2011
Procházková, Jiřina; Kozubík, Alois; Machala, Miroslav; Vondráček, Jan
In: Toxicology, vol. 279, no. 1-3, pp. 146–154, 2011, ISSN: 1879-3185 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/*drug effects/metabolism, Carcinoma, Cell Cycle/drug effects, Cell Nucleus/metabolism, Cell Proliferation/drug effects, Cells, Chromatin Immunoprecipitation, Cultured, Dose-Response Relationship, Drug, Gene Expression Regulation/*drug effects, Hepatocellular/pathology, Indoles/administration & dosage/metabolism/pharmacology, Liver Neoplasms/pathology, Liver/cytology/drug effects/metabolism, Polychlorinated Dibenzodioxins/*toxicity, Protein Transport, Rats, Receptors, Signal Transduction/drug effects, Stem Cells/drug effects/metabolism
@article{prochazkova_differential_2011,
title = {Differential effects of indirubin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the aryl hydrocarbon receptor (AhR) signalling in liver progenitor cells.},
author = {Jiřina Procházková and Alois Kozubík and Miroslav Machala and Jan Vondráček},
doi = {10.1016/j.tox.2010.10.003},
issn = {1879-3185 0300-483X},
year = {2011},
date = {2011-01-01},
journal = {Toxicology},
volume = {279},
number = {1-3},
pages = {146–154},
abstract = {In the present study, we investigated the effects of potential endogenous ligand indirubin on the aryl hydrocarbon receptor (AhR) signalling, with a focus on the AhR-dependent gene expression and cell cycle progression in rat liver progenitor cells, and compared them with the effects of a model toxic AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The low (picomolar and nanomolar) doses of indirubin, corresponding to expected endogenous levels, induced a transient translocation of AhR to the nucleus, while high (micromolar) doses induced a long-term AhR nuclear translocation, followed by its degradation, similar to the effects of TCDD. Whereas high doses of indirubin recruited AhR/ARNT1 dimer to rat Cyp1a1 promoter, the low doses did not induce its DNA binding, as revealed by the chromatin immunoprecipitation assay. This corresponded with the fact that the micromolar doses of indirubin significantly increased Cyp1a1/1b1 mRNA in a way similar to TCDD, while the low doses of indirubin were only poor inducers of Cyp1a1/1b1 expression. Comparable patterns of expression were observed also for other AhR gene targets, such as Nqo1 and Nrf2. Also, only micromolar doses of indirubin were able to mimic the effects of TCDD on cell cycle and proliferation of liver progenitor cells or hepatoma cells. Nevertheless, indirubin at low concentrations may have unique effects on gene expression in non-tumorigenic cells. Although both TCDD and the high doses of indirubin repressed plakoglobin (Jup) expression, the picomolar doses of indirubin, unlike the equimolar doses of TCDD, increased mRNA levels of this important desmosomal and adherens junctions constituent. These present data suggest that the outcome of AhR activation induced by indirubin at concentrations expected in vivo may differ from the AhR signalling triggered by exogenous toxic ligands, such as TCDD.},
note = {Place: Ireland},
keywords = {Animals, Aryl Hydrocarbon/*drug effects/metabolism, Carcinoma, Cell Cycle/drug effects, Cell Nucleus/metabolism, Cell Proliferation/drug effects, Cells, Chromatin Immunoprecipitation, Cultured, Dose-Response Relationship, Drug, Gene Expression Regulation/*drug effects, Hepatocellular/pathology, Indoles/administration & dosage/metabolism/pharmacology, Liver Neoplasms/pathology, Liver/cytology/drug effects/metabolism, Polychlorinated Dibenzodioxins/*toxicity, Protein Transport, Rats, Receptors, Signal Transduction/drug effects, Stem Cells/drug effects/metabolism},
pubstate = {published},
tppubtype = {article}
}
