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.
2010
Uhlírová, Radka; Horáková, Andrea Harnicarová; Galiová, Gabriela; Legartová, Sona; Matula, Pavel; Fojtová, Miloslava; Varecha, Miroslav; Amrichová, Jana; Vondrácek, Jan; Kozubek, Stanislav; Bártová, Eva
SUV39h- and A-type lamin-dependent telomere nuclear rearrangement. Journal Article
In: Journal of cellular biochemistry, vol. 109, no. 5, pp. 915–926, 2010, ISSN: 1097-4644 0730-2312, (Place: United States).
Abstract | Links | BibTeX | Tags: *Gene Rearrangement, Animals, DNA-Binding Proteins/metabolism, Epigenesis, Fibroblasts/metabolism, Flow Cytometry, Genetic, Humans, Intranuclear Inclusion Bodies/metabolism, Lamin Type A/*metabolism, Methyltransferases/*metabolism, Mice, Protein Transport, rap1 GTP-Binding Proteins/metabolism, Repressor Proteins/*metabolism, Shelterin Complex, Telomerase/metabolism, Telomere-Binding Proteins, Telomere/genetics/*metabolism, Telomeric Repeat Binding Protein 1/metabolism
@article{uhlirova_suv39h-_2010,
title = {SUV39h- and A-type lamin-dependent telomere nuclear rearrangement.},
author = {Radka Uhlírová and Andrea Harnicarová Horáková and Gabriela Galiová and Sona Legartová and Pavel Matula and Miloslava Fojtová and Miroslav Varecha and Jana Amrichová and Jan Vondrácek and Stanislav Kozubek and Eva Bártová},
doi = {10.1002/jcb.22466},
issn = {1097-4644 0730-2312},
year = {2010},
date = {2010-04-01},
journal = {Journal of cellular biochemistry},
volume = {109},
number = {5},
pages = {915–926},
abstract = {Telomeres are specialized chromatin structures that are situated at the end of linear chromosomes and play an important role in cell senescence and immortalization. Here, we investigated whether changes in histone signature influence the nuclear arrangement and positioning of telomeres. Analysis of mouse embryonic fibroblasts revealed that telomeres were organized into specific clusters that partially associated with centromeric clusters. This nuclear arrangement was influenced by deficiency of the histone methyltransferase SUV39h, LMNA deficiency, and the histone deacetylase inhibitor Trichostatin A (TSA). Similarly, nuclear radial distributions of telomeric clusters were preferentially influenced by TSA, which caused relocation of telomeres closer to the nuclear center. Telomeres also co-localized with promyelocytic leukemia bodies (PML). This association was increased by SUV39h deficiency and decreased by LMNA deficiency. These differences could be explained by differing levels of the telomerase subunit, TERT, in SUV39h- and LMNA-deficient fibroblasts. Taken together, our data show that SUV39h and A-type lamins likely play a key role in telomere maintenance and telomere nuclear architecture.},
note = {Place: United States},
keywords = {*Gene Rearrangement, Animals, DNA-Binding Proteins/metabolism, Epigenesis, Fibroblasts/metabolism, Flow Cytometry, Genetic, Humans, Intranuclear Inclusion Bodies/metabolism, Lamin Type A/*metabolism, Methyltransferases/*metabolism, Mice, Protein Transport, rap1 GTP-Binding Proteins/metabolism, Repressor Proteins/*metabolism, Shelterin Complex, Telomerase/metabolism, Telomere-Binding Proteins, Telomere/genetics/*metabolism, Telomeric Repeat Binding Protein 1/metabolism},
pubstate = {published},
tppubtype = {article}
}
Telomeres are specialized chromatin structures that are situated at the end of linear chromosomes and play an important role in cell senescence and immortalization. Here, we investigated whether changes in histone signature influence the nuclear arrangement and positioning of telomeres. Analysis of mouse embryonic fibroblasts revealed that telomeres were organized into specific clusters that partially associated with centromeric clusters. This nuclear arrangement was influenced by deficiency of the histone methyltransferase SUV39h, LMNA deficiency, and the histone deacetylase inhibitor Trichostatin A (TSA). Similarly, nuclear radial distributions of telomeric clusters were preferentially influenced by TSA, which caused relocation of telomeres closer to the nuclear center. Telomeres also co-localized with promyelocytic leukemia bodies (PML). This association was increased by SUV39h deficiency and decreased by LMNA deficiency. These differences could be explained by differing levels of the telomerase subunit, TERT, in SUV39h- and LMNA-deficient fibroblasts. Taken together, our data show that SUV39h and A-type lamins likely play a key role in telomere maintenance and telomere nuclear architecture.