Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α
Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α
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DOI：
10.1073/pnas.1222334110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Cheng, Sheue-Yann
中科院分区：
文献类型：
--
作者：
Fozzatti, Laura;Kim, Dong Wook;Cheng, Sheue-Yann
来自甲状腺激素受体α基因（THRA）突变患者的遗传证据表明，突变体的显性负活性是其病理表现的基础。然而，TRα1突变体在体内发挥显性负活性的分子机制尚不清楚。我们测试了这样的假设：THRA 突变患者的严重甲状腺功能减退症是由于 TR α 1 突变体无法正确释放核辅阻遏物 (NCOR)，从而抑制甲状腺激素介导的转录活性。我们将表达显性失活 TR α 1 突变体 (TR α 1PV) 的 Thra1(PV) 小鼠与表达不能招募 TR 或 PV 突变体的突变 Ncor1 等位基因的小鼠 (Ncor1(Delta ID) 小鼠) 进行杂交。 TR alpha 1PV 与 THRA 基因移码突变患者具有相同的 C 端突变序列。值得注意的是，NCOR1 Delta ID 改善了 Thra1(PV/+) 小鼠甲状腺-垂体轴的异常。在表达 NCOR1 Delta ID 的 Thra1(PV/+) 小鼠中，严重的生长迟缓、不育和骨骼发育延迟得到部分恢复。由于 TR α 1PV 无法募集 NCOR1 Delta ID 形成阻遏复合物，因此通过过氧化物酶体增殖物激活受体 γ 和 CCAAT/增强子结合蛋白 a 基因的去抑制部分纠正了受损的脂肪生成。因此，TR α 1 突变体对 NCOR1 的异常招募可能导致人类临床甲状腺功能减退症。因此，针对 TR α 1-NCOR1 相互作用或其下游作用的疗法可以作为治疗 TR α 1 突变介导的甲状腺功能减退症患者的潜在靶标进行测试。
Genetic evidence from patients with mutations of the thyroid hormone receptor alpha gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TR alpha 1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TR alpha 1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1(PV) mice, expressing a dominant negative TR alpha 1 mutant (TR alpha 1PV), with mice expressing a mutant Ncor1 allele (Ncor1(Delta ID) mice) that cannot recruit the TR or PV mutant. TR alpha 1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1 Delta ID ameliorated abnormalities in the thyroid-pituitary axis of Thra1(PV/+) mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1(PV/+) mice expressing NCOR1 Delta ID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor gamma and CCAAT/enhancerbinding protein a gene, due to the inability of TR alpha 1PV to recruit NCOR1 Delta ID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TR alpha 1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TR alpha 1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TR alpha 1 mutant-mediated hypothyroidismin patients.