Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT).

The activated aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) bind DNA as a heterodimer. Both proteins represent a novel class of basic helix-loop-helix (bHLH)-containing transcription factors in that (i) activation of AHR requires the binding of ligand (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), (ii) the xenobiotic responsive element (XRE) recognized by the AHR/ARNT heterodimer differs from the recognition sequence for nearly all other bHLH proteins, and (iii) both proteins contain a PAS homology region, which in the Drosophila PER and SIM proteins functions as a dimerization domain. A cDNA for mouse ARNT has been cloned, and potential functional domains of ARNT were investigated by deletion analysis. A mutant lacking all regions of ARNT other than the bHLH and PAS regions is unimpaired in TCDD-dependent dimerization and subsequent XRE binding and only modestly reduced in ability to complement an ARNT-deficient mutant cell line, c4, in vivo. Both the first and second alpha helices of the bHLH region are required for dimerization. The basic region is required for XRE binding but not for dimerization. Deletion of either the A or B segments of the PAS region slightly affects TCDD-induced heterodimerization, while deletion of the complete PAS region severely affects (but does not eliminate) dimerization. Thus, ARNT possesses multiple domains required for maximal heterodimerization. Mutants deleted for PAS A, PAS B, and the complete PAS region all retain some degree of XRE binding, yet none can rescue the c4 mutant. Therefore, both the PAS A and PAS B segments, besides contributing to dimerization, apparently fulfill additional, unknown functions required for biological activity of ARNT.

Download Full-text

In vivo up-regulation of aryl hydrocarbon receptor expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a dioxin-resistant rat model☆1☆Portions of this work were presented at the 20th International Symposium on Halogenated Environmental Organic Pollutants & POPS, Monterey, California (August 13–17, 2000).1Abbreviations: AHR, aryl hydrocarbon receptor; AP, alkaliSne phosphatase; ARNT, aryl hydrocarbon receptor nuclear translocator protein; dNTP, 2′-deoxynucleoside 5′-triphosphate; DRE, dioxin responsive element; H/W, Han/Wistar (Kuopio); L-E, Long-Evans (Turku AB); PCB, polychlorinated biphenyl; PCR, polymerase chain reaction; RT, reverse transcription; SD, Sprague Dawley; and TCDD, 2,3,7,8-tetrachlorodibenzo-pdioxin.

Biochemical Pharmacology ◽

10.1016/s0006-2952(01)00820-6 ◽

2001 ◽

Vol 62 (12) ◽

pp. 1565-1578 ◽

Cited By ~ 34

Author(s):

Monique-Andrée Franc ◽

Raimo Pohjanvirta ◽

Jouko Tuomisto ◽

Allan B Okey

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Polychlorinated Biphenyl ◽

Receptor Expression ◽

Translocator Protein ◽

Sprague Dawley ◽

Chain Reaction ◽

Aryl Hydrocarbon ◽

Polymerase Chain ◽

Responsive Element

Download Full-text

Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Cancers ◽

10.3390/cancers11040463 ◽

2019 ◽

Vol 11 (4) ◽

pp. 463 ◽

Cited By ~ 4

Author(s):

Wei-Min Chung ◽

Yen-Ping Ho ◽

Wei-Chun Chang ◽

Yuan-Chang Dai ◽

Lumin Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Androgen Receptor ◽

Epithelial Ovarian Cancer ◽

Aryl Hydrocarbon Receptor ◽

Proximal Promoter ◽

Luciferase Reporter ◽

Aryl Hydrocarbon ◽

Paclitaxel Treatment

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

Download Full-text

Activation of the aryl hydrocarbon receptor in vivo primes human T cells for interleukin 22 production and inhibits Th17 cells

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.129668y ◽

2010 ◽

Vol 69 (Suppl 2) ◽

pp. A74-A74

Author(s):

J-M Ramirez ◽

N C Brembilla ◽

O Sorg ◽

R Chicheportiche ◽

T Matthes ◽

...

