Intrinsic AhR function underlies cross-talk of dioxins with sex hormone signalings.
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 (ERalpha 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 ERalpha/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 ERalpha/AR as well as for mutants of ERalpha/AR lacking a ligand-binding domain. CA-AhR was recruited to estrogen-/androgen-responsive promoters with endogenous ERalpha/AR. Moreover, CA-AhR had an E3 ubiquitin ligase activity and promoted proteasomal degradation of ERalpha/AR. Thus, these findings indicate that the cross-talk function of the AhR with sex hormone receptors is an intrinsic function of the AhR.
Ohtake
Fumiaki
F
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Baba
Atsushi
A
Fujii-Kuriyama
Yoshiaki
Y
Kato
Shigeaki
S
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004147:Dioxins / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; D004147:Dioxins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex