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{slabakova_alternative_2017,

title = {Alternative mechanisms of miR-34a regulation in cancer.},

author = {Eva Slabáková and Zoran Culig and Ján Remšík and Karel Souček},

doi = {10.1038/cddis.2017.495},

issn = {2041-4889},

year  = {2017},

date = {2017-10-01},

journal = {Cell death & disease},

volume = {8},

number = {10},

pages = {e3100},

abstract = {MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.},

note = {Place: England},

keywords = {*Genes, Animals, Epigenesis, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Genetic/genetics, Humans, MicroRNAs/*genetics, Neoplasms/*genetics/*pathology, Neoplastic/genetics, Promoter Regions, Tumor Suppressor, Tumor Suppressor Protein p53/*genetics},

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{takacova_role_2009,

title = {Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX.},

author = {Martina Takacova and Tereza Holotnakova and Jan Vondracek and Miroslav Machala and Katerina Pencikova and Katarina Gradin and Lorenz Poellinger and Jaromir Pastorek and Silvia Pastorekova and Juraj Kopacek},

doi = {10.1042/BJ20080952},

issn = {1470-8728 0264-6021},

year  = {2009},

date = {2009-04-01},

journal = {The Biochemical journal},

volume = {419},

number = {2},

pages = {419–425},

abstract = {Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1alpha and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1alpha competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.},

note = {Place: England},

keywords = {alpha Subunit, Animals, Antigens, Aryl Hydrocarbon/genetics/metabolism/*physiology, Binding Sites, Blotting, Carbonic Anhydrase IX, Carbonic Anhydrases/genetics/*metabolism, Cell Hypoxia/genetics/*physiology, Cell Line, Chromatin Immunoprecipitation, Genetic/genetics, Humans, Hypoxia-Inducible Factor 1, Mice, Neoplasm/genetics, Polychlorinated Dibenzodioxins/pharmacology, Polymerase Chain Reaction, Promoter Regions, Protein Binding/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Tumor, Western},

pubstate = {published},

tppubtype = {article}

}