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PathwayInstitut National de la Santé et de la Recherche Médicale (INSERM U620), Equipe labellisée par la Ligue Nationale contre le Cancer (P.M., D.G., E.L., C.R., D.L.G., O.F.) and Université de Rennes 1, IFR140, Rennes, France (P.M, D.G., E.L., C.R., D.L.G., O.F.); and Department HITC, Hôpital Pontchaillou, CHU, Rennes, France (O.F.)
Received November 5, 2007; accepted December 17, 2007
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, one of the CaMK isoforms, similarly prevented CYP1A1 up-regulation. Both KN-93 and siRNA targeting CaMKI were found to abolish TCDD-mediated activation of CYP1A1 promoter and TCDD-triggered nuclear import of AhR, a crucial step of the AhR signaling pathway. TCDD-mediated inductions of various AhR targets, such as the drug metabolizing CYP1B1, the cytokine interleukin-1β, the chemokines interleukin-8 and CCL1, the adhesion molecule β7 integrin, and the AhR repressor, were also prevented by KN-93 in human macrophages. Taken together, these data identified the Ca2+/CaM/CaMKI pathway as an important contributing factor to AhR-mediated genomic response.
). In the absence of ligand, AhR, associated with 90-kDa heat shock protein, p23, and X-associated protein 2 (XAP2), is primarily located in the cytosol (Hankinson, 1995). After ligand binding, AhR moves to the nucleus, dissociates from the chaperone complex, and forms a heterodimer with the AhR nuclear translocator. This heterodimer binds to specific xenobiotic responsive elements (XRE) [core sequence: CACGCN(A/T)] found in the promoter of target genes and subsequently regulates their transcription (Swanson, 2002). In this way, TCDD and other AhR agonists [such as the carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs)] markedly induce expression of the drug-metabolizing enzyme CYP1A1, known to detoxify but also to bioactivate carcinogens, including PAHs, and commonly considered a paradigm of AhR gene targets (Barouki et al., 2007).
In addition to activation of AhR, TCDD and PAHs have been shown to increase intracellular concentration of Ca2+ ([Ca2+]i) (Burchiel et al., 1991; Archuleta et al., 1993; Davila et al., 1995; Tannheimer et al., 1997; Le Ferrec et al., 2002). It is noteworthy that blocking these [Ca2+]i changes through the use of intracellular Ca2+ chelator or store-operated channel blockers prevents induction of CYP1A1 (N'Diaye et al., 2006), thus suggesting cross-talk between Ca2+ variations and AhR-dependent regulatory pathways. Such interactions remain however to be characterized. For this purpose, it may be suitable to focus on key mediators of signaling pathways activated by Ca2+. Among these, the CaMKs represent a major one (Braun and Schulman, 1995). CaMKs correspond to a family of structurally related serine/threonine protein kinases that play important roles in proliferation (Rodriguez-Mora et al., 2005) and differentiation (Zayzafoon, 2006). It is noteworthy that such cellular processes are also known to be affected upon AhR activation (Barouki et al., 2007). This has led us in the present study to analyze the putative contribution of CaMKs to AhR-dependent genomic response. Using mainly mammary MCF-7 cells, we report that activity of CaMKI, one of the CaMK isoforms, is required for TCDD-triggered nuclear translocation of AhR and subsequent up-regulation of AhR target genes, especially of CYP1A1. Such data therefore highlight the Ca2+/CaM/CaMKI pathway as an important contributing factor to AhR-mediated genomic response.
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Materials and Methods |
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(Thr177), and goat anti-lamin A/C Abs were purchased from Santa Cruz Biotechnology (La Perray en Yvelines, France). [
-32P] ATP was from Amersham Biosciences. FITC-labeled anti-rabbit IgG Ab was purchased from Jackson Immunoresearch (Suffolk, UK). Chemicals were commonly used as stock solution in dimethyl sulfoxide. Final concentration of solvent did not exceed 0.2% (v/v); control cultures received the same volume of solvent as for treated counterparts.