In the present study, we investigated the effects of potential endogenous ligand indirubin on the aryl hydrocarbon receptor (AhR) signalling, with a focus on the AhR-dependent gene expression and cell cycle progression in rat liver progenitor cells, and compared them with the effects of a model toxic AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The low (picomolar and nanomolar) doses of indirubin, corresponding to expected endogenous levels, induced a transient translocation of AhR to the nucleus, while high (micromolar) doses induced a long-term AhR nuclear translocation, followed by its degradation, similar to the effects of TCDD. Whereas high doses of indirubin recruited AhR/ARNT1 dimer to rat Cyp1a1 promoter, the low doses did not induce its DNA binding, as revealed by the chromatin immunoprecipitation assay. This corresponded with the fact that the micromolar doses of indirubin significantly increased Cyp1a1/1b1 mRNA in a way similar to TCDD, while the low doses of indirubin were only poor inducers of Cyp1a1/1b1 expression. Comparable patterns of expression were observed also for other AhR gene targets, such as Nqo1 and Nrf2. Also, only micromolar doses of indirubin were able to mimic the effects of TCDD on cell cycle and proliferation of liver progenitor cells or hepatoma cells. Nevertheless, indirubin at low concentrations may have unique effects on gene expression in non-tumorigenic cells. Although both TCDD and the high doses of indirubin repressed plakoglobin (Jup) expression, the picomolar doses of indirubin, unlike the equimolar doses of TCDD, increased mRNA levels of this important desmosomal and adherens junctions constituent. These present data suggest that the outcome of AhR activation induced by indirubin at concentrations expected in vivo may differ from the AhR signalling triggered by exogenous toxic ligands, such as TCDD.
2009
Takacova, Martina; Holotnakova, Tereza; Vondracek, Jan; Machala, Miroslav; Pencikova, Katerina; Gradin, Katarina; Poellinger, Lorenz; Pastorek, Jaromir; Pastorekova, Silvia; Kopacek, Juraj
Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX. Journal Article
In: The Biochemical journal, vol. 419, no. 2, pp. 419–425, 2009, ISSN: 1470-8728 0264-6021, (Place: England).
Abstract | Links | BibTeX | Tags: alpha Subunit, Animals, Antigens, Aryl Hydrocarbon/genetics/metabolism/*physiology, Binding Sites, Blotting, Carbonic Anhydrase IX, Carbonic Anhydrases/genetics/*metabolism, Cell Hypoxia/genetics/*physiology, Cell Line, Chromatin Immunoprecipitation, Genetic/genetics, Humans, Hypoxia-Inducible Factor 1, Mice, Neoplasm/genetics, Polychlorinated Dibenzodioxins/pharmacology, Polymerase Chain Reaction, Promoter Regions, Protein Binding/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Tumor, Western
@article{takacova_role_2009,
title = {Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX.},
author = {Martina Takacova and Tereza Holotnakova and Jan Vondracek and Miroslav Machala and Katerina Pencikova and Katarina Gradin and Lorenz Poellinger and Jaromir Pastorek and Silvia Pastorekova and Juraj Kopacek},
doi = {10.1042/BJ20080952},
issn = {1470-8728 0264-6021},
year = {2009},
date = {2009-04-01},
journal = {The Biochemical journal},
volume = {419},
number = {2},
pages = {419–425},
abstract = {Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1alpha and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1alpha competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.},
note = {Place: England},
keywords = {alpha Subunit, Animals, Antigens, Aryl Hydrocarbon/genetics/metabolism/*physiology, Binding Sites, Blotting, Carbonic Anhydrase IX, Carbonic Anhydrases/genetics/*metabolism, Cell Hypoxia/genetics/*physiology, Cell Line, Chromatin Immunoprecipitation, Genetic/genetics, Humans, Hypoxia-Inducible Factor 1, Mice, Neoplasm/genetics, Polychlorinated Dibenzodioxins/pharmacology, Polymerase Chain Reaction, Promoter Regions, Protein Binding/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Tumor, Western},
pubstate = {published},
tppubtype = {article}
}
Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1alpha and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1alpha competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.