Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Nov;124(1):1-22.
doi: 10.1093/toxsci/kfr218. Epub 2011 Sep 9.

Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor

Michael S Denison  1 , Anatoly A Soshilov, Guochun He, Danica E DeGroot, Bin Zhao
Affiliations
Review

Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor

Michael S Denison et al. Toxicol Sci. 2011 Nov.

Abstract

The Ah receptor (AhR) is a ligand-dependent transcription factor that mediates a wide range of biological and toxicological effects that result from exposure to a structurally diverse variety of synthetic and naturally occurring chemicals. Although the overall mechanism of action of the AhR has been extensively studied and involves a classical nuclear receptor mechanism of action (i.e., ligand-dependent nuclear localization, protein heterodimerization, binding of liganded receptor as a protein complex to its specific DNA recognition sequence and activation of gene expression), details of the exact molecular events that result in most AhR-dependent biochemical, physiological, and toxicological effects are generally lacking. Ongoing research efforts continue to describe an ever-expanding list of ligand-, species-, and tissue-specific spectrum of AhR-dependent biological and toxicological effects that seemingly add even more complexity to the mechanism. However, at the same time, these studies are also identifying and characterizing new pathways and molecular mechanisms by which the AhR exerts its actions and plays key modulatory roles in both endogenous developmental and physiological pathways and response to exogenous chemicals. Here we provide an overview of the classical and nonclassical mechanisms that can contribute to the differential sensitivity and diversity in responses observed in humans and other species following ligand-dependent activation of the AhR signal transduction pathway.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
The classical mechanism of AhR-dependent gene activation. Ligand diffuses into the cell and binds to the cytosolic AhR complex resulting in the exposure of its nuclear localization sequence (NLS), likely dissociation of XAP2 from the complex and nuclear translocation of the activated AhR complex. Once in the nucleus, chaperone proteins (hsp90 and p23) are displaced from the AhR by ARNT, and the resulting AhR:ARNT dimers bind to and activate transcription from the DRE-containing promoters such as those for various CYPs, SOS1, AhRR, and TriPARP affecting indicated cellular pathways. The AhRR lacks a transactivation domain and exerts negative feedback regulation on the AhR pathway through its competition for ARNT and formation of inactive AhRR:ARNT transcriptional complexes on DREs. Following transcription, AhR is exported and degraded by the proteosome in the cytoplasm. Activation of CYPs can result in metabolism of exogenous and endogenous AhR ligands.
FIG. 2.
FIG. 2.
The diversity of classical and nonclassical mechanisms of action of the AhR and AhR ligands. In addition to the classical mechanism of transcriptional activation (which results in expression of CYPs and an estrogen receptor inhibitor [ERi]), the AhR has been observed to bind to alternative DRE elements as a dimer with either ARNT or other transcription factors resulting in activation (i.e., with RelB) or repression (with ARNT at iDREs) of transcription. Ligand-specific mechanisms have been described that result in altered AhR:ARNT DNA-binding specificity and/or recruitment of alternative coactivators. Independently of AhR binding to DNA, AhR (or AhR:ARNT) may act as a coactivator, and it may sequester other transcription factors (RelA) and/or target them for degradation (ER). Additional mechanisms include AhR-dependent competition for ARNT or coactivators used by other transcription factors and receptors (i.e., ERβ), resulting in squelching of ERβ-dependent transcription, direct activation of cell signaling pathways (NF-κB, Src1, PKA, Ca2+-dependent pathways, and others) and direct ability of AhR ligands (i.e., 3MC and PCB) to bind to and activate ERs. Other AhR ligands can stimulate calcium influx and calcium-dependent cell signaling events. Details of these nonclassical mechanisms are described in the text.
FIG. 3.
FIG. 3.
Homology model of the mouse AhR LBD and residues critical for TCDD ligand binding.
FIG. 4.
FIG. 4.
Representative structures of functional classes of AhR agonists, antagonists, and SAhRMs.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aarts JMMJG, Denison MS, Cox MA, Schalk MA, Garrison PM, Tullis K, de Haan LH, Brouwer A. Species-specific antagonism of Ah receptor action by 2,2',5,5'-tetrachloro- and 2,2',3,3',4,4'-hexachlorobiphenyl. Eur. J. Pharmacol. 1996;293:463–474. - PubMed
    1. Abdelrahim M, Ariazi E, Kim K, Khan S, Barhoumi R, Burghardt R, Liu S, Hill D, Finnell R, Wlodarczyk B, et al. 3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha. Cancer Res. 2006;66:2459–2467. - PubMed
    1. Abdelrahim M, Smith R, III, Safe S. Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Mol. Pharmacol. 2003;63:1373–1381. - PubMed
    1. Abel J, Haarmann-Stemmann T. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol. Chem. 2010;391:1235–1248. - PubMed
    1. Abnet CC, Tanguay RL, Heideman W, Peterson RE. Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells: greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. Toxicol. Appl. Pharmacol. 1999;159:41–51. - PubMed

Publication types

Substances

-