Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17462-7. doi: 10.1073/pnas.1107474108. Epub 2011 Oct 10.
Mutations in the ligand-binding domain of the thyroid hormone receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRβ mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed Thrb(PV) mice (a model of RTH) expressing a human TRβ mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1(ΔID) mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1ΔID, the abnormally elevated thyroid-stimulating hormone and TH levels found in Thrb(PV) mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1ΔID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRβ mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.
甲状腺激素受体 β（TRβ）配体结合域的突变导致甲状腺激素抵抗（RTH）。这些 TRβ 突变体以显性负性方式发挥作用，干扰野生型甲状腺激素受体（TRs）的转录活性，导致垂体-甲状腺轴失调和外周组织抵抗。TRβ 突变体引起 RTH 的分子机制被假设为突变体不能正确释放核共抑制因子（NCORs），从而抑制甲状腺激素（TH）介导的转录活性。为了在体内验证这一假设，我们将表达人类 TRβ 突变体（PV）的 Thrb(PV) 小鼠（RTH 模型）与表达不能募集 TR 或 PV 突变体的突变型 Ncor1 等位基因（Ncor1(ΔID) 小鼠）的小鼠进行杂交。值得注意的是，在存在 NCOR1ΔID 的情况下，Thrb(PV) 小鼠中发现的异常升高的促甲状腺激素和 TH 水平得到了适度但显著的纠正。此外，在表达 NCOR1ΔID 的小鼠中，甲状腺增生、体重减轻和 RTH 的其他特征也部分得到了逆转。总之，这些数据表明，RTH TRβ 突变体异常募集 NCOR1 导致人类出现临床 RTH。本研究表明，针对 TR-NCOR1 相互作用或其下游作用的治疗方法可以作为治疗 RTH 的潜在靶点进行测试。
