Latest Publications

@article{hyzdalova_transcriptional_2024,

title = {Transcriptional and phenotypical alterations associated with a gradual benzo[a]pyrene-induced transition of human bronchial epithelial cells into mesenchymal-like cells.},

author = {Martina Hýžďalová and Jiřina Procházková and Nicol Straková and Kateřina Pěnčíková and Simona Strapáčová and Jana Slováčková and Simona Kajabová and Helena Líbalová and Jan Topinka and Markéta Kabátková and Jan Vondráček and Steen Mollerup and Miroslav Machala},

doi = {10.1016/j.etap.2024.104424},

issn = {1872-7077 1382-6689},

year  = {2024},

date = {2024-04-01},

journal = {Environmental toxicology and pharmacology},

volume = {107},

pages = {104424},

abstract = {The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.},

note = {Place: Netherlands},

keywords = {*Benzo(a)pyrene/toxicity, *Epithelial Cells/metabolism, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Benzo[a]pyrene, DNA Damage, Epithelial-Mesenchymal Transition, Human bronchial epithelial cells, Humans, Ligands, Receptors},

pubstate = {published},

tppubtype = {article}

}

@article{prochazkova_aryl_2024,

title = {Aryl hydrocarbon receptor as a drug target in advanced prostate cancer therapy - obstacles and perspectives.},

author = {Jiřina Procházková and Zuzana Kahounová and Jan Vondráček and Karel Souček},

doi = {10.1080/21541264.2024.2334106},

issn = {2154-1272},

year  = {2024},

date = {2024-03-01},

journal = {Transcription},

pages = {1–20},

abstract = {Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.Abbreviation: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.},

note = {Place: United States},

keywords = {antibody-drug conjugates, Aryl hydrocarbon receptor, castration resistance, Prostate cancer},

pubstate = {published},

tppubtype = {article}

}

@article{vazquez-gomez_aryl_2023,

title = {Aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) play both distinct and common roles in the regulation of colon homeostasis and intestinal carcinogenesis.},

author = {Gerardo Vázquez-Gómez and Jiří Petráš and Zdeněk Dvořák and Jan Vondráček},

doi = {10.1016/j.bcp.2023.115797},

issn = {1873-2968 0006-2952},

year  = {2023},

date = {2023-10-01},

journal = {Biochemical pharmacology},

volume = {216},

pages = {115797},

abstract = {Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.},

note = {Place: England},

keywords = {*Receptors, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Carcinogenesis/genetics/metabolism, Colon cancer, Colon/metabolism, Dietary contaminants, Epithelial barrier, Inflammation, Inflammation/metabolism, Intestine, Mice, Microbial agonists, Pregnane X receptor, Pregnane X Receptor/metabolism, Steroid/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{sladekova_switching_2023,

title = {Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines.},

author = {Lucia Sládeková and Eliška Zgarbová and Radim Vrzal and David Vanda and Miroslav Soural and Klára Jakubcová and Gerardo Vázquez-Gómez and Jan Vondráček and Zdeněk Dvořák},

doi = {10.1016/j.toxlet.2023.09.012},

issn = {1879-3169 0378-4274},

year  = {2023},

date = {2023-09-01},

journal = {Toxicology letters},

volume = {387},

pages = {63–75},

abstract = {Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.},

note = {Place: Netherlands},

keywords = {*Receptors, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Caco-2 Cells, Humans, Indoles/pharmacology, Microbial indoles, Pregnane X receptor, Pregnane X Receptor/genetics, Steroid/metabolism, Tryptamine, Tryptamines/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{vyhlidalova_gut_2020,

title = {Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization.},

author = {Barbora Vyhlídalová and Kristýna Krasulová and Petra Pečinková and Adéla Marcalíková and Radim Vrzal and Lenka Zemánková and Jan Vančo and Zdeněk Trávníček and Jan Vondráček and Martina Karasová and Sridhar Mani and Zdeněk Dvořák},

doi = {10.3390/ijms21072614},

issn = {1422-0067},

year  = {2020},

date = {2020-04-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {7},

abstract = {We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1 mRNA in intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.},

