Latest Publications

@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{remsik_plasticity_2018,

title = {Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer.},

author = {Ján Remšík and Radek Fedr and Jiří Navrátil and Lucia Binó and Eva Slabáková and Pavel Fabian and Marek Svoboda and Karel Souček},

doi = {10.1038/bjc.2017.497},

issn = {1532-1827 0007-0920},

year  = {2018},

date = {2018-03-01},

journal = {British journal of cancer},

volume = {118},

number = {6},

pages = {813–819},

abstract = {Background:The intratumoural heterogeneity, often driven by epithelial-to-mesenchymal transition (EMT), significantly contributes to chemoresistance and disease progression in adenocarcinomas. Methods:We introduced a high-throughput screening platform to identify surface antigens that associate with epithelial–mesenchymal plasticity in well-defined pairs of epithelial cell lines and their mesenchymal counterparts. Using multicolour flow cytometry, we then analysed the expression of 10 most robustly changed antigens and identified a 10-molecule surface signature, in pan-cytokeratin-positive/EpCAM-positive and -negative fractions of dissociated breast tumours. Results:We found that surface CD9, CD29, CD49c, and integrin ß5 are lost in breast cancer cells that underwent EMT in vivo. The tetraspanin family member CD9 was concordantly downregulated both in vitro and in vivo and associated with epithelial phenotype and favourable prognosis. Conclusions:We propose that overall landscape of 10-molecule surface signature expression reflects the epithelial–mesenchymal plasticity in breast cancer.},

note = {Place: England},

keywords = {Antigens, Biomarkers, Breast Neoplasms/*genetics/*immunology/pathology, Cell Line, Cell Plasticity/immunology, Cellular Reprogramming/physiology, Epithelial-Mesenchymal Transition/immunology, Female, Flow Cytometry, Genetic, High-Throughput Screening Assays, Humans, Neoplasm Metastasis, Neoplasm/*biosynthesis/immunology, Surface/*biosynthesis/immunology, Tetraspanin 29/biosynthesis/immunology, Transcription, Tumor},

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}

}

@article{uhlirova_suv39h-_2010,

title = {SUV39h- and A-type lamin-dependent telomere nuclear rearrangement.},

author = {Radka Uhlírová and Andrea Harnicarová Horáková and Gabriela Galiová and Sona Legartová and Pavel Matula and Miloslava Fojtová and Miroslav Varecha and Jana Amrichová and Jan Vondrácek and Stanislav Kozubek and Eva Bártová},

doi = {10.1002/jcb.22466},

issn = {1097-4644 0730-2312},

year  = {2010},

date = {2010-04-01},

journal = {Journal of cellular biochemistry},

volume = {109},

number = {5},

pages = {915–926},

abstract = {Telomeres are specialized chromatin structures that are situated at the end of linear chromosomes and play an important role in cell senescence and immortalization. Here, we investigated whether changes in histone signature influence the nuclear arrangement and positioning of telomeres. Analysis of mouse embryonic fibroblasts revealed that telomeres were organized into specific clusters that partially associated with centromeric clusters. This nuclear arrangement was influenced by deficiency of the histone methyltransferase SUV39h, LMNA deficiency, and the histone deacetylase inhibitor Trichostatin A (TSA). Similarly, nuclear radial distributions of telomeric clusters were preferentially influenced by TSA, which caused relocation of telomeres closer to the nuclear center. Telomeres also co-localized with promyelocytic leukemia bodies (PML). This association was increased by SUV39h deficiency and decreased by LMNA deficiency. These differences could be explained by differing levels of the telomerase subunit, TERT, in SUV39h- and LMNA-deficient fibroblasts. Taken together, our data show that SUV39h and A-type lamins likely play a key role in telomere maintenance and telomere nuclear architecture.},

note = {Place: United States},

keywords = {*Gene Rearrangement, Animals, DNA-Binding Proteins/metabolism, Epigenesis, Fibroblasts/metabolism, Flow Cytometry, Genetic, Humans, Intranuclear Inclusion Bodies/metabolism, Lamin Type A/*metabolism, Methyltransferases/*metabolism, Mice, Protein Transport, rap1 GTP-Binding Proteins/metabolism, Repressor Proteins/*metabolism, Shelterin Complex, Telomerase/metabolism, Telomere-Binding Proteins, Telomere/genetics/*metabolism, Telomeric Repeat Binding Protein 1/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{pliskova_deregulation_2005,

title = {Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events.},

author = {Martina Plísková and Jan Vondrácek and Borivoj Vojtesek and Alois Kozubík and Miroslav Machala},

doi = {10.1093/toxsci/kfi040},

issn = {1096-6080 1096-0929},

year  = {2005},

date = {2005-02-01},

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

volume = {83},

number = {2},

pages = {246–256},

abstract = {Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are carcinogens suggested to be involved in development of human cancer. Several recent studies have reported that PAHs can activate estrogen receptors (ER), either directly or indirectly by producing estrogenic metabolites. We hypothesized that the activation of ER by PAHs or their metabolites could induce cell proliferation in estrogen-sensitive cells. In the present study, we found that two PAHs, benz[a]anthracene (BaA) and BaP, can stimulate proliferation of human breast carcinoma MCF-7 cells at concentrations 100 nM and higher. This effect was ER-dependent, because it was blocked by the pure antiestrogen ICI 182,780. Although both PAHs partially inhibited S-phase entry and DNA synthesis induced by 17beta-estradiol, they stimulated S-phase entry when applied to MCF-7 cells synchronized by serum deprivation. This was in contrast with model antiestrogenic aryl hydrocarbon receptor ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which fully suppressed S-phase entry. BaP, which is a strong mutagen, was found to induce p53 tumor suppressor expression, a partial S-phase arrest and at higher concentrations also cell death. Pifithrin-alpha, a synthetic inhibitor of p53 activity, abolished both S-phase arrest and apoptosis induced by genotoxic PAHs, and it potentiated the proliferative effect of BaP. Thus, both genotoxic and nongenotoxic events seem to interact in the effects of BaP on cell proliferation. Taken together, our data indicate that both BaA and BaP can stimulate cell proliferation through activation of ER. The proliferative effects of these carcinogenic compounds might contribute to tumor promotion in estrogen-sensitive tissues.},

note = {Place: United States},

keywords = {Benz(a)Anthracenes/*toxicity, Benzo(a)pyrene/*toxicity, Benzothiazoles, Breast Neoplasms/drug therapy/*genetics/metabolism, Bromodeoxyuridine/metabolism, Carcinogens/*toxicity, Carcinoma/drug therapy/*genetics/metabolism, Cell Cycle/drug effects, Cell Line, Cell Proliferation/*drug effects, Cell Survival/drug effects, DNA Replication/drug effects, Dose-Response Relationship, Drug, Drug Interactions, Epigenesis, Estradiol/*analogs & derivatives/pharmacology, Estrogen, Estrogen Antagonists/pharmacology, Female, Fulvestrant, Genetic, Humans, Receptors, Thiazoles/pharmacology, Toluene/*analogs & derivatives/pharmacology, Tumor, Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/metabolism},

pubstate = {published},

tppubtype = {article}

}