Latest Publications

@article{verlande_metabolic_2018,

title = {Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization.},

author = {Amandine Verlande and Michaela Krafčíková and David Potěšil and Lukáš Trantírek and Zbyněk Zdráhal and Moustafa Elkalaf and Jan Trnka and Karel Souček and Nora Rauch and Jens Rauch and Walter Kolch and Stjepan Uldrijan},

doi = {10.15252/embr.201744524},

issn = {1469-3178 1469-221X},

year  = {2018},

date = {2018-02-01},

journal = {EMBO reports},

volume = {19},

number = {2},

pages = {320–336},

abstract = {Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAF(V600E)-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF(V600E)-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.},

note = {Place: England},

keywords = {*Protein Multimerization, *Stress, 14-3-3 Proteins/chemistry/metabolism, cell cycle arrest, Cell Cycle Checkpoints/genetics, Cell Line, Cell Survival, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases/*metabolism, Glucose/metabolism, Glycolysis, GTP Phosphohydrolases/genetics/metabolism, Humans, Melanoma, Melanoma/genetics/metabolism, Membrane Proteins/genetics/metabolism, metabolic stress, Mutation, Oxygen Consumption, Physiological, Protein Kinases/chemistry/genetics/*metabolism, raf Kinases/chemistry/genetics/*metabolism, RAF‐ERK signaling, Recombinant Fusion Proteins, Tumor},

pubstate = {published},

tppubtype = {article}

}

@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}

}