note = {Place: Switzerland},

keywords = {*Gastrointestinal Microbiome/drug effects, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/*metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/*metabolism, Cell Line, Cytochrome P-450 CYP1A1/genetics, Gene Expression, Genes, Genetic, Humans, Indoles, Ligands, Metabolic Networks and Pathways, Mice, Microbiome, Promoter Regions, Protein Binding, Protein Multimerization, Receptors, Reporter, tryptophan, Tryptophan/*metabolism, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{svobodova_2378-tetrachlorodibenzo-p-dioxin_2019,

title = {2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Disrupts Control of Cell Proliferation and Apoptosis in a Human Model of Adult Liver Progenitors.},

author = {Jana Svobodová and Jiřina Procházková and Markéta Kabátková and Martin Krkoška and Lenka Šmerdová and Helena Líbalová and Jan Topinka and Jiří Kléma and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1093/toxsci/kfz202},

issn = {1096-0929},

year  = {2019},

date = {2019-12-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {172},

number = {2},

pages = {368–384},

abstract = {The aryl hydrocarbon receptor (AhR) activation has been shown to alter proliferation, apoptosis, or differentiation of adult rat liver progenitors. Here, we investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation on a human model of bipotent liver progenitors, undifferentiated HepaRG cells. We used both intact undifferentiated HepaRG cells, and the cells with silenced Hippo pathway effectors, yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which play key role(s) in tissue-specific progenitor cell self-renewal and expansion, such as in liver, cardiac, or respiratory progenitors. TCDD induced cell proliferation in confluent undifferentiated HepaRG cells; however, following YAP, and, in particular, double YAP/TAZ knockdown, TCDD promoted induction of apoptosis. These results suggested that, unlike in mature hepatocytes, or hepatocyte-like cells, activation of the AhR may sensitize undifferentiated HepaRG cells to apoptotic stimuli. Induction of apoptosis in cells with silenced YAP/TAZ was associated with upregulation of death ligand TRAIL, and seemed to involve both extrinsic and mitochondrial apoptosis pathways. Global gene expression analysis further suggested that TCDD significantly altered expression of constituents and/or transcriptional targets of signaling pathways participating in control of expansion or differentiation of liver progenitors, including EGFR, Wnt/β-catenin, or tumor growth factor-β signaling pathways. TCDD significantly upregulated cytosolic proapoptotic protein BMF (Bcl-2 modifying factor) in HepaRG cells, which could be linked with an enhanced sensitivity of TCDD-treated cells to apoptosis. Our results suggest that, in addition to promotion of cell proliferation and alteration of signaling pathways controlling expansion of human adult liver progenitors, AhR ligands may also sensitize human liver progenitor cells to apoptosis.},

note = {Place: United States},

keywords = {*Models, Adaptor Proteins, Apoptosis, Apoptosis/*drug effects/genetics, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Biological, Cell Line, Cell Proliferation, Cell Proliferation/*drug effects/genetics, Gene Expression/drug effects, HepaRG cells, Hippo signaling, Humans, Liver/*drug effects/pathology, Polychlorinated Dibenzodioxins/*toxicity, Receptors, RNA, Signal Transducing/genetics, Signal Transduction, Small Interfering/genetics, Stem Cells/*drug effects/pathology, Trans-Activators/genetics, Transcription Factors/genetics, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Transfection, YAP-Signaling Proteins},

pubstate = {published},

tppubtype = {article}

}

@article{prochazkova_adaptive_2018,

title = {Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands.},

author = {Jiřina Procházková and Simona Strapáčová and Lucie Svržková and Zdeněk Andrysík and Martina Hýžďalová and Eva Hrubá and Kateřina Pěnčíková and Helena Líbalová and Jan Topinka and Jiří Kléma and Joaquín M. Espinosa and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.toxlet.2018.04.024},