Cell Culture. Human mammary MCF-7 cells were cultured in Dulbecco's modified Eagle's medium with 4500 mg/l D-glucose, 110 mg/l sodium pyruvate, and nonessential amino acids, supplemented with 100 U/ml penicillin, 100 U/ml streptomycin, and 10% fetal calf serum. Primary human macrophages were obtained from granulocyte macrophage-colony-stimulating factor-exposed blood monocytes and cultured as described previously (van Grevenynghe et al., 2003).
Intracellular Ca2+ Measurements. Variations in [Ca2+]i were analyzed by spectrofluorometry using the Ca2+-sensitive probe Fura-2-AM, as reported previously (Le Ferrec et al., 2002). In brief, MCF-7 cells were cultured in 24-well plates and incubated with the acetoxy cell-permeant form of Fura-2 (Fura-2 AM; 1.5 µM) for 30 min at 37°C in HEPES-buffered medium (10 mM HEPES, 134.8 mM NaCl, 4.7 mM KCl, 1 mM MgCl2, 1.2 mM KH2PO4, 1 mM CaCl2, and 10 mM glucose, pH 7.4, at 37°C), supplemented with 0.006% Pluronic acid. After removing Fura-2-AM, cells were placed in the spectrofluorometer (SpectraMax Gemini XS; Molecular Devices, Toronto, ON, Canada) and a well scan was performed at indicated times. Cells were irradiated alternately with light at wavelengths of 340 and 380 nm, and fluorescence from the trapped dye was measured at 510 nm. The ratio of fluorescence intensities recorded after excitation at 340 nm and 380 nm, defined as the F340/F380 ratio, was used to estimate [Ca2+]i changes, knowing that [Ca2+]i increase results in an enhanced F340/F380 ratio (Le Ferrec et al., 2002; N'Diaye et al., 2006). Effects of chemical treatment on [Ca2+]i were expressed as 
F340/F380 ratio (i.e., the F340/F380 ratio after the addition of chemicals minus the F340/F380 ratio measured before treatment).
Ethoxyresorufin O-deethylase Activity Assay. EROD activity, corresponding to the O-deethylation of ethoxyresorufin, and mainly supported by CYP1A1 enzyme in living MCF-7 cells, was measured as described previously (Sparfel et al., 2006). In brief, MCF-7 cells were incubated in phosphate-buffered saline, pH 7.4, containing 50 µM ethoxyresorufin and 1.5 mM salicylamide, and kinetic reading was performed at 37°C with a SpectraMax Gemini SX spectrofluorometer over a 30 min-period.
RNA Isolation and Analysis. Total RNAs, extracted using the TRIzol method (Invitrogen), were subjected to reverse transcriptionreal-time quantitative polymerase chain reaction (RT-qPCR) analyses as described previously (Monteiro et al., 2007). Relative quantification of mRNA levels was performed after normalization of the total amount of cDNA tested to an 18 S RNA endogenous reference. The sequences of the primers used for RT-qPCR analysis are given in Table 1.
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Reverse Transfection of siRNA. For inhibiting expression of CaMKs, we first used "The Human siArray Reverse Transfection Format siRNA library," targeting the various isoforms of the CaMK family (Dharmacon RNA Technologies, Lafayette, CO). This siRNA library corresponds to pools of four siRNA directed against different regions of targeted mRNA (Smart pool) for each CaMK isoform and spotted in 96 multiwell plates. In each well, 6.25 pmol of desiccated siRNAs were rehydrated using 0.125 µl of Dharmafect I reagent diluted in 25 µl of transfection medium (Opti-MEM; Invitrogen) for 40 min at room temperature. Next, 35,000 MCF-7 cells diluted in complete culture medium were added to each well. Twenty-four hours later, transfection medium was replaced by fresh medium for an additional 48 h. MCF-7 cells were next used for TCDD exposure and CYP1A1-related EROD activity assay. As control in siArray assays, the siCONTROL nontargeting siRNA (iNT1, 5'-UAGCGACUAAACACAUCAAtt-3') and five other siRNAs (provided with siRNA library from Dharmacon) were used; values of TCDD-induced EROD activities obtained from cells-transfected with these six control siRNAs were averaged and arbitrarily set at 100% as control values for EROD activity. For specific knockdown of CaMKI isoform, we used the siRNA iCaMKI (5'-GCGGUUACCCUCCCUUCUAtt-3') and the siRNA iNT1 as a nontargeting control, as reported above.
