2018
Verlande, Amandine; Krafčíková, Michaela; Potěšil, David; Trantírek, Lukáš; Zdráhal, Zbyněk; Elkalaf, Moustafa; Trnka, Jan; Souček, Karel; Rauch, Nora; Rauch, Jens; Kolch, Walter; Uldrijan, Stjepan
Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. Journal Article
In: EMBO reports, vol. 19, no. 2, pp. 320–336, 2018, ISSN: 1469-3178 1469-221X, (Place: England).
Abstract | Links | BibTeX | Tags: *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
@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}
}
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.
2006
Andrysík, Zdenek; Machala, Miroslav; Chramostová, Katerina; Hofmanová, Jirina; Kozubík, Alois; Vondrácek, Jan
In: Toxicology and applied pharmacology, vol. 211, no. 3, pp. 198–208, 2006, ISSN: 0041-008X, (Place: United States).
Abstract | Links | BibTeX | Tags: *Epithelial Cells/cytology/drug effects/enzymology, *Liver/cytology/drug effects/enzymology, Animals, Apoptosis/*drug effects, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/*metabolism, JNK Mitogen-Activated Protein Kinases/metabolism, p38 Mitogen-Activated Protein Kinases/*metabolism, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats
@article{andrysik_activation_2006,
title = {Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis.},
author = {Zdenek Andrysík and Miroslav Machala and Katerina Chramostová and Jirina Hofmanová and Alois Kozubík and Jan Vondrácek},
doi = {10.1016/j.taap.2005.06.007},
issn = {0041-008X},
year = {2006},
date = {2006-03-01},
journal = {Toxicology and applied pharmacology},
volume = {211},
number = {3},
pages = {198–208},
abstract = {Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-alpha, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage induced by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.},
note = {Place: United States},
keywords = {*Epithelial Cells/cytology/drug effects/enzymology, *Liver/cytology/drug effects/enzymology, Animals, Apoptosis/*drug effects, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/*metabolism, JNK Mitogen-Activated Protein Kinases/metabolism, p38 Mitogen-Activated Protein Kinases/*metabolism, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats},
pubstate = {published},
tppubtype = {article}
}
Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-alpha, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage induced by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.