Latest Publications

@article{lenart_tacstd2_2022,

title = {TACSTD2 upregulation is an early reaction to lung infection.},

author = {Sára Lenárt and Peter Lenárt and Lucia Knopfová and Hana Kotasová and Vendula Pelková and Veronika Sedláková and Ondřej Vacek and Jana Pokludová and Vladimír Čan and Jan Šmarda and Karel Souček and Aleš Hampl and Petr Beneš},

doi = {10.1038/s41598-022-13637-9},

issn = {2045-2322},

year  = {2022},

date = {2022-06-01},

journal = {Scientific reports},

volume = {12},

number = {1},

pages = {9583},

abstract = {TACSTD2 encodes a transmembrane glycoprotein Trop2 commonly overexpressed in carcinomas. While the Trop2 protein was discovered already in 1981 and first antibody-drug conjugate targeting Trop2 were recently approved for cancer therapy, the physiological role of Trop2 is still not fully understood. In this article, we show that TACSTD2/Trop2 expression is evolutionarily conserved in lungs of various vertebrates. By analysis of publicly available transcriptomic data we demonstrate that TACSTD2 level consistently increases in lungs infected with miscellaneous, but mainly viral pathogens. Single cell and subpopulation based transcriptomic data revealed that the major source of TACSTD2 transcript are lung epithelial cells and their progenitors and that TACSTD2 is induced directly in lung epithelial cells following infection. Increase in TACSTD2 expression may represent a mechanism to maintain/restore epithelial barrier function and contribute to regeneration process in infected/damaged lungs.},

note = {Place: England},

keywords = {*Antigens, *Cell Adhesion Molecules/metabolism, Animals, Epithelial Cells/metabolism, Lung/metabolism, Neoplasm/metabolism, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}

@article{svobodova_aryl_2015,

title = {The aryl hydrocarbon receptor-dependent disruption of contact inhibition in rat liver WB-F344 epithelial cells is linked with induction of survivin, but not with inhibition of apoptosis.},

author = {Jana Svobodová and Markéta Kabátková and Lenka Šmerdová and Petra Brenerová and Zdeněk Dvořák and Miroslav Machala and Jan Vondráček},

doi = {10.1016/j.tox.2015.04.001},

issn = {1879-3185 0300-483X},

year  = {2015},

date = {2015-07-01},

journal = {Toxicology},

volume = {333},

pages = {37–44},

abstract = {Inhibition of apoptosis by the ligands of the aryl hydrocarbon receptor (AhR) has been proposed to play a role in their tumor promoting effects on liver parenchymal cells. However, little is presently known about the impact of toxic AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on apoptosis in other liver cell types, such as in liver epithelial/progenitor cells. In the present study, we focused on the effects of TCDD on apoptosis regulation in a model of liver progenitor cells, rat WB-F344 cell line, during the TCDD-elicited release from contact inhibition. The stimulation of cell proliferation in this cell line was associated with deregulated expression of a number of genes known to be under transcriptional control of the Hippo signaling pathway, a principal regulatory pathway involved in contact inhibition of cell proliferation. Interestingly, we found that mRNA and protein levels of survivin, a known Hippo target, which plays a role both in cell division and inhibition of apoptosis, were significantly up-regulated in rat liver epithelial cell model, as well as in undifferentiated human liver HepaRG cells. Using the short interfering RNA-mediated knockdown, we confirmed that survivin plays a central role in cell division of WB-F344 cells. When evaluating the effects of TCDD on apoptosis induction by camptothecin, a genotoxic topoisomerase I inhibitor, we observed that the pre-treatment of WB-F344 cells with TCDD increased number of cells with apoptotic nuclear morphology, and it potentiated cleavage of both caspase-3 and poly(ADP-ribose) polymerase I. This indicated that despite the observed up-regulation of survivin, apoptosis induced by the genotoxin was potentiated in the model of rat liver progenitor cells. The present results indicate that, unlike in hepatocytes, AhR agonists may not prevent induction of apoptosis elicited by DNA-damaging agents in a model of rat liver progenitor cells.},

