From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

Rejano-Gordillo, Claudia M.; Marín-Díaz, Beatriz; Ordiales-Talavero, Ana; Merino, Jaime M.; González-Rico, Francisco J.; Fernandez-Salguero, Pedro

doi:10.3390/ijms232314919

Cited by 9 publications

(6 citation statements)

References 216 publications

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“…It has attracted great attention since the 1970s as it acts as a chemosensory protein associated with the metabolism of various xenobiotics, the activation of which can lead to toxic outcomes [3][4][5]. However, in recent decades, significant experimental evidence has revealed that the AhR is also involved in the regulation of genes governing many pathophysiological processes, including cell growth and differentiation, cell cycle and migration, apoptosis, haematopoiesis, and carcinogenesis [6][7][8][9]. Particular attention has been paid to its key regulatory roles in the immune system [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA

Motta

Bonati

2023

IJMS

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of structurally diverse chemicals, including halogenated aromatic hydrocarbons. In this work, we investigate the effects of the binding of the AhR prototypical ligand, TCDD, on the stability of the AhR:ARNT complex, as well as the mechanisms by which ligand-induced perturbations propagate to the DNA recognition site responsible for gene transcription. To this aim, a reliable structural model of the overall quaternary structure of the AhR:ARNT:DRE complex is proposed, based on homology modelling. The model shows very good agreement with a previous one and is supported by experimental evidence. Moreover, molecular dynamics simulations are performed to compare the dynamic behaviour of the AhR:ARNT heterodimer in the presence or absence of the TCDD. Analysis of the simulations, performed by an unsupervised machine learning method, shows that TCDD binding to the AhR PASB domain influences the stability of several inter-domain interactions, in particular at the PASA-PASB interface. The inter-domain communication network suggests a mechanism by which TCDD binding allosterically stabilizes the interactions at the DNA recognition site. These findings may have implications for the comprehension of the different toxic outcomes of AhR ligands and drug design.

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Section: Introductionmentioning

confidence: 99%

TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA

Motta

Bonati

2023

IJMS

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“…In addition, we would like to point out that DIF-2 and TH-DIF-1 have the same molecular weight of 293.14 and further that TH-DIF-1, a precursor of DIF-1 in vivo, possesses DIF-2-type activity in chemotaxis modulation in Ax2 cells but never induces stalk cell differentiation in HM1030 cells. These observations suggest that DIF receptors may not have strict structural specificity for ligands, similar to the aryl hydrocarbon receptor found in mammals, which can be activated by multiple lipophilic ligands [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Derivatives of Differentiation-Inducing Factor 1 Differentially Control Chemotaxis and Stalk Cell Differentiation in Dictyostelium discoideum

Kuwayama

Kikuchi

Kubohara

2023

Biology

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Differentiation-inducing factors 1 and 2 (DIF-1 and DIF-2) are small lipophilic signal molecules that induce stalk cell differentiation but differentially modulate chemotaxis toward cAMP in the cellular slime mold Dictyostelium discoideum; DIF-1 suppresses chemotactic cell movement in shallow cAMP gradients, whereas DIF-2 promotes it. The receptor(s) for DIF-1 and DIF-2 have not yet been identified. We examined the effects of nine derivatives of DIF-1 on chemotactic cell movement toward cAMP and compared their chemotaxis-modulating activity and stalk cell differentiation–inducing activity in wild-type and mutant strains. The DIF derivatives differentially affected chemotaxis and stalk cell differentiation; for example, TM-DIF-1 suppressed chemotaxis and showed poor stalk-inducing activity, DIF-1(3M) suppressed chemotaxis and showed strong stalk-inducing activity, and TH-DIF-1 promoted chemotaxis. These results suggest that DIF-1 and DIF-2 have at least three receptors: one for stalk cell induction and two for chemotaxis modulation. In addition, our results show that the DIF derivatives can be used to analyze the DIF-signaling pathways in D. discoideum.

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“…AHR is a pivotal player in orchestrating epigenetic regulations impacting transcriptome alterations, chromatin architecture adjustments, and involvement in crucial signaling pathways [171]. Epigenetic mechanisms such as aberrant DNA methylation, histone modification, and microRNAs can drive changes in gene expression, potentially leading to developmental programming [172].…”

Section: Othersmentioning

confidence: 99%

The Impact of the Aryl Hydrocarbon Receptor on Antenatal Chemical Exposure-Induced Cardiovascular–Kidney–Metabolic Programming

Tain,

Hsu

2024

IJMS

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Early life exposure lays the groundwork for the risk of developing cardiovascular–kidney–metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.

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From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

Cited by 9 publications

References 216 publications

TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA

TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA

Derivatives of Differentiation-Inducing Factor 1 Differentially Control Chemotaxis and Stalk Cell Differentiation in Dictyostelium discoideum

The Impact of the Aryl Hydrocarbon Receptor on Antenatal Chemical Exposure-Induced Cardiovascular–Kidney–Metabolic Programming

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