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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)
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Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)

机译：体内对甲状腺激素的抗性是由核受体心脏加压素（NCOR1）调节的

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摘要

Mutations in the ligand-binding domain of the thyroid hormone receptor β (TRp) 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 compressors (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 Ncori allele (Ncor1~ΔID mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1AID, 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 NCOR1AID. 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.
机译：甲状腺激素受体β（TRp）的配体结合域中的突变导致对甲状腺激素（RTH）的抗性。这些TRβ突变体以显性负性方式起作用，干扰野生型甲状腺激素受体（TRs）的转录活性，导致垂体-甲状腺轴失调和周围组织的抵抗力。推测TRβ突变体引起RTH的分子机制是该突变体无法正确释放核压缩机（NCOR），从而抑制了甲状腺激素（TH）介导的转录活性。为了在体内测试该假设，我们将表达人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Ncori等位基因的小鼠（Ncor1〜ΔID小鼠）杂交。值得注意的是，在存在NCOR1AID的情况下，在Thrb〜PV小鼠中发现的甲状腺刺激激素异常升高和TH水平得到了适度但显着的纠正。此外，在表达NCOR1AID的小鼠中，甲状腺增生，体重减轻和RTH的其他特征也被部分恢复。综上所述，这些数据表明，RTHTRβ突变体异常募集NCOR1会导致人类临床RTH。本研究表明，针对TR-NCOR1相互作用或其下游作用的疗法可作为治疗RTH的潜在靶标进行测试。

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    Laura Fozzatti; Changxue Lu; Dong Wook Kim; Jeong Won Park; Inna Astapova; Oksana Gavrilova; Mark C. Willingham; Anthony N. Hollenberg; Sheue-yann Cheng;

  • 作者单位

    Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Division of Endocrinology, Metabolism and Diabetes, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02215;

    National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    Department of Pathology, Wake Forest University, Winston-Salem, NC 27157;

    Division of Endocrinology, Metabolism and Diabetes, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02215;

    Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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