Biochemical and Biophysical Research Communications
ReviewMolecular mechanisms of AhR functions in the regulation of cytochrome P450 genes
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)
P450 gene induction by structurally diverse xenochemicals: contral role of nuclear receptors CAR, PXR and PPAR
Arch. Biochem. Biophys.
(1999)- et al.
Functional role of AhR in the expression of toxic effects by TCDD
Biochim. Biophys. Acta
(2003) - et al.
Study of P450 function using gene knockout and transgenic mice
Arch. Biochem. Biophys.
(2003) Role of coactivators in transcriptional activation of the aryl hydrocarbon receptor
Arch. Biochem. Biophys.
(2005)- et al.
Analysis of structural requirements for Ah receptor antagonist activity: ellipticines, flavones and related compounds
Biochem. Pharmacol.
(1996) - et al.
Ligand binding and activation of the Ah receptor
Chem. Biol. Interact.
(2002) Aryl hydrocarbon receptors: diversity and evolution
Chem. Biol. Interact.
(2002)- et al.
Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formyl indolo[3,2-b]carbazole
Chem. Biol. Interact.
(1998) - et al.
Suspension-mediated induction of Hepa 1c1c7 CYP1a-1 expression dependent on the Ah receptor signal transduction palthway
J. Biol. Chem.
(1994) - et al.
Cytochrome P450 1A1 is rapidly induced in normal humen keratinocytes in the absence of xenobiotics
J. Biol. Chem.
(1994)