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Cellular Protein Extracts and Immunoblotting Analysis. Cellular protein extracts were prepared using a cell lysis buffer containing 50 mM HEPES, 150 mM NaCl, 1 mM EGTA, 0.1% Tween 20, 10% glycerol, and 100 µM phenylmethylsulfonyl fluoride, supplemented with an EDTA-free cocktail protease inhibitor (Roche Diagnostic, Meylan, France), whereas nuclear extracts were isolated from MCF-7 cells using the BD Transfactor extraction kit (BD Biosciences, San Jose, CA). Protein samples (50 µg) were next subjected to electrophoresis in a 10% acrylamide gel and electrophoretically transferred to a nitrocellulose membrane (Bio-Rad Laboratories, Marne la Coquette, France). After blocking with Tris-buffered saline containing 4% bovine serum albumin and 0.1% Tween 20 for 1 h at room temperature, membranes were incubated overnight at 4°C with primary Ab. After incubation with appropriate horseradish peroxidase-conjugated secondary Ab for 1 h, immunolabeled proteins were visualized by autoradiography using chemiluminescence.
Reporter Gene Activity and Transient Transfection. The pCYP1A1-FL(-1566) construct containing a 1639-base-pair region (from -1566 to +73) of the human CYP1A1 gene upstream of the firefly luciferase reporter gene (a gift from Pr. Barouki, INSERM U747, Paris, France) and the pGL3-XRE3-FL construct, containing only three XRE sequences from CYP1A1 gene, have been described previously (Morel and Barouki, 1998). MCF-7 cells were cultured in 24-well plates and cotransfected with pRL-TK vector (Promega, Charbonnières, France) that codes for Renilla reniformis luciferase plus a plasmid carrying the firefly luciferase or pCYP1A1-FL(-1566) or pGL3-XRE3-FL constructs. Transient transfection of MCF-7 cells was performed by the FuGENE6 transfection reagent according to manufacturer's instructions (Roche Applied Science, Indianapolis, IN). In brief, 250 µl of transfection medium (Opti-MEM) containing 225 ng of firefly luciferase reporter plasmid was added per well along with 25 ng of the pRL-TK plasmid and 0.75 µl of FuGENE6 transfection reagent. After a 24-h period, cells were exposed to TCDD for a 6-h period. Dual luciferase assays (firefly and R. reniformis) were then performed with a kit according to the manufacturer's instructions (Promega). Data were expressed in arbitrary unit (a.u.), relative to the value of luciferase activity levels found in TCDD-untreated cells, arbitrarily set at 1 unit.
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-32P]ATP (specific activity, 0.5 µCi), was added to cellular extracts. After a 5-min incubation at 30°C, the kinase reaction was stopped by adding 12.5 µl of termination buffer. The biotinylated peptide substrate was then captured by spotting 10 µl of the reaction on an individual square on the SAM Biotin Capture Membrane. After various washing with 2 M NaCl and 2 M NaCl in 1% H3PO4, the membrane was dried, and individual squares were placed in scintillation liquid for radioactivity counting. Statistical Analysis. Quantitative data are usually given as means ± S.D. of values from at least three independent experiments. Significant differences were routinely evaluated with the paired Student's t test. The level of significance was p < 0.05.
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; N'Diaye et al., 2006).
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).
TCDD-Mediated CYP1A1 Up-Regulation Was Impaired by Chemical Inhibition of the CaMK Pathway. To test a putative role of Ca2+/CaM/CaMK pathway in TCDD-mediated up-regulation of CYP1A1, we first analyzed the effect of TCDD on global CaMK activity in MCF-7 cells. As shown in Fig. 2A, TCDD triggered a marked and transient increase of CaMK activity, which reached levels similar to those observed in response to norepinephrine, a well known activator of CaMK activity (Fatima et al., 2003). Chemical inhibition of the Ca2+/CaM/CaMK signaling pathway using either the CaMK inhibitor KN-93 or the CaM antagonist W7 was next found to counteract TCDD-mediated induction of CYP1A1 activity (Fig. 2B) or expression at protein (Fig. 2C) or mRNA (Fig. 2D) levels in MCF-7 cells. By contrast, KN-92, an inactive chemical analog of KN-93, failed to alter the up-regulation of CYP1A1 activity (Fig. 2B) and the expression (Fig. 2C) due to TCDD, thus highlighting the specificity of the effects of the CaMK inhibitor KN-93. This conclusion was further reinforced by the lack of effects of KN-93 toward [Ca2+]i changes occurring in MCF-7 cells exposed to TCDD (data not shown).
