Thyroid hormone receptor β mutants:: Dominant negative regulators of peroxisome proliferator-activated receptor γ action
Thyroid hormone receptor β mutants:: Dominant negative regulators of peroxisome proliferator-activated receptor γ action
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DOI：
10.1073/pnas.0508556102
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发表时间：
2005-11-08
影响因子：
11.1
通讯作者：
Cheng, SY
中科院分区：
文献类型：
--
作者：
Araki, O;Ying, H;Cheng, SY
甲状腺激素（T3）和过氧化物酶体增殖物在维持脂质稳态方面具有重叠的代谢作用。它们的作用由各自的受体介导：甲状腺激素受体（TR）和过氧化物酶体增殖物激活受体（PPAR）。我们最近发现，一个显性负TR β突变体（PV），导致遗传性疾病，甲状腺激素抵抗，行为抑制的配体（曲格列酮）介导的转录活性的过氧化物酶体增殖物激活受体γ在培养的甲状腺细胞。这一发现表明TR β突变体可以与PPAR γ信号通路发生串扰。本研究探讨了PV抑制PPAR γ转录活性的分子机制。凝胶位移分析表明，PV，类似于野生型TR β，结合过氧化物酶体增殖反应元件（PPRE）作为同源二聚体和异源二聚体与PPAR γ或类维生素A X受体（RXR），从而与PPAR γ竞争结合PPRE和螯合RXR。PPRE结合的PV与辅阻遏物的缔合[例如，核受体辅阻遏物（NCoR）]，导致转录抑制是独立的T3和曲格列酮。染色质免疫沉淀试验进一步证明，尽管存在配体，但在体内，NCoR被募集到PPRE结合的PV上的PPAR γ靶基因，脂蛋白脂肪酶，表明PV对PPAR γ介导的转录活性的主导作用。因此，PV的显性负作用不限于野生型TR。TR β突变体通过显性负作用影响PPAR γ功能的发现，为TR调节参与代谢途径、脂质稳态和致癌作用的PPAR γ靶基因的分子机制提供了见解。
Thyroid hormone (T3) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis. Their actions are mediated by their respective receptors: thyroid hormone receptors (TR) and peroxisome proliferator-activated receptors (PPAR). We recently found that a dominantly negative TR beta mutant (PV) that causes a genetic disease, resistance to thyroid hormone, acts to repress the ligand (troglitazone)-mediated transcriptional activity of PPAR gamma in cultured thyroid cells. This finding suggests that TR beta mutants could crosstalk with PPAR gamma-signaling pathways. The present study explored the molecular mechanisms by which PV represses the PPAR gamma transcriptional activity. Gel-shift assays show that the PV, similar to wild-type TR beta, bound to the peroxisome proliferator response element (PPRE) as homodinners and heterodimers with PPAR gamma or the retinoid X receptor (RXR), thereby competing with PPAR gamma for binding to PPRE and for sequestering RXR. Association of PPRE-bound PV with corepressors [e.g., nuclear receptor corepressor (NCoR)] that led to transcriptional repression was independent of T3 and troglitazone. Chromatin immunoprecipitation assay further demonstrated that, despite the presence of ligands, NCoR was recruited to PPRE-bound PV on a PPAR gamma-target gene, the lipoprotein lipase, in vivo, suggesting the dominant action of PV on PPAR gamma-mediated transcriptional activity. Thus, the dominant negative action of PV is not limited on the wild-type TRs. The findings that TR beta mutants affect PPAR gamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPAR gamma-target genes involved in metabolic pathways, lipid homeostasis, and carcinogenesis.