Ah receptor signals cross-talk with multiple developmental pathways

Puga, Alvaro; Tomlinson, Craig R.; Xia, Ying

doi:10.1016/j.bcp.2004.06.043

Cited by 161 publications

(110 citation statements)

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“…Thus, alternative mechanisms have been investigated (Mulero-Navarro et al, 2005;Diry et al, 2006). The activation of this receptor has been shown to elicit diverse cellular alterations, including modifications of cell cycle regulation, cell migration and contact inhibition (Mulero-Navarro et al, 2005;Puga et al, 2005;Diry et al, 2006). These alterations could possibly mediate part of the long-term toxicities of the AhR ligands in animals and humans; chronic exposure to several AhR ligands, which are common and persistent pollutants, is frequent in industrialized populations (tobacco smoke, air pollution, food contamination).…”

Section: Introductionmentioning

confidence: 99%

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

et al. 2009

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Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.

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Section: Introductionmentioning

confidence: 99%

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

et al. 2009

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“…Upon binding with a ligand, Ahr undergoes a conformation change, translocates to the nucleus, and dimerizes with Ahr nuclear translocator (Arnt). Within the nucleus, the Ahr/Arnt heterodimer binds to a specific sequence, designated as the xenobiotic responsive element (XRE), which causes a variety of toxicological effects (17)(18)(19)(20). Interestingly, it has been recently reported that Ahr is a ligand-dependent E3 ubiquitin ligase (21), implying that Ahr has dual functions in controlling intracellular protein levels, serving both as a transcriptional factor to promote the induction of target proteins and as a ligand-dependent E3 ubiquitin ligase to regulate selective protein degradation.…”

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confidence: 99%

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Kimura

Naka

Nohara

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

456

418

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IL-17-producing T helper cells (Th17) have been recently identified as a previously undescribed subset of helper T cells. Here, we demonstrate that aryl hydrocarbon receptor (Ahr) has an important regulatory function in the commitment of Th17 cells. Ahr was robustly induced under Th17-polarizing conditions. Ahr-deficient naïve T cells showed a considerable loss in the ability to differentiate into Th17 cells when induced by TGF-␤ plus IL-6. We were able to demonstrate that Ahr interacts with Stat1 and Stat5, which negatively regulate Th17 development. Whereas Stat1 activation returned to its basal level in Ahr wild type naïve T cells 24 h after stimulation with TGF-␤ plus IL-6, Stat1 remained activated in Ahr-deficient naïve T cells after stimulation. These results indicate that Ahr participates in Th17 cell differentiation through regulating Stat1 activation, a finding that constitutes additional mechanisms in the modulation of Th17 cell development. It has been demonstrated that these Th17 cells are associated with autoimmune conditions, such as experimental autoimmune encephalitis (EAE) and collagen-induced arthritis (CIA) (1-3). Th17 differentiation is regulated by various cytokines. Th17 differentiation was induced by TGF-␤ and IL-6 in mice, and IL-1␤ but not TGF-␤, has been shown to participate in the development of Th17 cells together with IL-6 in humans (2, 4). The development of Th17 cells is regulated negatively by IFN-␥, IL-27, and IL-2, the signals of which are dependent on Stat1 (IFN-␥ and IL-27) and Stat5 (IL-2), respectively (5-7). The orphan nuclear receptors, retinoid-related orphan receptor ␥ (ROR␥) and ROR␣, have been identified as the key transcription factors that determine the differentiation of Th17 lineage (8, 9). More recently, two groups have reported that the aryl hydrocarbon receptor (Ahr) activated by its ligand regulates Treg and Th17 cell development (10, 11). However, it is not clear how Ahr participates in the development of Th17 cells. In this paper, we demonstrate that Ahr is involved in the differentiation of Th17 cells by regulating Stat1 activation, which suppresses Th17 cell differentiation, under Th17-polarizing conditions. Ahr, also known as dioxin receptor, is a ligand-activated transcription factor that belongs to the basic-helix-loop-helix-PER-ARNT-SIM family (12,13). Ahr is present in the cytoplasm, where it forms a complex with heat shock protein (HSP) 90, Ahr-interacting protein (AIP), and p23 (14-16). Upon binding with a ligand, Ahr undergoes a conformation change, translocates to the nucleus, and dimerizes with Ahr nuclear translocator (Arnt). Within the nucleus, the Ahr/Arnt heterodimer binds to a specific sequence, designated as the xenobiotic responsive element (XRE), which causes a variety of toxicological effects (17)(18)(19)(20). Interestingly, it has been recently reported that Ahr is a ligand-dependent E3 ubiquitin ligase (21), implying that Ahr has dual functions in controlling intracellular protein levels, serving both as a transcriptional factor to prom...

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“…The most prominent result of AHR activation is induced expression of the Cytochrome P4501A (CYP1A) subfamily of phase I detoxification enzymes (Hankinson, 1995), but numerous other transcripts are also altered directly or indirectly (eg, Frueh et al, 2001;Puga et al, 2000). AHR also functions through cross-talk with additional nuclear receptors and signaling pathways (eg, Carlson and Perdew, 2002;Matsumura, 2012;Puga et al, 2005).…”

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confidence: 99%

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

2016

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Gene duplication confers genetic redundancy that can facilitate subfunctionalization, the partitioning of ancestral functions between paralogs. We capitalize on a recent genome duplication in Xenopus laevis (African clawed frog) to interrogate possible functional differentiation between alloalleles of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds and plays a role in the physiology and development of the cardiovascular, hepatic, and immune systems in vertebrates. X. laevis has 2 AHR genes, AHR1a and AHR1b. To test the hypothesis that the encoded proteins exhibit different molecular functions, we used TALENs in XLK-WG cells, generating mutant lines lacking functional versions of each AHR and measuring the transcriptional responsiveness of several target genes to the toxic xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the candidate endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). Mutation of either AHR1a or AHR1b reduced TCDD induction of the canonical AHR target, Cytochrome P4501A6, by 75%, despite the much lower abundance of AHR1b in wild-type cells. More modestly induced target genes, encoding aryl hydrocarbon receptor repressor (AHRR), spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), and gap junction protein gamma 1 (GJC1), were regulated solely by AHR1a. AHR1b was responsible for CYP1A6 induction by FICZ, while AHR1a mediated FICZ induction of AHRR. We conclude that AHR1a and AHR1b have distinct transcriptional functions in response to specific agonists, even within a single cell type. Functional analysis of frog AHR paralogs advances the understanding of AHR evolution and as well as the use of frog models of developmental toxicology such as FETAX.

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Ah receptor signals cross-talk with multiple developmental pathways

Cited by 161 publications

References 103 publications

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

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