scholarly journals The dioxin (aryl hydrocarbon) receptor as a model for adaptive responses of bHLH/PAS transcription factors

FEBS Letters ◽  
2007 ◽  
Vol 581 (19) ◽  
pp. 3616-3625 ◽  
Author(s):  
Sebastian G.B. Furness ◽  
Michael J. Lees ◽  
Murray L. Whitelaw
Keyword(s):  
Transcription Factors ◽  
Aryl Hydrocarbon Receptor ◽  
Adaptive Responses ◽  
Aryl Hydrocarbon

2,3,7,8-Tetrachlorodibenzo-p-dioxin-inducible aryl hydrocarbon receptor-mediated change in CYP1A1 chromatin structure occurs independently of transcription

1989 ◽  
Vol 9 (12) ◽  
pp. 5733-5737
Author(s):  
L K Durrin ◽  
J P Whitlock
Keyword(s):  
Protein Synthesis ◽  
Transcription Factors ◽  
Aryl Hydrocarbon Receptor ◽  
Chromatin Structure ◽  
Restriction Endonucleases ◽  
Aryl Hydrocarbon ◽  
Tetrachlorodibenzo P Dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces, in a receptor-dependent fashion, an increase in the accessibility of CYP1A1 chromatin to restriction endonucleases. The 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced change in chromatin structure occurs rapidly and does not require ongoing RNA or protein synthesis. The increased accessibility of chromatin DNA may facilitate its subsequent interaction with other transcription factors.

The Aryl Hydrocarbon Receptor Antagonist Stemregenin 1 Stimulates Expression of NK Cell Related Transcription Factors, Thereby It Facilitates Generation of Highly Functional NK Cells in Vitro

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3833-3833
Author(s):  
Mieke WH Roeven ◽  
Jeanette Cany ◽  
Frans Maas ◽  
Arwa Kohela ◽  
Jansen Joop ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Aryl Hydrocarbon Receptor ◽  
Nk Cells ◽  
Progenitor Cells ◽  
Culture System ◽  
Nk Cell ◽  
Aryl Hydrocarbon ◽  
Nk Cell Differentiation

Abstract Introduction Allogeneic stem cell transplantation (SCT) can be a curative treatment for hematological malignancies. The therapeutic effectiveness is attributed to the graft-versus-tumor (GVT) effect, mediated by alloreactive T cells and natural killer (NK) cells. Although T cells can induce a potent GVT effect, they can also induce graft-versus-host disease (GVHD), causing high morbidity and mortality. Interestingly, after non-myeloablative allogeneic SCT, early NK cell repopulation has been associated with decreased relapse rates, without increasing GVHD incidence, illustrating a possible role for donor NK cell adoptive transfer after allogeneic SCT. However, isolation of sufficient numbers of activated NK cells from donor origin is challenging. Recently, it has been described that antagonizing the aryl hydrocarbon receptor (AhR) using the antagonist StemReginin1 (SR1) promotes expansion of human hematopoietic stem cells. Furthermore, AhR turned out to regulate differentiation of multiple immune cells like dendritic cells, regulatory T cells, γδ T cells, and also NK cells. Therefore, we investigated if SR1 could enhance NK cell generation in a cytokine-based culture system. Methods CD34+ hematopoietic progenitor cells (HPCs) were isolated using immunomagnetic beads from G-CSF mobilized aphaeresis material. These HPCs were expanded during 14 days in medium containing SCF, Flt3L, TPO, IL-7 and IL-15 and subsequently differentiated into NK cells using IL-15 and IL-2. HPC-NK cell expansions were performed with or without SR1. RNA was collected from the cultures weekly and expression of NK cell related genes was analyzed using qPCR. After 35 days, HPC-NK cells were assessed for their cytolytic functions against acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines and primary AML blasts. In addition, expression levels of typical NK-activating receptors and differentiation markers were analyzed by flow cytometry. Results Interestingly, SR1 induced expression of TOX, ID2, EOMES, GATA3 and SH2D1B, which are important factors involved in early and late NK cell differentiation. In addition, SR1 improved the expansion, differentiation, and functionality of the NK cells generated. In the presence of SR1, we were able to expand PB-derived HPCs up to 1000-fold in 5 weeks. The SR1-generated HPC-NK cell products contained 80 – 92% NK cells, which expressed high levels of activating NKG2D and natural cytotoxicity receptors. Furthermore, functional analysis showed marked degranulation and cytokine release upon co-culture with AML and MM cell lines and efficient lysis of primary AML blasts at low NK-target ratios. Conclusion Addition of the AHR antagonist SR1 in our culture system induces expression of transcription factors involved in NK cell differentiation and thereby facilitates the generation of high numbers of functional NK cells from G-CSF mobilized CD34+ progenitor cells. These NK cells hold great promise for future donor NK cell-mediated therapy after allogeneic SCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Estrogen receptor and aryl hydrocarbon receptor signaling pathways

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04016 ◽  
Author(s):  
Jason Matthews ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factors ◽  
Estrogen Receptors ◽  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Xenobiotic Metabolism ◽  
Positive Role ◽  
Aryl Hydrocarbon

Estrogen receptors (ERs) and the aryl hydrocarbon receptor (AhR) are ligand activated transcription factors and members of the nuclear receptor and bHLH-PAS superfamilies, respectively. AhR is involved in xenobiotic metabolism and in mediating the toxic effects of dioxin-like compounds. Crosstalk has been observed among AhR and nuclear receptors, but has been most well studied with respect to ER signaling. Activated AhR inhibits ER activity through a number of different mechanisms, whereas ERα has been reported to have a positive role in AhR signaling. Here we will discuss recent data revealing that dioxin bound AhR recruits ERα to AhR regulated genes. We will also consider the implications of ER recruitment to AhR target genes on ER and AhR signaling.