issn = {1879-3169 0378-4274},

year  = {2018},

date = {2018-08-01},

journal = {Toxicology letters},

volume = {292},

pages = {162–174},

abstract = {Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals, and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling and analyze TCDD-induced changes in A549 transcriptome, both sensitive and non-sensitive to CH223191 co-treatment. Comparison of our data with results from previously reported microarray and ChIP-seq experiments enabled us to identify candidate genes, which expression status reflects exposure of lung cancer cells to TCDD, and to predict processes, pathways (e.g. ER stress, Wnt/β-cat, IFNɣ, EGFR/Erbb1), putative TFs (e.g. STAT, AP1, E2F1, TCF4), which may be implicated in adaptive response of lung cells to TCDD-induced AhR activation. Importantly, TCDD-like expression fingerprint of selected genes was observed also in A549 cells exposed acutely to both toxic (benzo[a]pyrene, benzo[k]fluoranthene) and endogenous AhR ligands (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester and 6-formylindolo[3,2-b]carbazole). Overall, our results suggest novel cellular candidates, which could help to improve monitoring of AhR-dependent transcriptional activity during acute exposure of lung cells to distinct types of environmental pollutants.},

note = {Place: Netherlands},

keywords = {A549 Cells, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/metabolism, Azo Compounds/toxicity, Basic Helix-Loop-Helix Transcription Factors/*agonists/metabolism, Benzo(a)pyrene/toxicity, Carbazoles/toxicity, Dioxins, Environmental Pollutants/*toxicity, Fluorenes/toxicity, Gene Expression Profiling/methods, Gene Expression Regulation, Gene Regulatory Networks/drug effects, Genetic/drug effects, Global gene expression profiling, Humans, Indoles/toxicity, Ligands, Lung cancer, Lung Neoplasms/*genetics/metabolism, Neoplastic/*drug effects, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins/toxicity, Pyrazoles/toxicity, Receptors, Signal Transduction/drug effects, Thiazoles/toxicity, Time Factors, Transcription, Transcriptional Activation/drug effects, Transcriptome/*drug effects},

pubstate = {published},

tppubtype = {article}

}

@article{brenerova_pure_2016,

title = {Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells.},

author = {Petra Brenerová and Timo Hamers and Jorke H. Kamstra and Jan Vondráček and Simona Strapáčová and Patrik L. Andersson and Miroslav Machala},

doi = {10.1007/s11356-015-4819-6},

issn = {1614-7499 0944-1344},

year  = {2016},

date = {2016-02-01},

journal = {Environmental science and pollution research international},

volume = {23},

number = {3},

pages = {2099–2107},

abstract = {The relative potencies of non-ortho-substituted coplanar polychlorinated biphenyl (PCB) congeners to activate the aryl hydrocarbon receptor (AhR) and to cause the AhR-dependent toxic events are essential for their risk assessment. Since some studies suggested that abundant non-dioxin-like PCB congeners (NDL-PCBs) may alter the AhR activation by PCB mixtures and possibly cause non-additive effects, we evaluated potential suppressive effects of NDL-PCBs on AhR activation, using a series of 24 highly purified NDL-PCBs. We investigated their impact on the model AhR agonist-induced luciferase reporter gene expression in rat hepatoma cells and on induction of CYP1A1/1B1 mRNAs and deregulation of AhR-dependent cell proliferation in rat liver epithelial cells. PCBs 128, 138, and 170 significantly suppressed AhR activation (with IC50 values from 1.4 to 5.6 μM), followed by PCBs 28, 47, 52, and 180; additionally, PCBs 122, 153, and 168 showed low but still significant potency to reduce luciferase activity. Detection of CYP1A1 mRNA levels in liver epithelial cells largely confirmed these results for the most abundant NDL-PCBs, whereas the other AhR-dependent events (CYP1B1 mRNA expression, induction of cell proliferation in confluent cells) were less sensitive to NDL-PCBs, thus indicating a more complex regulation of these endpoints. The present data suggest that some NDL-PCBs could modulate overall dioxin-like effects in complex mixtures.},

note = {Place: Germany},

keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/*metabolism, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P450, Disruption of contact inhibition, DR-CALUX® assay, Epithelial Cells/cytology/drug effects/metabolism, Gene Expression/drug effects, Hepatocytes/cytology/drug effects/metabolism, Liver/*drug effects/metabolism, NDL-PCBs, Polychlorinated Biphenyls/*chemistry/*toxicity, Rats, Receptors, Relative effect potency, Signal Transduction/drug effects},

