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This Article Full Text Full Text (PDF) All Versions of this Article: JME-08-0153v1 42/5/415    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tagami, T. Articles by Naruse, M. Search for Related Content PubMed PubMed Citation Articles by Tagami, T. Articles by Naruse, M.

Department of Endocrinology and Metabolism, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan

(Correspondence should be addressed to T Tagami; Email: ttagami{at}kyotolan.hosp.go.jp)

Transcriptional regulation is mediated by thyroid hormone (tri-iodothyronine, T₃) receptors (TR), which bind to T₃ response elements as heterodimers with retinoid X receptors (RXR). TR binds to corepressor proteins (CoR) in the absence of T₃, which mediate transcriptional repression and to coactivator proteins (CoA) in the presence of T₃, which mediate transcriptional stimulation, by recruiting additional proteins to the promoter. To determine the relationship between TR functions and cofactor bindings, we selected 13 single-point mutants on the ligand binding domain of TR, of which T₃ bindings were well preserved and created VP16 chimeric receptors. Using mammalian two-hybrid assays, RXR binding in the absence of T₃ was almost abolished for Y406K (helix; H10) and L422R (H11), while it was preserved for most other TR mutants. RXR binding was increased for I280K, V284R (H3), and C309K (H6). Addition of T₃ enhanced RXR binding and T₃ restored the RXR binding to Y406K but not to L422R. CoR binding was reduced for P214R, W219K (H1), R316H (H6), D366R (H9), and M423A (H11) in addition to the mutants of which RXR binding was affected, and CoA binding was impaired for I280K, V284R (H3), C309K (H6), and E457K (H12), indicating that sites for CoR, CoA, and RXR binding partially overlap. CoR binding was well correlated with T₃-independent transcriptional regulation and CoA binding was well correlated with T₃-dependent regulation, while RXR binding was not correlated with any of these functions among TR mutants, suggesting that transcriptional regulation by TR is mainly mediated by an exchange of CoRs and CoAs.