A Novel Computational Approach for the Prediction of Networked Transcription Factors of Aryl Hydrocarbon-Receptor-Regulated Genes

2004 ◽  
Vol 66 (6) ◽  
pp. 1557-1572 ◽  
Author(s):  
Alexander Kel ◽  
Susanne Reymann ◽  
Volker Matys ◽  
Paul Nettesheim ◽  
Edgar Wingender ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Aryl Hydrocarbon Receptor ◽  
Computational Approach ◽  
Aryl Hydrocarbon

scholarly journals 2,3,7,8-Tetrachlorodibenzo-p-dioxin-inducible aryl hydrocarbon receptor-mediated change in CYP1A1 chromatin structure occurs independently of transcription.

1989 ◽  
Vol 9 (12) ◽  
pp. 5733-5737 ◽  
Author(s):  
L K Durrin ◽  
J P Whitlock
Keyword(s):  
Protein Synthesis ◽  
Transcription Factors ◽  
Aryl Hydrocarbon Receptor ◽  
Chromatin Structure ◽  
Restriction Endonucleases ◽  
Aryl Hydrocarbon ◽  
Tetrachlorodibenzo P Dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces, in a receptor-dependent fashion, an increase in the accessibility of CYP1A1 chromatin to restriction endonucleases. The 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced change in chromatin structure occurs rapidly and does not require ongoing RNA or protein synthesis. The increased accessibility of chromatin DNA may facilitate its subsequent interaction with other transcription factors.

Large Scale Screening for DNA Damage-Induced Transcription Factors as Potential Targets for Treatment of CLL with p53 Apoptotic Defect.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3439-3439
Author(s):  
Victoria Weston ◽  
Paul Moss ◽  
A. Malcolm R Taylor ◽  
Tatjana Stankovic
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Dna Binding ◽  
Aryl Hydrocarbon Receptor ◽  
P53 Pathway ◽  
Binding Motifs ◽  
Aryl Hydrocarbon ◽  
Dna Damaging Agents ◽  
Dna Binding Motifs ◽  
The Impact

Abstract Abstract 3439 Poster Board III-327 Chronic lymphocytic leukaemia (CLL) is a malignancy with a variable clinical course in which a proportion of patients exhibits rapid clinical progression despite treatment. One of the major causes of treatment resistance is alterations in the ATM/p53 pathway imposed by mutations in either the ATM or TP53 genes. Consequently, there is an urgent need to devise novel therapeutic approaches that will be able to counteract the p53 apoptotic defect in these tumours. We have previously shown that DNA damage induces a complex ATM-dependent network of pro-survival and pro-apoptotic transcriptional responses (both p53-dependent and -independent) and that the balance between these responses determines CLL cellular death. Therefore, it is plausible to expect that manipulation of ATM-dependent transcription to either reduce pro-survival or increase pro-apoptotic signals can sensitise ATM and TP53 mutant CLL tumours to DNA damaging agents. Individual transcription factors (TFs) that govern ATM-dependent transcription are largely unknown. In this study we aimed to identify those factors by employing a DNA/Protein Transcription Factor ComboArray (Panomics/Affymetrix) which includes 345 DNA binding motifs for a range of transcription factors, DNA binding proteins and response elements. We compared the ability of nuclear cell extracts from 3 combined ATM wildtype primary CLL samples and 3 combined ATM mutant primary CLL samples to bind to biotin-labelled DNA binding motifs prior to irradiation (IR)-induced DNA damage, 2h and 6h post-IR. Following hybridisation of nuclear protein-bound biotin-labelled probes to the array and HRP visualisation, we identified 49 binding motifs (several of which were detected more than once through alternative sequences) which, in response to DNA damage, exhibited reduced binding in ATM mutant compared to the ATM wildtype CLL nuclear extracts. The most prominent differentially bound DNA binding motifs included those for GATA1 and 2, Transcriptional enhancer factor 1 (TEF1), c-Rel, Aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator binding element (AhR/Arnt), forkhead box I1 (HFH-3), Slow/Cardiac Troponin C (cTnC/CEF-2), E2A immunoglobulin enhancer binding factors (E12/E47), Pax-4, Wilms tumour 1 (WT1), antioxidant recognition element (ARE) and interferon-a stimulated response element (ISRE). We validated differential binding of individual TFs by electro-mobility shift analysis (EMSA) and selected six that were positively corroborated in an independent cohort of primary ATM mutant and ATM wildtype CLL tumour cells. We subsequently investigated the impact of altering the activity of the identified ATM-dependent TFs on the sensitivity of ATM mutant CLL tumours to DNA damage. Among the selected TFs, as a proof of principle, ARE demonstrated both ATM-dependent binding by EMSA as well as the capacity to modulate the DNA damage response in CLL cells: pharmacological activation of this TF by Dimethyl fumarate (DMF) sensitised ATM mutant cells to IR-induced DNA damage. In summary, we have identified a number of ATM-regulated transcription factors that could be directly or indirectly targeted to increase the sensitivity of CLL cells with a defective ATM/p53 pathway to DNA damaging agents. We also suggest that the DNA damage-dependent TF screen represents a feasible approach to identify novel molecular targets that may sensitise other subtypes of treatment-resistant CLL tumours. Disclosures No relevant conflicts of interest to declare.

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