Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism.
Polychlorinated biphenyls (PCBs) are environmental compounds that disrupt the endocrine system, and exposure to low doses causes abnormalities, particularly in the developing central nervous system. Because they are structurally similar to thyroid hormone (TH), PCBs might affect systems involving this hormone. We previously found, using reporter assays, that hydroxylated-PCB at doses as low as 10(-10) m suppress TH-induced transcriptional activation of TH receptor (TR). To understand the molecular mechanisms of this process, we examined whether PCBs alter coactivator or corepressor interaction with TR. Polychlorinated biphenyls suppressed steroid receptor coactivator-1 enhanced TR-mediated transcription, but did not reduce TR/steroid receptor coactivator-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. Thus, the suppression was probably not caused by coactivator dissociation. Nuclear receptor co-repressor was not recruited to TR by PCBs either in vivo or in vitro, indicating that TR corepressor binding did not induce the suppression. We then examined whether PCB influences TR binding to the thyroid hormone-response element (TRE). Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB. These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB.
Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Wataru
W
Miyazaki
Toshiharu
T
Iwasaki
Akira
A
Takeshita
Yoichiro
Y
Kuroda
Noriyuki
N
Koibuchi
D004785:Environmental Pollutants / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056920:Nuclear Receptor Coactivator 1; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D004785:Environmental Pollutants; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D011078:Polychlorinated Biphenyls; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1