Review
Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes

https://doi.org/10.1016/j.bbrc.2005.08.162Get rights and content

Abstract

AhR, a ligand-activated transcription factor, mediates xenobiotic signaling to enhance the expression of target genes, including drug-metabolizing cytochrome P450s. The recent development of several new techniques, including chromatin immunoprecipitation and RNA interference, has expanded and deepened our knowledge of AhR function in the xenobiotic signal transduction. In this review, we briefly summarize our current understanding of the activation and inactivation of AhR activities and discuss the future directions of AhR research.

Section snippets

Activation of AhR

Normally, AhR exists in a dormant state within the cytoplasm in association with a complex of HSP90, XAP2, and p23. Upon ligand binding, AhR in the complex is activated by a conformation change that exposes a nuclear localization signal(s) (NLS). The ligand-activated AhR in the complex translocates into the nucleus and forms a heterodimer with the closely related Arnt protein already present in the nucleus by dissociating from the complex [5], [6].

Structure–activity relationship studies

Cis-acting DNA elements

The regulatory DNA elements responsible for the induction of CYP1 by polyaromatic hydrocarbons like TCDD, called XREs, were first identified by transient DNA transfection experiments using a reporter gene, whose expression was driven by the CYP1A1 promoter [27]. Later, additional experiments introducing a variety of mutations at this locus defined the consensus sequence and designated this sequence the DRE or AhRE [5], [28]. All CYP genes whose expression are induced by PAH or HAH, including

Trans-acting factor for XRE

Mouse genetics initially implicated the existence of a mediator of the xenobiotic signaling, leading to the induction of CYP1A1 expression. This mediator was later identified as a factor binding to xenobiotics, which was designated the aryl hydrocarbon receptor or AhR [39]. This factor was also dubbed the dioxin receptor (DR), due to the high avidity with which it bound TCDD. Approximately a decade later, GMSA revealed that a factor that bound the XRE sequence in a TCDD-dependent manner

Degradation of the AhR

To understand the mechanisms of gene regulation, it is important to investigate both the upregulation and termination phases of inducible transcription. Recent reports have suggested that AhR is rapidly downregulated following ligand binding by degradation [49]. Experiments using the proteasome inhibitor MG132 suggested that the downregulation of AhR is mediated by the proteasome. The concentrations of AhR proteins in the nuclear fractions of cultured cells are highest after 1–2 h of TCDD

Acknowledgments

We thank Mrs. Y. Nemoto for clerical work. The work performed in our laboratory was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan and funds for Core Research for Evolution Science and Technology (CREST) and for Solution-Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation, Japan.

References (53)

  • Y.C. Cho et al.

    Disruption of cell–cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts

    Toxicol. Appl. Pharmacol.

    (2004)
  • T. Ikuta et al.

    Cell density regulates intracellar localization of aryl hydrocarbon receptor

    J. Biol. Chem.

    (2004)
  • A. Puga et al.

    Role of the aryl hydrocarbon receptor in cell cycle regulation

    Chem. Biol. Interact.

    (2002)
  • N. Dzeletovic et al.

    Regulation of dioxin receptor function by omeprazole

    J. Biol. Chem.

    (1997)
  • M. Backlund et al.

    Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases

    Cell. Signal.

    (2005)
  • E.S. Shen et al.

    Protein–DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor

    J. Biol. Chem.

    (1992)
  • L. Zhang et al.

    Characterization of the mouse CYP1B1 gene Identification of an enhancer region that directs aryl hydrocarbon receptor-mediated constitutive and induced expression

    J. Biol. Chem.

    (1998)
  • K. Sogawa et al.

    A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer

    Biochem. Biophys. Res. Commun.

    (2004)
  • K. Kurose et al.

    Transcription factor NF2d9 (LBP-1a) interacts with the positive regulatory element for the xenobiotic responsive element

    Biochim. Biophys. Acta

    (2005)
  • A. Poland et al.

    Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase

    J. Biol. Chem.

    (1976)
  • M. Ema et al.

    cDNA cloning and structure of mouse putative Ah receptor

    Biochem. Biophys. Res. Commun.

    (1992)
  • S. Wang et al.

    Functional involvement of the Brahma/SWI2-related gene 1 protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex

    J. Biol. Chem.

    (2002)
  • S. Wang et al.

    Role of mediator in transcriptional activation by the aryl hydrocarbon receptor

    J. Biol. Chem.

    (2004)
  • R.S. Pollenz

    The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation

    Chem. Biol. Interact.

    (2002)
  • N.A. Davarinos et al.

    Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytoplasmic proteasome following nuclear export

    J. Biol. Chem.

    (1999)
  • B.J. Roberts et al.

    Degradation of the basic helix–loop–helix/Per-ARNT-Sim homology domain dioxin receptor via the ubiquitin/proteasome pathway

    J. Biol. Chem.

    (1999)
  • Cited by (0)

    View full text