Knockdown of the CaMKI Isoform Counteracted TCDD-Mediated CYP1A1 Induction. Because the CaMK family comprises several isoforms (Haribabu et al., 1995; Hook and Means, 2001), with at least some of them expressed in MCF-7 cells (Rodriguez-Mora et al., 2005), we were next interested in determining which isoform of the CaMK family was involved in the up-regulation of CYP1A1 upon TCDD exposure. To this purpose, we performed knockdown expression of eight main CaMK isoforms (CaMKI, -
, and -; CAMKII,-β,-, and -; and CaMKIV) using RNA interference. We first used SMART pools of small interfering RNA from Dharmacon corresponding to pools of four siRNAs directed against each CaMK isoform. As indicated in Fig. 3A, only the SMART pool of siRNAs targeting the CaMKI isoform (GenBank accession number NM_003656) was found to significantly reduce TCDD-mediated up-regulation of CYP1A1 activity. We then separately analyzed the effects of the different siRNAs found in this SMART pool and selected the one that markedly down-regulated CaMKI mRNA levels in MCF-7 cells without affecting those of other CaMK isoforms such as CaMKII RNA (data not shown). Transfection of MCF-7 cells by this siRNA, termed iCaMKI, was further demonstrated to inhibit TCDD-triggered induction of CYP1A1 activity (Fig. 3B) and CYP1A1 expression at both protein (Fig. 3C) and mRNA (Fig. 3D) level. In addition, it concomitantly blocked TCDD-triggered increase of CaMK activity (Fig. 3E). It is noteworthy that exposure to TCDD resulted in increased CaMKI (Thr177) phosphorylation and probably, thereby, in full CaMKI activation (Haribabu et al., 1995) (Fig. 3F).
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. To understand how CaMKI regulates TCDD-induced CYP1A1 regulation, we performed transient transfection of MCF-7 cells with a plasmid construct corresponding to -1566 base pairs of the 5'-flanking region of the CYP1A1 gene upstream to the luciferase reporter gene (pCYP1A1-FL construct), and containing five XRE consensus elements. TCDD treatment was found to induce activity of the reporter gene (Fig. 4A), in agreement with previous studies (Morel and Barouki, 1998; Le Ferrec et al., 2002). Cotreatment with the CaMK inhibitor KN-93 significantly abolished this induction (Fig. 4A). KN-93 also counteracted the TCDD-mediated increase of the luciferase activity when using a reporter gene construct driven by three XRE (pGL3-XRE3-FL construct) (Fig. 4B). This XRE-driven luciferase activity inducible by TCDD was also similarly inhibited by knockdown expression of CaMKI (Fig. 4C).
CaMKI Inhibition and Knockdown Prevented TCDD-Triggered Nuclear Import of AhR. Down-regulation of TCDD-induced transcriptional activation of CYP1A1 by inhibition of CaMKI expression and/or activity may be due to direct interference with the final nuclear step of the AhR signaling pathway (i.e., XRE-driven induction of CYP1A1 promoter activity) or, alternatively, to an interaction with an upstream step of the AhR pathway, such as AhR nuclear import in response to TCDD. To investigate this point, AhR cellular distribution in untreated and TCDD-treated MCF-7 cells was monitored by Western blotting and by immunofluorescence labeling (Fig. 5). Treatment by TCDD triggered an important increase of AhR nuclear content as demonstrated by Western blot analysis of nuclear fractions (Fig. 5A); likewise, immunolocalization studies indicated that AhR was found to be primarily localized in cytoplasm of untreated cells, whereas it was mainly detected in the nucleus of TCDD-exposed cells (Fig. 5B). This TCDD-induced AhR nuclear import was largely abrogated by cotreatment with KN-93 (Fig. 5, A and B). SiRNA-mediated knockdown of CaMKI expression also markedly reduced TCDD-triggered nuclear translocation of AhR, as shown by Western blotting (Fig. 5C) and AhR immunolocalization studies (Fig. 5D).