Keyword(s):

T Cells ◽

Aryl Hydrocarbon Receptor ◽

Th17 Cells ◽

Interleukin 22 ◽

Aryl Hydrocarbon ◽

Human T Cells

Download Full-text

In vitro and in vivo approaches for identifying the role of aryl hydrocarbon receptor in the development of nonalcoholic fatty liver disease

Toxicology Letters ◽

10.1016/j.toxlet.2019.10.010 ◽

2020 ◽

Vol 319 ◽

pp. 85-94 ◽

Cited By ~ 3

Author(s):

Xiang-Yu Zhu ◽

Hong-Guang Xia ◽

Zhi-Hao Wang ◽

Biao Li ◽

Hai-Yan Jiang ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Aryl Hydrocarbon Receptor ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Aryl Hydrocarbon

Download Full-text

Understanding ligands driven mechanism of wild and mutant aryl hydrocarbon receptor in presence of phytochemicals combating Parkinson’s disease: an in silico and in vivo study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1590240 ◽

2019 ◽

Vol 38 (3) ◽

pp. 807-826 ◽

Cited By ~ 2

Author(s):

Surya Narayan Rath ◽

Lingaraja Jena ◽

Manorama Patri

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Aryl Hydrocarbon Receptor ◽

In Silico ◽

In Vivo Study ◽

Aryl Hydrocarbon

Download Full-text

The UVR Filter Octinoxate Modulates Aryl Hydrocarbon Receptor Signaling in Keratinocytes via Inhibition of CYP1A1 and CYP1B1

Toxicological Sciences ◽

10.1093/toxsci/kfaa091 ◽

2020 ◽

Vol 177 (1) ◽

pp. 188-201

Author(s):

Sarah J Phelan-Dickinson ◽

Brian C Palmer ◽

Yue Chen ◽

Lisa A DeLouise

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Biological Effects ◽

Mouse Skin ◽

Daily Basis ◽

Luciferase Reporter ◽

Mrna Levels ◽

Aryl Hydrocarbon ◽

Ic50 Values ◽

Cyp1b1 Mrna

Abstract Ultraviolet radiation (UVR) is a consistent part of the environment that has both beneficial and harmful effects on human health. UVR filters in the form of commercial sunscreens have been widely used to reduce the negative health effects of UVR exposure. Despite their benefit, literature suggests that some filters can penetrate skin and have off-target biological effects. We noted that many organic filters are hydrophobic and contain aromatic rings, making them potential modulators of Aryl hydrocarbon Receptor (AhR) signaling. We hypothesized that some filters may be able to act as agonists or antagonists on the AhR. Using a luciferase reporter cell line, we observed that the UVR filter octinoxate potentiated the ability of the known AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), to activate the AhR. Cotreatments of keratinocytes with octinoxate and FICZ lead to increased levels of cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) mRNA transcripts, in an AhR-dependent fashion. Mechanistic studies revealed that octinoxate is an inhibitor of CYP1A1 and CYP1B1, with IC50 values at approximately 1 µM and 586 nM, respectively. In vivo topical application of octinoxate and FICZ also elevated CYP1A1 and CYP1B1 mRNA levels in mouse skin. Our results show that octinoxate is able to indirectly modulate AhR signaling by inhibiting CYP1A1 and CYP1B1 enzyme function, which may have important downstream consequences for the metabolism of various compounds and skin integrity. It is important to continue studying the off-target effects of octinoxate and other UVR filters, because they are used on skin on a daily basis world-wide.

Download Full-text

Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins.

Molecular and Cellular Biology ◽

10.1128/mcb.11.6.3037 ◽

1991 ◽

Vol 11 (6) ◽

pp. 3037-3042 ◽

Cited By ~ 85

Author(s):

H L Hsu ◽

J T Cheng ◽

Q Chen ◽

R Baer

Keyword(s):

Protein Interactions ◽

Lymphoblastic Leukemia ◽

Control Cell ◽

Biochemical Properties ◽

Binding Activity ◽

Sequence Motif ◽

Cell Type ◽

Dimerization Domain ◽

Helix Loop Helix

Almost 30% of patients with T-cell acute lymphoblastic leukemia (T-ALL) bear structural alterations of tal-1, a presumptive proto-oncogene that encodes sequences homologous to the helix-loop-helix (HLH) DNA-binding and dimerization domain. Analysis of the tal-1 gene product reveals that its HLH domain mediates protein-protein interactions with either of the ubiquitously expressed HLH proteins E47 and E12. The resultant tal-1/E47 and tal-1/E12 heterodimers specifically recognize the E-box DNA sequence motif found in eucaryotic transcriptional enhancers. Hence, the tal-1 protein shares biochemical properties with other tissue-specific HLH proteins that control cell type determination during myogenesis (e.g., MyoD1) and neurogenesis (e.g., achaete-scute). The data suggest that HLH heterodimers involving tal-1 may function in vivo as transcriptional regulatory factors that influence cell type determination during hematopoietic development.

Download Full-text