Intrinsic AhR function underlies cross-talk of dioxins with sex hormone signalings

• Published in: Biochemical and biophysical research communications 2008-06, Vol.370 (4), p.541-546
• Main Authors: Ohtake, Fumiaki, Baba, Atsushi, Fujii-Kuriyama, Yoshiaki, Kato, Shigeaki
• Format: Article
• Language: English
• Subjects: AhR; Androgens - metabolism; Androgens - pharmacology; Cell Line, Tumor; Cross-talk; Dioxin receptor; Dioxins - toxicity; Estrogen; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Estrogens - pharmacology; Gene Expression Regulation; Humans; Ligands; Mutation; Promoter Regions, Genetic - drug effects; Proteasomal degradation; Proteasome Endopeptidase Complex - metabolism; Protein Structure, Tertiary - genetics; Receptors, Androgen - metabolism; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Sex hormone receptor; Transcription; Transcription, Genetic - drug effects; Ubiquitin ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.03.054

The arylhydrocarbon receptor (AhR) mediates sex steroid hormone-related actions in both normal physiology and in dioxin toxicity. In addition to regulation of direct target genes, the ligand-activated AhR associates with estrogen or androgen receptors (ERα or AR) to regulate transcription as a functional unit. Given that endogenous and exogenous AhR-ligands are structurally diverse, it is unclear whether cross-talk regulation of ERα/AR by the activated AhR is an intrinsic function of the AhR or the result of ligand-type-selective differences. To ensure uniform activity of the AhR irrespective of ligand-type-specific differences, we employed CA-AhR, which lacks the ligand-binding domain and has a constitutive activity. We found that CA-AhR, in the absence of a ligand, acted as a transcriptional co-regulator for the unliganded ERα/AR as well as for mutants of ERα/AR lacking a ligand-binding domain. CA-AhR was recruited to estrogen-/androgen-responsive promoters with endogenous ERα/AR. Moreover, CA-AhR had an E3 ubiquitin ligase activity and promoted proteasomal degradation of ERα/AR. Thus, these findings indicate that the cross-talk function of the AhR with sex hormone receptors is an intrinsic function of the AhR.