甲状腺激素的分子方面的行动。
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程SY,伦纳德杰,戴维斯PJ
甲状腺激素的分子方面的行动。
Endocr启2010年4月,31 (2):139 - 70。doi: 10.1210 / er.2009 - 0007。2010年1月5 Epub。
- PubMed ID
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20051527 (在PubMed]
- 文摘
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细胞内的甲状腺激素可能发起的细胞核,在质膜,在细胞质和线粒体。甲状腺激素核受体(TRs)调解T的生物活性(3)通过转录监管。α和β两种TR基因,编码4 T(3)绑定受体亚型(α1,beta1, beta2, beta3)。TRs调控的转录活动在多个水平。除了受T(3)转录活动是由甲状腺激素反应的类型元素位于T(3)目标基因的启动子,由发展tissue-dependent TR亚型的表达,并通过一系列核coregulatory蛋白质。这些核coregulatory蛋白调节的转录活动TRs T(3)端依赖的方式。在缺乏T(3),辅阻遏物采取行动抑制基底转录活动,而在T(3)的存在,激活转录辅活化因子函数。TRs的关键作用是明显TRbeta基因的突变导致甲状腺激素抵抗展示一组症状由于减少目标组织的敏感性T (3)。转基因敲天国TRs的小鼠模型也显示,突变可能导致甲状腺激素抵抗之外的其他异常,包括甲状腺癌、垂体肿瘤、侏儒症、代谢异常。因此,TRs的有害突变的影响比之前预想的更严重。 These genetic-engineered mouse models provide valuable tools to ascertain further the molecular actions of unliganded TRs in vivo that could underlie the pathogenesis of hypothyroidism. Actions of thyroid hormone that are not initiated by liganding of the hormone to intranuclear TR are termed nongenomic. They may begin at the plasma membrane or in cytoplasm. Plasma membrane-initiated actions begin at a receptor on integrin alphavbeta3 that activates ERK1/2 and culminate in local membrane actions on ion transport systems, such as the Na(+)/H(+) exchanger, or complex cellular events such as cell proliferation. Concentration of the integrin on cells of the vasculature and on tumor cells explains recently described proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on certain cancer cells, including gliomas. Thus, hormonal events that begin nongenomically result in effects in DNA-dependent effects. l-T(4) is an agonist at the plasma membrane without conversion to T(3). Tetraiodothyroacetic acid is a T(4) analog that inhibits the actions of T(4) and T(3) at the integrin, including angiogenesis and tumor cell proliferation. T(3) can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alphavbeta3. Downstream consequences of phosphatidylinositol 3-kinase activation by T(3) include specific gene transcription and insertion of Na, K-ATPase in the plasma membrane and modulation of the activity of the ATPase. Thyroid hormone, chiefly T(3) and diiodothyronine, has important effects on mitochondrial energetics and on the cytoskeleton. Modulation by the hormone of the basal proton leak in mitochondria accounts for heat production caused by iodothyronines and a substantial component of cellular oxygen consumption. Thyroid hormone also acts on the mitochondrial genome via imported isoforms of nuclear TRs to affect several mitochondrial transcription factors. Regulation of actin polymerization by T(4) and rT(3), but not T(3), is critical to cell migration. This effect has been prominently demonstrated in neurons and glial cells and is important to brain development. The actin-related effects in neurons include fostering neurite outgrowth. A truncated TRalpha1 isoform that resides in the extranuclear compartment mediates the action of thyroid hormone on the cytoskeleton.