchased from Peptide Institute Inc (Osaka, Japan).

Reporter assay

293F cells were transfected using the Lipofectamine Plus reagent (Invitrogen) according to the manufacturer's protocol. Luciferase reporter plasmids were co-transfected with the GR-expression vectors as indicated in the figure legends together with 2 ng/well of pRL-CMV plasmid (Promega, Madison, WI). After 3 h of transfection, the media were replaced with fresh media containing 0.2% fetal bovine serum. Dexamethasone (10–7 M), H2O2 (0.1 mM) or CoCl2 (0.2 mM) were then added to the cells and incubated for an additional 12 h. Cell extract preparation and dual luciferase assays were performed according to the manufacturer's protocols (Promega). Individual transfections performed in triplicate wells were repeated at least 3 times.

Preparation of stably transfected cell lines

TAP-tagged human GR-expressing retroviruses were produced using a pQCXIN vector (BD Bioscience). The 293F cells were infected by incubating them with the virus and 6 µg/mL hexadimethrine bromide (Sigma). Cells stably expressing the GR were combined and cultured with 700 µg/mL G418 (Promega) prior to colony selection.

RNA extraction and RT-PCR

Total cellular RNA was isolated from A549 cells by ISOGEN (Wako). RT reaction was performed using SuperScript (Invitrogen) and the indicated mRNAs were amplified by PCR as previously reported (Kitagawa et al. 2003).

Immunoprecipitation and Western blotting

After treating 293F cells or A549 cells with either H2O2 or CoCl2 for the indicated time, cells were washed twice with ice-cold phosphate-buffered saline, resuspended in 1 mL ice-cold lysis buffer [10 mM Tris–HCl (pH 4.7), 10 mM NaCl, 3 mM MgCl2, 0.5% (vol/vol) NP-40] and incubated on ice for 30 min. Cells were then centrifuged again for 5 min at 500g and the sedimented nuclear fractions resuspended in TNE buffer [10 mM Tris–HCl (pH 7.5), 0.15 M NaCl, 1 mM EDTA, 1% NP-40] and incubated for 30 min on ice. After centrifugation, supernatants were used as cell extracts for immunoprecipitation using anti-GR antibody with protein G Sepharose and then Western blotted with an anti-GR polyclonal antibody or anti-Brg-1 antibody.

ChIP assay

Soluble chromatin from A549 cells was prepared with the acetyl-histone H4 immunoprecipitation assay kit (Upstate Biotechnology, Billerica, MA) and was immunoprecipitated with antibodies against the indicated proteins (Kitagawa et al. 2003). Specific primer pairs were designed to amplify the promoter region of human {alpha}ENAC (5'-TTCCTTTCCAGCGCTGGCCAC-3' and 5'-CCTCCAACCTTGTCCAGACCC-3'), human collagenase 1 (5'-GCAGAGTGTGTCTCTTTCGCACAC-3' and 5'-GCCCTTCCAGAAAGCCAGAGGCTG-3'), human IL-8 (5'-GGGCCATCAGTTGCAAATC-3' and 5'-TTCCTTCCGGTGGTTTCTTC-3') from genomic DNA (Kitagawa et al. 2002; Kassel et al. 2004). PCR conditions were optimized to allow semi-quantitative measurement and PCR products were visualized on 2% agarose/TAE gels.


   Acknowledgements
 
We thank Dr S. Kido, and T. Matsumoto in Tokushima University for plasmid transferring. Also we thank Ms Hiraga for manuscript handling.


   Footnotes
 
Communicated by: Kohei Miyazono

* Correspondence: E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp


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 Discussion
 Experimental procedures
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Received: 11 June 2007
Accepted: 10 August 2007





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