Latest Publications

@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}

}

@article{prochazkova_interplay_2011,

title = {The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors.},

author = {Jirina Procházková and Markéta Kabátková and Vítezslav Bryja and Lenka Umannová and Ondrej Bernatík and Alois Kozubík and Miroslav Machala and Jan Vondrácek},

doi = {10.1093/toxsci/kfr129},

issn = {1096-0929},

year  = {2011},

date = {2011-08-01},

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

volume = {122},

number = {2},

pages = {349–360},

abstract = {β-catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/β-catenin pathway, which plays an important role in liver biology. Using a model of contact-inhibited liver progenitor cells, we examined the interactions of Wnt/β-catenin signaling with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which mediates the toxicity of dioxin-like compounds, including their effects on development and hepatocarcinogenesis. We found that AhR and Wnt/β-catenin cooperated in the induction of AhR transcriptional targets, such as Cyp1a1 and Cyp1b1. However, simultaneously, the activation of AhR led to a decrease of dephosphorylated active β-catenin pool, as well as to hypophosphorylation of Dishevelled, participating in regulation of Wnt signaling. A sustained AhR activation by its model ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), led to a downregulation of a number of Wnt/β-catenin pathway target genes. TCDD also induced a switch in cytokeratin expression, where downregulation of cytokeratins 14 and 19 was accompanied with an increased cytokeratin 8 expression. Together with a downregulation of additional markers associated with stem-like phenotype, this indicated that the AhR activation interfered with differentiation of liver progenitors. The downregulation of β-catenin was also related to a reduced cell adhesion, disruption of E-cadherin-mediated cell-cell junctions and an increased G1-S transition in liver progenitor cell line. In conclusion, although β-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/β-catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon Hydroxylases/genetics/metabolism, Aryl Hydrocarbon/genetics/*metabolism, beta Catenin/genetics/*metabolism, Cadherins/genetics, Cell Adhesion, Cell Differentiation, Cell Line, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, Down-Regulation/drug effects, Hepatocytes/drug effects, Inbred F344, Liver/*drug effects, Polychlorinated Dibenzodioxins/toxicity, Rats, Receptors, Wnt Proteins/genetics/*metabolism, Wnt Signaling Pathway},

pubstate = {published},

tppubtype = {article}

}