Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface
Tania M. Ortiga-Carvalho, … , Samuel Refetoff, Fredric E. Wondisford
Tania M. Ortiga-Carvalho, … , Samuel Refetoff, Fredric E. Wondisford
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2517-2523. https://doi.org/10.1172/JCI24109.
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Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface

Abstract

Thyroid hormone (TH) action is mediated by TH receptors (TRs), which are members of the nuclear hormone receptor superfamily. In vitro studies have demonstrated that TR activity is regulated by interactions with corepressor and coactivator proteins (CoRs and CoAs, respectively). TH stimulation is thought to involve dissociation of CoRs and recruitment of CoAs to the liganded TR. In contrast, negative regulation by TH is thought to occur via recruitment of CoRs to the liganded TR. The physiological role of CoAs bound to TRs, however, has yet to be defined. In this study, we used gene-targeting techniques to mutate the TR-β locus within its activation function–2 (AF-2) domain (E457A). This mutation was chosen because it completely abolished CoA recruitment in vitro, while preserving normal triiodothyronine (T3) binding and CoR interactions. As expected, TH-stimulated gene expression was reduced in homozygous E457A mice. However, these animals also displayed abnormal regulation of the hypothalamic-pituitary-thyroid axis. Serum thyroxine, T3, and thyroid-stimulating hormone (TSH) levels and pituitary Tshb mRNA levels were inappropriately elevated compared with those of WT animals, and L-T3 treatment failed to suppress serum TSH and pituitary Tshb mRNA levels. Therefore, the AF-2 domain of TR-β is required for positive and, paradoxically, for negative regulation by TH in vivo.

Authors

Tania M. Ortiga-Carvalho, Nobuyuki Shibusawa, Amisra Nikrodhanond, Karen J. Oliveira, Danielle S. Machado, Xiao-Hui Liao, Ronald N. Cohen, Samuel Refetoff, Fredric E. Wondisford

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Figure 5

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Effect of TH deficiency and excess on regulation of the H-P-T axis. (A) ...
Effect of TH deficiency and excess on regulation of the H-P-T axis. (A) Serum TSH levels were sequentially determined in TR-βWT/WT, TR-βE457A/WT, and TR-βE457A/E457A mice after they had been on the LoI/PTU diet and given MMI water for 5 weeks and had received the additional treatment with different doses of L-T3 for 5 days each. *P < 0.01 vs. WT. (B) Total serum T3 levels at the end of the L-T3 treatment. (C and D) Tshb and Tsha mRNA levels in the anterior pituitary of TR-βWT/WT, TR-βE457A/WT, and TR-βE457A/E457A mice using a quantitative RT-PCR analysis. Data were normalized for each mRNA level relative to values for the WT animals. Five to 10 animals were evaluated in each group, and data are shown as mean ± SEM.