Latest Publications

@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{steinmetz_oncogene_2014,

title = {The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid.},

author = {Birgit Steinmetz and Hubert Hackl and Eva Slabáková and Ilse Schwarzinger and Monika Smějová and Andreas Spittler and Itziar Arbesu and Medhat Shehata and Karel Souček and Rotraud Wieser},

doi = {10.4161/15384101.2014.946869},

issn = {1551-4005 1538-4101},

year  = {2014},

date = {2014-01-01},

journal = {Cell cycle (Georgetown, Tex.)},

volume = {13},

number = {18},

pages = {2931–2943},

abstract = {The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARβ gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-β superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed.},

note = {Place: United States},

keywords = {*Oncogenes, acute myeloid leukemia, acute promyelocytic leukemia, all-trans retinoic acid, AML, APL, Apoptosis, Apoptosis/drug effects, Ar, ATRA, ATRA regulation, Cell Cycle, Cell Cycle Checkpoints/drug effects, Cell Differentiation/drug effects, dimethyl sulfoxide, DMSO, DNA-Binding Proteins/genetics/*metabolism, Down-Regulation/drug effects, Em, Epithelial Cells/drug effects/metabolism, Er, EVI1, EVI1 modulation, EVI1 regulation, false discovery rate, FBS, FC, FDR, fetal bovine serum, fold change, GDF15, Gene Expression Profiling, Gene Knockdown Techniques, Genetic/*drug effects, GFP, green fluorescent protein, Growth Differentiation Factor 15/genetics/metabolism, HL-60 Cells, Humans, mcoEvi1, MDS, MDS1 and EVI1 Complex Locus Protein, murine codon optimized Evi1, myelodysplastic syndrome, Myeloid Cells/drug effects/*metabolism, myeloid differentiation, penicillin streptomycin glutamine, Proto-Oncogenes/genetics, PSG, RAR, RARE, Real-Time Polymerase Chain Reaction, Reproducibility of Results, retinoic acid receptor, retinoic acid response element, SE, standard error, Transcription, Transcription Factors/genetics/*metabolism, Tretinoin/*pharmacology},

pubstate = {published},

tppubtype = {article}

}