CaMK Activity Was Involved in TCDD-Mediated Up-Regulation of Various AhR Target Genes in Primary Culture of Human Macrophages. The last part of our study was designed to determine whether CaMK activity was required for TCDD-mediated regulation of various AhR target genes in addition to CYP1A1. Using primary human macrophages, a convenient model for analyzing phenotypic effects of AhR ligands (van Grevenynghe et al., 2004; Lecureur et al., 2005; N'Diaye et al., 2006; Monteiro et al., 2007) and in which AhR ligands trigger [Ca2+]i increase (N'Diaye et al., 2006), we found that cotreatment with the CaMK inhibitor KN-93 was capable of counteracting the TCDD-mediated up-regulation of several AhR target genes, such as the drug metabolizing CYP1B1, the cytokine interleukin-1β, the chemokines interleukin-8 and CCL1, the adhesion molecule β7 integrin, and the AhR repressor (Fig. 6).
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; Pallardy et al., 1992; Archuleta et al., 1993), macrophages (N'Diaye et al., 2006; Pappas et al., 2003), intestinal (Le Ferrec et al., 2002), and mammary cells (Tannheimer et al., 1997) and can therefore be considered a hallmark of AhR agonist exposure. It is noteworthy that this change of [Ca2+]i has been recently demonstrated to be required for regulation of the AhR target genes CYP1A1 and CCL1, in human Caco-2 intestinal cells (Le Ferrec et al., 2002) and human macrophages (N'Diaye et al., 2006), respectively. Likewise, chemical inhibition of TCDD-mediated [Ca2+]i increase in human mammary MCF-7 cells was also reported to counteract CYP1A1 induction in the present study. Taken together, these data strongly suggest that Ca2+-related signaling pathway may take place, or interfere, in the AhR signaling pathway. The data reported in the present study, through identifying the requirement of the CaMK pathway, one of the major Ca2+-related transduction pathway, for TCDD-mediated regulation of AhR target genes, fully support this hypothesis. The possible implication of CaMK activity in the AhR signaling pathway was first pointed out by the fact that CaMK activity was increased in response to TCDD exposure in MCF-7 cells. Moreover, the specific CaMK inhibitor KN-93, unlike its inactive counterpart KN-92, prevented TCDD-mediated induction of both CYP1A1 activity and expression in MCF-7 cells. Besides CYP1A1 regulation, KN-93 also blocked TCDD-related induction of various AhR target genes in human macrophages, likely indicating that CaMK activity is essential for global AhR-mediated genomic response to TCDD exposure.
Involvement of the CaMK signaling pathway in AhR-genomic effects was moreover supported by the fact that W7, a CaM antagonist that prevents Ca2+/CaM-triggered activation of CaMKs (Tanaka et al., 1983), nearly fully antagonized TCDD-mediated up-regulation of CYP1A1 activity and expression. Moreover, knockdown of CaMK expression by RNA interference inhibited CYP1A1 induction in response to TCDD. This use of siRNA is important to fully demonstrate the involvement of CaMK activity in TCDD-mediated CYP1A1 up-regulation because it allows neutralization of any potential lack of specificity of the chemical inhibitors used in the study, including a putative AhR antagonist-like activity of KN-93, which should be formally considered. In addition, siRNA-related experiments allowed us to demonstrate that, among CaMK isoforms, expression/activity of the CaMKI isoform is most likely to be required for AhR-dependent up-regulation of target genes in MCF-7 cells. Indeed, knockdown of the expression of this isoform markedly inhibited the up-regulation of CYP1A1 activity and expression occurring in TCDD-treated MCF-7 cells. In addition, it concomitantly abrogated the TCDD-related increase of CaMK activity, thus fully supporting a major role for CaMKI isoform in TCDD-stimulated CaMK activity in MCF-7 cells. Moreover, TCDD treatment was found to notably result in CaMKI activation, through the phosphorylation of the critical threonine residue at position 177 (Haribabu et al., 1995). It is noteworthy that the CaMKI isoform has been demonstrated to be broadly distributed in various tissues (Haribabu et al., 1995), like AhR (Barouki et al., 2007), suggesting that it may participate to the AhR signaling pathway in a rather systemic manner.