note = {Place: Ireland},

keywords = {AhR, Animals, Apoptosis, Apoptosis/*drug effects, Aryl Hydrocarbon/*agonists/metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/metabolism, BIRC5/survivin, Camptothecin/*toxicity, Caspase 3/metabolism, Cell Line, Contact inhibition, Contact Inhibition/*drug effects, Epithelial Cells/*drug effects/metabolism/pathology, Genetic/drug effects, Hippo signaling, Humans, Inbred F344, Inhibitor of Apoptosis Proteins/genetics/metabolism, Liver/*drug effects/metabolism/pathology, Microtubule-Associated Proteins/genetics/*metabolism, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases/metabolism, Polychlorinated Dibenzodioxins/*toxicity, Rats, Receptors, RNA Interference, Signal Transduction/drug effects, Survivin, TCDD, Time Factors, Topoisomerase I Inhibitors/*toxicity, Transcription, Transfection, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}

@article{umannova_tumor_2008,

title = {Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression.},

author = {Lenka Umannová and Miroslav Machala and Jan Topinka and Zuzana Nováková and Alena Milcová and Alois Kozubík and Jan Vondrácek},

doi = {10.1016/j.mrfmmm.2008.02.001},

issn = {0027-5107},

year  = {2008},

date = {2008-04-01},

journal = {Mutation research},

volume = {640},

number = {1-2},

pages = {162–169},

abstract = {Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant, which may contribute to the development of human cancer. The ultimate carcinogenic BaP metabolite produced by cytochrome P450 enzymes (CYP), such as CYP1A1 and CYP1B1, anti-BaP-7,8-diol-9,10-epoxide, binds covalently to DNA and causes mutations. The levels of various CYP isoforms can be significantly modulated under inflammatory conditions. As the chronic inflammation is known to contribute to carcinogenesis, we investigated interactions of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), and BaP in regulation of the expression of CYP1A1/1B1 and induction of DNA damage in rat liver epithelial WB-F344 cells. TNF-alpha enhanced induction of CYP1B1, while it simultaneously suppressed the BaP-induced CYP1A1 expression. The observed deregulation of CYP1 induction was found to be associated with a significantly enhanced formation of DNA adducts. The elevated DNA damage corresponded with increased phosphorylation of p53 tumor suppressor at Ser-15 residue, enhanced accumulation of cells in the S-phase of cell cycle and potentiation of BaP-induced apoptosis. Inhibition of CYP1B1 by fluoranthene significantly decreased both the formation of DNA adducts and the induction of apoptosis in WB-F344 cells treated with BaP and TNF-alpha, thus suggesting that this isoform might be responsible for genotoxic effects of BaP in nonparenchymal liver cells. Our results seem to indicate that inflammatory conditions might enhance genotoxic effects of carcinogenic polycyclic aromatic hydrocarbons through upregulation of CYP1B1 expression.},

note = {Place: Netherlands},

keywords = {Animals, Aryl Hydrocarbon Hydroxylases/*metabolism, Benzo(a)pyrene/*toxicity, Cell Line, Cytochrome P-450 CYP1B1, Drug Synergism, Epithelial Cells/drug effects/enzymology, Liver/*drug effects/*enzymology, Male, Rats, Tumor Necrosis Factor-alpha/*pharmacology, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_aryl_2005,

title = {Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.},

author = {Jan Vondrácek and Miroslav Machala and Vítezslav Bryja and Katerina Chramostová and Pavel Krcmár and Cornelia Dietrich and Ales Hampl and Alois Kozubík},

doi = {10.1093/toxsci/kfi009},

issn = {1096-6080 1096-0929},

year  = {2005},

date = {2005-01-01},

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

volume = {83},

number = {1},

pages = {53–63},

abstract = {Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Proliferation/*drug effects, Cyclin A/biosynthesis, Cyclin D2, Cyclin-Dependent Kinases/biosynthesis, Cyclins/biosynthesis, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Hydroxylation, Liver/*cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}