And now for something completely different: Diversity in ligand-dependent activation of Ah receptor responses

Denison, Michael S.; Faber, Samantha C.

doi:10.1016/j.cotox.2017.01.006

Cited by 96 publications

(74 citation statements)

References 68 publications

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“…Ligand binding to the AhR has been extensively studied, and the overall fingerprint amino acid residues (those presumably in contact with the bound ligand), as well as the amino acid residues implicated in differences in AhR affinity among many species, have been characterized [30,39,40,43,44]. Transcriptional activation by the ligand-transformed AhR:ARNT complex has also been a major focus of multiple studies resulting in the elucidation of the classical DRE-mediated pathway, as well as several alternative mechanisms (reviewed in [1,45,46]). However, the mechanistic events linking ligand binding and transcriptional activation (i.e., those constituting AhR transformation) remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanistic events linking ligand binding and transcriptional activation (i.e., those constituting AhR transformation) remain poorly understood. Interest in this mechanism has been further increased by the observation that ligand-specific outcomes of AhR transformation and DNA binding (the classical DRE-dependent paradigm) cannot fully explain the diversity in AhR response [1,[45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

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Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Soshilov

Motta

Bonati

et al. 2020

IJMS

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of an AhR lacking the entire PASB structurally diverse chemicals, including halogenated aromatic hydrocarbons. Ligand-dependent transformation of the AhR into its DNA binding form involves a ligand-dependent conformational change, heat shock protein 90 (hsp90), dissociation from the AhR complex and AhR dimerization with the AhR nuclear translocator (ARNT) protein. The mechanism of AhR transformation was examined using mutational approaches and stabilization of the AhR:hsp90 complex with sodium molybdate. Insertion of a single mutation (F281A) in the hsp90-binding region of the AhR resulted in its constitutive (ligand-independent) transformation/DNA binding in vitro. Mutations of AhR residues within the Arg-Cys-rich region (R212A, R217A, R219A) and Asp371 (D371A) impaired AhR transformation without a significant effect on ligand binding. Stabilization of AhR:hsp90 binding with sodium molybdate decreased transformation/DNA binding of the wild type AhR but had no effect on constitutively active AhR mutants. Interestingly, transformation of the AhR in the presence of molybdate allowed detection of an intermediate transformation ternary complex containing hsp90, AhR, and ARNT. These results are consistent with a stepwise transformation mechanism in which binding of ARNT to the liganded AhR:hsp90 complex results in a progressive displacement of hsp90 and conversion of the AhR into its high affinity DNA binding form. The available molecular insights into the signaling mechanism of other Per-ARNT-Sim (PAS) domains and structural information on hsp90 association with other client proteins are consistent with the proposed transformation mechanism of the AhR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Soshilov

Motta

Bonati

et al. 2020

IJMS

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“…The key for dual roles of the AhR in intestinal health and disease is not entirely elucidated. Ligand-dependent activation of the AhR can result in an extremely diverse spectrum of biological and toxic effects that occur in a ligand-, species-and tissue-specific manner [26]. On the basis of a novel computational approach for molecular docking to the homology model of the AhR LBD, specific residues within the AhR binding cavity that play a critical role in binding of three distinct groups of chemicals were recently predicted and experimentally confirmed by Giani Tagliabue et al [27].…”

Section: Discussionmentioning

confidence: 98%

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Vyhlídalová

Krasulová

Pečinková

et al. 2020

IJMS

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The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.

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“…In contrast with our data, activation of the AhR pathway with xenobiotic agonists of the dioxin family has been described to lead to a premature reproductive senescence in female mice (27). In this context, reported different agonistic mechanisms of AhR ligands, including at the level of the estrogen receptor, have been reported, which may be involved in this apparent discrepancy (28).…”

Section: Discussionmentioning

confidence: 99%

Lack of the aryl hydrocarbon receptor accelerates aging in mice

et al. 2019

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The aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor, largely known for its role in xenobiotic metabolism and detoxification as well as its crucial role as a regulator of inflammation. Here, we have compared a cohort wild‐type and AhR‐null mice along aging to study the relationship between this receptor and age‐associated inflammation, termed as “inflammaging,” both at a systemic and the CNS level. Our results show that AhR deficiency is associated with a premature aged phenotype, characterized by early inflammaging, as shown by an increase in plasma cytokines levels. The absence of AhR also promotes the appearance of brain aging anatomic features, such as the loss of the white matter integrity. In addition, AhR–/– mice present an earlier spatial memory impairment and an enhanced astrogliosis in the hippocampus when compared with their age‐matched AhR+/+ controls. Importantly, we have found that AhR protein levels decrease with age in this brain structure, strongly suggesting a link between AhR and aging.—Bravo‐Ferrer, I., Cuartero, M. I., Medina, V., Ahedo‐Quero, D., Peña‐Martínez, C., Pérez‐Ruíz, A., Fernández‐Valle, M. E., Hernández‐Sánchez, C., Fernández‐Salguero, P. M., Lizasoain, I., Moro, M. A. Lack of the aryl hydrocarbon receptor accelerates aging in mice. FASEB J. 33, 12644–12654 (2019). http://www.fasebj.org

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And now for something completely different: Diversity in ligand-dependent activation of Ah receptor responses

Cited by 96 publications

References 68 publications

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

Lack of the aryl hydrocarbon receptor accelerates aging in mice

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