pubstate = {published},

tppubtype = {article}

}

@article{kabatkova_interactive_2015,

title = {Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription.},

author = {Markéta Kabátková and Jana Svobodová and Kateřina Pěnčíková and Dilshad Shaik Mohatad and Lenka Šmerdová and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1016/j.toxlet.2014.09.023},

issn = {1879-3169 0378-4274},

year  = {2015},

date = {2015-01-01},

journal = {Toxicology letters},

volume = {232},

number = {1},

pages = {113–121},

abstract = {Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.},

note = {Place: Netherlands},

keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/genetics/metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/genetics/metabolism, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Proliferation/*drug effects, Cell Transformation, Connexin 43/genetics/metabolism, Dose-Response Relationship, Drug, Enzyme Activation, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/*toxicity, Gap junctions, Gap Junctions/*drug effects/metabolism/pathology, Gene Expression Regulation/drug effects, Genetic/*drug effects, Inflammation, Inflammation/chemically induced/genetics/metabolism/pathology, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Molecular Weight, Neoplastic/chemically induced/metabolism/pathology, p38 Mitogen-Activated Protein Kinases/metabolism, PAHs, Rats, Receptors, Signal Transduction/drug effects, Time Factors, Transcription, Tumor Necrosis Factor-alpha/*toxicity},

pubstate = {published},

tppubtype = {article}

}

@article{prochazkova_aryl_2013,

title = {Aryl hydrocarbon receptor negatively regulates expression of the plakoglobin gene (jup).},

author = {Jiřina Procházková and Markéta Kabátková and Lenka Šmerdová and Jiří Pacherník and Dominika Sykorová and Jiří Kohoutek and Pavlína Šimečková and Eva Hrubá and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1093/toxsci/kft110},

issn = {1096-0929},

year  = {2013},

date = {2013-08-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {134},

number = {2},

pages = {258–270},

abstract = {Plakoglobin is an important component of intercellular junctions, including both desmosomes and adherens junctions, which is known as a tumor suppressor. Although mutations in the plakoglobin gene (Jup) and/or changes in its protein levels have been observed in various disease states, including cancer progression or cardiovascular defects, the information about endogenous or exogenous stimuli orchestrating Jup expression is limited. Here we show that the aryl hydrocarbon receptor (AhR) may regulate Jup expression in a cell-specific manner. We observed a significant suppressive effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model toxic exogenous activator of the AhR signaling, on Jup expression in a variety of experimental models derived from rodent tissues, including contact-inhibited rat liver progenitor cells (where TCDD induces cell proliferation), rat and mouse hepatoma cell models (where TCDD inhibits cell cycle progression), cardiac cells derived from the mouse embryonic stem cells, or cardiomyocytes isolated from neonatal rat hearts. The small interfering RNA (siRNA)-mediated knockdown of AhR confirmed its role in both basal and TCDD-deregulated Jup expression. The analysis of genomic DNA located textasciitilde2.5kb upstream of rat Jup gene revealed a presence of evolutionarily conserved AhR binding motifs, which were confirmed upon their cloning into luciferase reporter construct. The siRNA-mediated knockdown of Jup expression affected both proliferation and attachment of liver progenitor cells. The present data indicate that the AhR may contribute to negative regulation of Jup gene expression in rodent cellular models, which may affect cell adherence and proliferation.},

note = {Place: United States},

keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*physiology, Base Sequence, cardiomyocytes., Cell Adhesion, Cell Line, Cell Proliferation, Cloning, desmosomes, dioxin, DNA Primers, Down-Regulation, gamma Catenin/*genetics, Gene Expression Regulation/*physiology, Genetic, Inbred F344, liver progenitor cells, Molecular, plakoglobin, Polychlorinated Dibenzodioxins/pharmacology, Promoter Regions, Rats, Real-Time Polymerase Chain Reaction, Receptors},

pubstate = {published},

tppubtype = {article}

}