Inhibition of CaMK activity and knockdown of CaMKI expression markedly prevented TCDD-mediated induction of CYP1A1 promoter activity and of XRE-driven reporter activity, indicating that the CaMK pathway was required for transcriptional activity triggered by AhR in the nucleus. However, transcriptional activity of AhR, at least, depends on previous steps, including AhR nuclear import and heterodimerization with AhR nuclear translocator. Because CaMKI has been implicated in cellular localization of several proteins (Kao et al., 2001), its effect toward AhR cellular distribution was checked. Regarding this point, we have found that both cotreatment by KN-93 and knockdown of CaMKI expression inhibited TCDD-induced nuclear translocation of AhR, suggesting that AhR nuclear import may be an initial step of the AhR signaling pathway requiring CaMK activity. It should be kept in mind, however, that the initial cytosolic step of the AhR signaling cascade, which takes place before AhR nuclear import, can also constitute the primary target of the CaMK pathway; in this context, a putative interaction of CaMKI activity with cytosolic AhR partners, such as XAP2 (de Oliveira et al., 2007; Pollenz and Barbour, 2000) or the 90-kDa heat shock protein (Ogiso et al., 2004), may be interesting to consider. Further studies are therefore required to better understand the molecular mechanism by which the Ca2+/CaM/CaMKI pathway participates in the AhR-related genomic response.
In addition to CaMKI, various protein kinases (Tan et al., 2004) have been shown to participate to transduction signaling elicited by AhR agonists. Some of these kinases, such as the tyrosine kinases Fyn and Lck (Archuleta et al., 1993), are presumed to be involved in [Ca2+]i increase in response to AhR agonists, whereas others, such as Src-kinase (Enan and Matsumura, 1996), protein kinase-C, and mitogen-activated protein kinases (Tan et al., 2002), may be more directly implicated in the control of AhR complex activity and in the regulation of AhR target genes. In addition, extracellular signal-regulated kinase has been shown to be involved in regulation of the AhR response (Tan et al., 2002; Lecureur et al., 2005) via the control of AhR degradation (Chen et al., 2005). Besides protein kinases, the proteolytic enzyme calpain, well known to be activated by Ca2+, has also been recently hypothesized to be involved in Ca2+-related control of the AhR signal transduction pathway (Dale and Eltom, 2006). These data are controversial, however, because calpain inhibitors did not affect TCDD-mediated up-regulation of CYP1A1 in several cell culture lines from different species (Pollenz, 2007). In agreement with these results, we have found that the calpain inhibitor III failed to alter TCDD-induced CYP1A1 expression in MCF-7 cells (data not shown), thus ruling out a major role for calpain in the AhR signaling pathways in such cells. Whether calpain may be implicated in the regulation of AhR target genes distinct from CYP1A1 remains to be determined. By contrast, we have found that CaMK activity, playing a role in the AhR signaling pathway in both normal and cancerous cell models (i.e., human primary macrophages and mammary tumoral MCF-7 cells), concerns regulation of various AhR target genes, including drug-metabolizing enzymes and cytokines/chemokines.
In summary, the data reported in the present study indicate for the first time that the Ca2+/CaM/CaMKI pathway is involved in the AhR-mediated genomic response, notably in the AhR nuclear import step of the AhR signaling pathway.
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P.M. received a fellowship from the Ligue Nationale contre le Cancer
ABBREVIATIONS: AhR, aryl hydrocarbon receptor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; XAP2, X-associated protein 2; XRE, enobiotic responsive elements; PAH, polycyclic aromatic hydrocarbon; CaM, calmodulin; CaMK, Ca2+/CaM-dependent protein kinase; 2-APB, 2-Aminoethoxydiphenylborate; BAPTA-AM, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester; KN-93, 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; KN-92, 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; W7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; AM, acetoxymethyl ester; Ab, antibody; EROD, ethoxyresorufin O-deethylase; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; siRNA, small interfering RNA.
Address correspondence to: David Gilot, INSERM U620, Université de Rennes1, Faculté des Sciences Pharmaceutiques et Biologiques, IFR140, 2 Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France. E-mail: david.gilot{at}rennes.inserm.fr
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